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1.
  • Andersson, Linda, 1973, et al. (author)
  • Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking
  • 2021
  • In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 42:43, s. 4481-4492
  • Journal article (peer-reviewed)abstract
    • AIMS: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.METHODS AND RESULTS: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors.CONCLUSIONS: Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.
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2.
  • Andersson, Linda, 1973, et al. (author)
  • Rip2 modifies VEGF-induced signalling and vascular permeability in myocardial ischemia
  • 2015
  • In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 107:4, s. 478-486
  • Journal article (peer-reviewed)abstract
    • In myocardial ischemia, vascular endothelial growth factor (VEGF) induces permeability by activating a signalling pathway that includes VEGF receptor 2 (VEGFR2), resulting in increased oedema and inflammation and thereby expanding the area of tissue damage. In this study, we investigated the role of receptor-interacting protein 2 (Rip2) in VEGF signalling and myocardial ischemia/reperfusion injury.
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3.
  • Cinato, Mathieu, et al. (author)
  • Cardiac Plin5 interacts with SERCA2 and promotes calcium handling and cardiomyocyte contractility
  • 2023
  • In: Life Science Alliance. - : Life Science Alliance, LLC. - 2575-1077. ; 6:4
  • Journal article (peer-reviewed)abstract
    • The adult heart develops hypertrophy to reduce ventricular wall stress and maintain cardiac function in response to an increased workload. Although pathological hypertrophy generally prog-resses to heart failure, physiological hypertrophy may be car-dioprotective. Cardiac-specific overexpression of the lipid-droplet protein perilipin 5 (Plin5) promotes cardiac hypertrophy, but it is unclear whether this response is beneficial. We analyzed RNA -sequencing data from human left ventricle and showed that car-diac PLIN5 expression correlates with up-regulation of cardiac contraction-related processes. To investigate how elevated cardiac Plin5 levels affect cardiac contractility, we generated mice with cardiac-specific overexpression of Plin5 (MHC-Plin5 mice). These mice displayed increased left ventricular mass and cardiomyocyte size but preserved heart function. Quantitative proteomics identified sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) as a Plin5-interacting protein. In situ proximity ligation assay further confirmed the Plin5/SERCA2 interaction. Live imaging showed in-creases in intracellular Ca2+ release during contraction, Ca2+ removal during relaxation, and SERCA2 function in MHC-Plin5 versus WT cardiomyocytes. These results identify a role of Plin5 in improving cardiac contractility through enhanced Ca2+ signaling.
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4.
  • Andersson, Linda, 1973, et al. (author)
  • Deficiency in perilipin 5 reduces mitochondrial function and membrane depolarization in mouse hearts.
  • 2017
  • In: The international journal of biochemistry & cell biology. - : Elsevier BV. - 1878-5875 .- 1357-2725. ; 91:Pt A, s. 9-13
  • Journal article (peer-reviewed)abstract
    • Myocardial triglycerides stored in lipid droplets are important in regulating the intracellular delivery of fatty acids for energy generation in mitochondria, for membrane biosynthesis, and as agonists for intracellular signaling. Previously, we showed that deficiency in the lipid droplet protein perilipin 5 (Plin5) markedly reduces triglyceride storage in cardiomyocytes and increases the flux of fatty acids into phospholipids. Here, we investigated whether Plin5 deficiency in cardiomyocytes alters mitochondrial function. We found that Plin5 deficiency reduced mitochondrial oxidative capacity. Furthermore, in mitochondria from Plin5((-/)(-)) hearts, the fatty acyl composition of phospholipids in mitochondrial membranes was altered and mitochondrial membrane depolarization was markedly compromised. These findings suggest that mitochondria isolated from hearts deficient in Plin5, have specific functional defects.
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5.
  • Bjursten, Sara, et al. (author)
  • Early rise in brain damage markers and high ICOS expression in CD4+and CD8+T cells during checkpoint inhibitor-induced encephalomyelitis
  • 2021
  • In: Journal for Immunotherapy of Cancer. - : BMJ. - 2051-1426. ; 9:7
  • Journal article (peer-reviewed)abstract
    • We report a case of rapid eradication of melanoma brain metastases and simultaneous near-fatal encephalomyelitis following double immune checkpoint blockade. Brain damage marker S-100B and C reactive protein increased before symptoms or signs of encephalomyelitis and peaked when the patient fell into a coma. At that point, additional brain damage markers and peripheral T cell phenotype was analyzed. The analyses were repeated four times during the patient's recovery. Axonal damage marker neurofilament light polypeptide (NFL) and astrocytic damage marker glial fibrillar acidic protein (GFAP) were very high in blood and cerebrospinal fluid and gradually normalized after immunosuppression and intensive care. The costimulatory receptor inducible T cell costimulatory receptor (ICOS) was expressed on a high proportion of CD4+ and CD8+T cells as encephalomyelitis symptoms peaked and then gradually decreased in parallel with clinical improvement. Both single and double immune checkpoint inhibitor-treated melanoma patients with other serious immune-related adverse events (irAE) (n=9) also expressed ICOS on a significantly higher proportion of CD4+ and CD8+T cells compared with controls without irAE (n=12). In conclusion, our results suggest a potential role for ICOS on CD4+ and CD8+T cells in mediating encephalomyelitis and other serious irAE. In addition, brain damage markers in blood could facilitate early diagnosis of encephalitis.
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6.
  • Drevinge, Christina, 1983, et al. (author)
  • Perilipin 5 is protective in the ischemic heart
  • 2016
  • In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 219, s. 446-454
  • Journal article (peer-reviewed)abstract
    • Background: Myocardial ischemia is associated with alterations in cardiac metabolism, resulting in decreased fatty acid oxidation and increased lipid accumulation. Here we investigate how myocardial lipid content and dynamics affect the function of the ischemic heart, and focus on the role of the lipid droplet protein perilipin 5 (Plin5) in the pathophysiology of myocardial ischemia. Methods and results: We generated Plin5(-/-) mice and found that Plin5 deficiency dramatically reduced the triglyceride content in the heart. Under normal conditions, Plin5(-/-) mice maintained a close to normal heart function by decreasing fatty acid uptake and increasing glucose uptake, thus preserving the energy balance. However, during stress or myocardial ischemia, Plin5 deficiency resulted in myocardial reduced substrate availability, severely reduced heart function and increased mortality. Importantly, analysis of a human cohort with suspected coronary artery disease showed that a common noncoding polymorphism, rs884164, decreases the cardiac expression of PLIN5 and is associated with reduced heart function following myocardial ischemia, indicating a role for Plin5 in cardiac dysfunction. Conclusion: Our findings indicate that Plin5 deficiency alters cardiac lipid metabolism and associates with reduced survival following myocardial ischemia, suggesting that Plin5 plays a beneficial role in the heart following ischemia. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.
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7.
  • Klevstig, Martina, et al. (author)
  • Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia
  • 2019
  • In: Journal of Molecular and Cellular Cardiology. - : Elsevier BV. - 0022-2828 .- 1095-8584. ; 137, s. 1-8
  • Journal article (peer-reviewed)abstract
    • Aims: The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression. Materials and methods: We combined clinical studies, advanced expression analysis of human heart biopsies and analyses in genetically modified mice lacking cardiac expression of the MTTP-A isoform of MTTP. Results: Our results indicate that lower cardiac MTTP expression in humans is associated with structural and perfusion abnormalities in patients with ischemic heart disease. MTTP-A deficiency in mice heart does not affect total MTTP expression, activity or lipid concentration in the heart. Despite this, MTTP-A deficient mice displayed impaired cardiac function after a myocardial infarction. Expression analysis of MTTP indicates that MTTP expression is linked to cardiac function and responses in the heart. Conclusions: Our results indicate that MTTP may play an important role for the heart function in conjunction to ischemic events.
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8.
  • Laudette, Marion, et al. (author)
  • Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function
  • 2023
  • In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 119:7, s. 1537-1552
  • Journal article (peer-reviewed)abstract
    • Aims Pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is expressed mainly in the liver and at low levels in the heart, regulates cholesterol levels by directing low-density lipoprotein receptors to degradation. Studies to determine the role of PCSK9 in the heart are complicated by the close link between cardiac function and systemic lipid metabolism. Here, we sought to elucidate the function of PCSK9 specifically in the heart by generating and analysing mice with cardiomyocyte-specific Pcsk9 deficiency (CMPcsk9−/− mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells. Methods and results Mice with cardiomyocyte-specific deletion of Pcsk9 had reduced contractile capacity, impaired cardiac function, and left ventricular dilatation at 28 weeks of age and died prematurely. Transcriptomic analyses revealed alterations of signalling pathways linked to cardiomyopathy and energy metabolism in hearts from CM-Pcsk9−/− mice vs. wild-type littermates. In agreement, levels of genes and proteins involved in mitochondrial metabolism were reduced in CM-Pcsk9−/− hearts. By using a Seahorse flux analyser, we showed that mitochondrial but not glycolytic function was impaired in cardiomyocytes from CM-Pcsk9−/− mice. We further showed that assembly and activity of electron transport chain (ETC) complexes were altered in isolated mitochondria from CM-Pcsk9−/− mice. Circulating lipid levels were unchanged in CM-Pcsk9−/− mice, but the lipid composition of mitochondrial membranes was altered. In addition, cardiomyocytes from CM-Pcsk9−/− mice had an increased number of mitochondria–endoplasmic reticulum contacts and alterations in the morphology of cristae, the physical location of the ETC complexes. We also showed that acute Pcsk9 silencing in adult cardiomyocyte-like cells reduced the activity of ETC complexes and impaired mitochondrial metabolism. Conclusion PCSK9, despite its low expression in cardiomyocytes, contributes to cardiac metabolic function, and PCSK9 deficiency in cardiomyocytes is linked to cardiomyopathy, impaired heart function, and compromised energy production.
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9.
  • Mardani, Ismena, et al. (author)
  • Plin2-deficiency reduces lipophagy and results in increased lipid accumulation in the heart.
  • 2019
  • In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
  • Journal article (peer-reviewed)abstract
    • Myocardial dysfunction is commonly associated with accumulation of cardiac lipid droplets (LDs). Perilipin 2 (Plin2) is a LD protein that is involved in LD formation, stability and trafficking events within the cell. Even though Plin2 is highly expressed in the heart, little is known about its role in myocardial lipid storage. A recent report shows that cardiac overexpression of Plin2 result in massive myocardial steatosis suggesting that Plin2 stabilizes LDs. In this study, we hypothesized that deficiency in Plin2 would result in reduced myocardial lipid storage. In contrast to our hypothesis, we found increased accumulation of triglycerides in hearts, and specifically in cardiomyocytes, from Plin2-/- mice. Although Plin2-/- mice had markedly enhanced lipid levels in the heart, they had normal heart function under baseline conditions and under mild stress. However, after an induced myocardial infarction, stroke volume and cardiac output were reduced in Plin2-/- mice compared with Plin2+/+ mice. We further demonstrated that the increased triglyceride accumulation in Plin2-deficient hearts was caused by altered lipophagy. Together, our data show that Plin2 is important for proper hydrolysis of LDs.
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10.
  • Pirazzi, Carlo, et al. (author)
  • Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro
  • 2012
  • In: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 57:6, s. 1276-1282
  • Journal article (peer-reviewed)abstract
    • Background & Aims: The robust association between non-alcoholic fatty liver disease (NAFLD) and the genetic variant I148M (rs738409) in PNPLA3 has been widely replicated. The aim of this study was to investigate the effect of the PNPLA3 I148M mutation on: (1) hepatic secretion of very low density lipoproteins (VLDL) in humans; and (2) secretion of apolipoprotein B (apoB) from McA-RH 7777 cells, which secrete VLDL-sized apoB-containing lipoproteins. Methods: VLDL kinetics was analyzed after a bolus infusion of stable isotopes in 55 overweight/obese men genotyped for the PNPLA3 I148M variant. Intracellular lipid content, apoB secretion and glycerolipid metabolism were studied in McA-RH 7777 cells overexpressing the human 1481 wild type or 148M mutant PNPLA3 protein. Results: In humans, carriers of the PNPLA3 148M allele had increased liver fat compared to 1481 homozygotes, and kinetic analysis showed a relatively lower secretion of the large, triglyceride-rich VLDL (VLDL1) in 148M carriers vs. 1481 homozygotes for the same amount of liver fat. McA-RH 7777 cells overexpressing the 148M mutant protein showed a higher intracellular triglyceride content with a lower apoB secretion and fatty acid efflux, compared to cells overexpressing the 1481 wild type protein. The responses with 148M matched those observed in cells expressing the empty vector, indicating that the mutation results in loss of function. Conclusions: We have shown that PNPLA3 affects the secretion of apoB-containing lipoproteins both in humans and in vitro and that the 148M protein is a loss-of-function mutation. We propose that PNPLA3 148M promotes intracellular lipid accumulation in the liver by reducing the lipidation of VLDL.
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11.
  • Chaudhari, Aditi, et al. (author)
  • ARAP2 promotes GLUT1-mediated basal glucose uptake through regulation of sphingolipid metabolism
  • 2016
  • In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981. ; 1861:11, s. 1643-1651
  • Journal article (peer-reviewed)abstract
    • Lipid droplet formation, which is driven by triglyceride synthesis, requires several droplet-associated proteins. We identified ARAP2 (an ADP-ribosylation factor 6 GTPase-activating protein) in the lipid droplet proteome of NIH-3T3 cells and showed that knockdown of ARAP2 resulted in decreased lipid droplet formation and triglyceride synthesis. We also showed that ARAP2 knockdown did not affect fatty acid uptake but reduced basal glucose uptake, total levels of the glucose transporter GLUT1, and GLUT1 levels in the plasma membrane and the lipid micro-domain fraction (a specialized plasma membrane domain enriched in sphingolipids). Microarray analysis showed that ARAP2 knockdown altered expression of genes involved in sphingolipid metabolism. Because sphingolipids are known to play a key role in cell signaling, we performed lipidomics to further investigate the relationship between ARAP2 and sphingolipids and potentially identify a link with glucose uptake. We found that ARAP2 knockdown increased glucosylceramide and lactosylceramide levels without affecting ceramide levels, and thus speculated that the rate-limiting enzyme in glycosphingolipid synthesis, namely glucosylceramide synthase (GCS), could be modified by ARAP2. In agreement with our hypothesis, we showed that the activity of GCS was increased by ARAP2 knockdown and reduced by ARAP2 overexpression. Furthermore, pharmacological inhibition of GCS resulted in increases in basal glucose uptake, total GLUT1 levels, triglyceride biosynthesis from glucose, and lipid droplet formation, indicating that the effects of GCS inhibition are the opposite to those resulting from ARAP2 knockdown. Taken together, our data suggest that ARAP2 promotes lipid droplet formation by modifying sphingolipid metabolism through GCS.
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12.
  • Cinato, Mathieu, et al. (author)
  • Role of Perilipins in Oxidative Stress-Implications for Cardiovascular Disease
  • 2024
  • In: ANTIOXIDANTS. - 2076-3921. ; 13:2
  • Research review (peer-reviewed)abstract
    • Oxidative stress is the imbalance between the production of reactive oxygen species (ROS) and antioxidants in a cell. In the heart, oxidative stress may deteriorate calcium handling, cause arrhythmia, and enhance maladaptive cardiac remodeling by the induction of hypertrophic and apoptotic signaling pathways. Consequently, dysregulated ROS production and oxidative stress have been implicated in numerous cardiac diseases, including heart failure, cardiac ischemia-reperfusion injury, cardiac hypertrophy, and diabetic cardiomyopathy. Lipid droplets (LDs) are conserved intracellular organelles that enable the safe and stable storage of neutral lipids within the cytosol. LDs are coated with proteins, perilipins (Plins) being one of the most abundant. In this review, we will discuss the interplay between oxidative stress and Plins. Indeed, LDs and Plins are increasingly being recognized for playing a critical role beyond energy metabolism and lipid handling. Numerous reports suggest that an essential purpose of LD biogenesis is to alleviate cellular stress, such as oxidative stress. Given the yet unmet suitability of ROS as targets for the intervention of cardiovascular disease, the endogenous antioxidant capacity of Plins may be beneficial.
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13.
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14.
  • Ekstrand, Matias, et al. (author)
  • Depletion of ATP and glucose in advanced human atherosclerotic plaques
  • 2017
  • In: PLoS One. - : Public Library of Science (PLoS). - 1932-6203. ; 12:6
  • Journal article (peer-reviewed)abstract
    • Severe hypoxia develops close to the necrotic core of advanced human atherosclerotic plaques, but the energy metabolic consequences of this hypoxia are not known. In animal models, plaque hypoxia is also associated with depletion of glucose and ATP. ATP depletion may impair healing of plaques and promote necrotic core expansion. To investigate if ATP depletion is present in human plaques, we analyzed the distribution of energy metabolites (ATP, glucose, glycogen and lactate) in intermediate and advanced human plaques.Snap frozen carotid endarterectomies from 6 symptomatic patients were analyzed. Each endarterectomy included a large plaque ranging from the common carotid artery (CCA) to the internal carotid artery (ICA). ATP, glucose, and glycogen concentrations were lower in advanced (ICA) compared to intermediate plaques (CCA), whereas lactate concentrations were higher. The lowest concentrations of ATP, glucose and glycogen were detected in the perinecrotic zone of advanced plaques.Our study demonstrates severe ATP depletion and glucose deficiency in the perinecrotic zone of human advanced atherosclerotic plaques. ATP depletion may impair healing of plaques and promote disease progression.
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15.
  • Glise, Lars, 1988, et al. (author)
  • pH-Dependent Protonation of Histidine Residues Is Critical for Electrostatic Binding of Low-Density Lipoproteins to Human Coronary Arteries
  • 2022
  • In: Arteriosclerosis Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 42:8, s. 1037-1047
  • Journal article (peer-reviewed)abstract
    • Background: The initiating step in atherogenesis is the electrostatic binding of LDL (low-density lipoprotein) to proteoglycan glycosaminoglycans in the arterial intima. However, although proteoglycans are widespread throughout the intima of most coronary artery segments, LDL is not evenly distributed, indicating that LDL retention is not merely dependent on the presence of proteoglycans. We aim to identify factors that promote the interaction between LDL and the vessel wall of human coronary arteries. Methods: We developed an ex vivo model to investigate binding of labeled human LDL to human coronary artery sections without the interference of cellular processes. Results: By staining consecutive sections of human coronary arteries, we found strong staining of sulfated glycosaminoglycans throughout the arterial intima, whereas endogenous LDL deposits were focally distributed. Ex vivo binding of LDL was uniform at all intimal areas with sulfated glycosaminoglycans. However, lowering the pH from 7.4 to 6.5 triggered a 35-fold increase in LDL binding. The pH-dependent binding was abolished by pretreating LDL with diethyl-pyrocarbonate, which blocks the protonation of histidine residues, or cyclohexanedione, which inhibits the positive charge of site B on LDL. Thus, both histidine protonation and site B are required for strong electrostatic LDL binding to the intima. Conclusions: This study identifies histidine protonation as an important component for electrostatic LDL binding to human coronary arteries. Our findings show that the local pH will have a profound impact on LDL's affinity for sulfated glycosaminoglycans, which may influence the retention and accumulation pattern of LDL in the arterial vasculature.
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16.
  • Klevstig, Martina, et al. (author)
  • Targeting acid sphingomyelinase reduces cardiac ceramide accumulation in the post-ischemic heart
  • 2016
  • In: Journal of Molecular and Cellular Cardiology. - : Elsevier BV. - 0022-2828 .- 1095-8584. ; 93, s. 69-72
  • Journal article (peer-reviewed)abstract
    • Ceramide accumulation is known to accompany acute myocardial ischemia, but its role in the pathogenesis of ischemic heart disease is unclear. In this study, we aimed to determine how ceramides accumulate in the ischemic heart and to determine if cardiac function following ischemia can be improved by reducing ceramide accumulation. To investigate the association between ceramide accumulation and heart function, we analyzed myocardial left ventricle biopsies from subjects with chronic ischemia and found that ceramide levels were higher in biopsies from subjects with reduced heart function. Ceramides are produced by either de novo synthesis or hydrolysis of sphingomyelin catalyzed by acid and/or neutral sphingomyelinase. We used cultured HL-1 cardiomyocytes to investigate these pathways and showed that acid sphingomyelinase activity rather than neutral sphingomyelinase activity or de novo sphingolipid synthesis was important for hypoxia-induced ceramide accumulation. We also used mice with a partial deficiency in acid sphingomyelinase (Smpd1(+/-) mice) to investigate if limiting ceramide accumulation under ischemic conditions would have a beneficial effect on heart function and survival. Although we showed that cardiac ceramide accumulation was reduced in Smpd1(+/-) mice 24 h after an induced myocardial infarction, this reduction was not accompanied by an improvement in heart function or survival. Our findings show that accumulation of cardiac ceramides in the post-ischemic heart is mediated by acid sphingomyelinase. However, targeting ceramide accumulation in the ischemic heart may not be a beneficial treatment strategy.
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17.
  • Levin, Malin, 1973, et al. (author)
  • Cardiomyocytes, sphingolipids and cardio myotoxicity
  • 2023
  • In: Current Opinion in Lipidology. - 0957-9672. ; 34:4, s. 180-188
  • Journal article (peer-reviewed)abstract
    • Purpose of reviewSphingolipids are structurally diverse membrane lipids localized in lipid bilayers. Sphingolipids are not only important structural components of cellular membranes, but they are also important regulators of cellular trafficking and signal transduction and are implicated in several diseases. Here, we review the latest insights into sphingolipids and their role in cardiac function and cardiometabolic disease.Recent findingsThe underlying mechanisms linking sphingolipids to cardiac dysfunction are still not fully clarified. Sphingolipids, and in particular ceramides, have emerged as important players in lipotoxicity, mediating inflammation, impaired insulin signalling and apoptosis. In addition, recent findings highlight the importance of glycosphingolipid homeostasis in cardiomyocyte membranes, where they are required to maintain & beta;-adrenergic signalling and contractile capacity to preserve normal heart function. Thus, glycosphingolipid homeostasis in cardiac membranes characterizes a novel mechanism linking sphingolipids to cardiac disease.Modulation of cardiac sphingolipids may represent a promising therapeutic approach. Sustained investigation of the link between sphingolipids and cardiomyocyte function is therefore needed and we hope that this review may inspire researchers to further elucidate the action of these lipids.
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18.
  • Li, Lu, 1964, et al. (author)
  • ARF6 Regulates Neuron Differentiation through Glucosylceramide Synthase
  • 2013
  • In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:3
  • Journal article (peer-reviewed)abstract
    • The small GTPase ADP ribosylation factor 6 (ARF6) mediates endocytosis and has in addition been shown to regulate neuron differentiation. Here we investigated whether ARF6 promotes differentiation of Neuro-2a neuronal cells by modifying the cellular lipid composition. We showed that knockdown of ARF6 by siRNA in Neuro-2a cells increased neuronal outgrowth as expected. ARF6 knockdown also resulted in increased glucosylceramide levels and decreased sphingomyelin levels, but did not affect the levels of ceramide or phospholipids. We speculated that the ARF6 knockdown-induced increase in glucosylceramide was caused by an effect on glucosylceramide synthase and, in agreement, showed that ARF6 knockdown increased the mRNA levels and activity of glucosylceramide synthase. Finally, we showed that incubation of Neuro-2a cells with the glucosylceramide synthase inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) normalized the increased neuronal outgrowth induced by ARF6 knockdown. Our results thus show that ARF6 regulates neuronal differentiation through an effect on glucosylceramide synthase and glucosylceramide levels.
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19.
  • Olofsson, Sven-Olof, 1947, et al. (author)
  • Triglyceride containing lipid droplets and lipid droplet-associated proteins.
  • 2008
  • In: Current opinion in lipidology. - 0957-9672. ; 19:5, s. 441-7
  • Journal article (peer-reviewed)abstract
    • PURPOSE OF REVIEW: Cytosolic lipid droplets are now recognized as dynamic organelles. This review summarizes our current understanding of the mechanisms involved in the formation of lipid droplets, the importance of lipid droplet-associated proteins and the link between lipid droplet accumulation and development of insulin resistance. RECENT FINDINGS: Lipid droplets are formed as primordial droplets and they increase in size by fusion. This fusion process requires the alpha-soluble N-ethylmaleimide-sensitive factor adaptor protein receptor SNAP23, which is also involved in the insulin-dependent translocation of a glucose transporter to the plasma membrane. Recent data suggest that SNAP23 is the link between increased lipid droplet accumulation and development of insulin resistance. Lipid droplets also form tight interactions with other organelles. Furthermore, additional lipid droplet-associated proteins have been identified and shown to play a role in droplet assembly and turnover, and in sorting and trafficking events. SUMMARY: Recent studies have identified a number of key proteins that are involved in the formation and turnover of lipid droplets, and SNAP23 has been identified as a link between accumulation of lipid droplets and development of insulin resistance. Further understanding of lipid droplet biology could indicate potential therapeutic targets to prevent accumulation of lipid droplets and associated complications.
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20.
  • Pandita, Ankur, et al. (author)
  • Intussusceptive angiogenesis in human metastatic malignant melanoma. : Intussusception in human melanoma
  • 2021
  • In: The American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 191:11, s. 2023-2038
  • Journal article (peer-reviewed)abstract
    • Angiogenesis supplies oxygen and nutrients to growing tumors. Inhibiting angiogenesis may stop tumor growth, but vascular endothelial growth factor inhibitors have limited effect in most tumors. The limited effect may be explained by an additional, less vascular endothelial growth factor-driven, form of angiogenesis known as intussusceptive angiogenesis. The importance of intussusceptive angiogenesis in human tumors is not known. Epifluorescence and confocal microscopy was used to visualize intravascular pillars, the hallmark structure of intussusceptive angiogenesis, in tumors. Human malignant melanoma metastases, patient-derived melanoma xenografts in mice (PDX), and genetically engineered BRAF-induced, PTEN-deficient (BPT) mice (BrafCA/+Ptenf/fTyr-Cre+/0-mice) were analyzed for pillars. Gene expression in human melanoma metastases and PDXs was analyzed by RNA sequencing. Matrix metalloproteinase 9 (MMP9) protein expression and T-cell and macrophage infiltration in tumor sections were determined with multiplex immunostaining. Intravascular pillars were detected in human metastases but rarely in PDXs and not in BPT mice. The expression of MMP9 mRNA was higher in human metastases compared with PDXs. High expression of MMP9 protein as well as infiltration of macrophages and T-cell infiltration were detected in proximity to intravascular pillars. MMP inhibition blocked formation of pillars, but not tubes or tip cells, invitro. In conclusion, intussusceptive angiogenesis may contribute to the growth of human melanoma metastases. MMP inhibition blocked pillar formation invitro and should be further investigated as a potential anti-angiogenic drug target in metastatic melanoma.
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21.
  • Pirazzi, Carlo, et al. (author)
  • PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells
  • 2014
  • In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:15, s. 4077-4085
  • Journal article (peer-reviewed)abstract
    • Retinoids are micronutrients that are stored as retinyl esters in the retina and hepatic stellate cells (HSCs). HSCs are key players in fibrogenesis in chronic liver diseases. The enzyme responsible for hydrolysis and release of retinyl esters from HSCs is unknown and the relationship between retinoid metabolism and liver disease remains unclear. We hypothesize that the patatin-like phospholipase domain-containing 3 (PNPLA3) protein is involved in retinol metabolism in HSCs. We tested our hypothesis both in primary human HSCs and in a human cohort of subjects with non-alcoholic fatty liver disease (N = 146). Here we show that PNPLA3 is highly expressed in human HSCs. Its expression is regulated by retinol availability and insulin, and increased PNPLA3 expression results in reduced lipid droplet content. PNPLA3 promotes extracellular release of retinol from HSCs in response to insulin. We also show that purified wild-type PNPLA3 hydrolyzes retinyl palmitate into retinol and palmitic acid. Conversely, this enzymatic activity is markedly reduced with purified PNPLA3 148M, a common mutation robustly associated with liver fibrosis and hepatocellular carcinoma development. We also find the PNPLA3 I148M genotype to be an independent (P = 0.009 in a multivariate analysis) determinant of circulating retinol-binding protein 4, a reliable proxy for retinol levels in humans. This study identifies PNPLA3 as a lipase responsible for retinyl-palmitate hydrolysis in HSCs in humans. Importantly, this indicates a potential novel link between HSCs, retinoid metabolism and PNPLA3 in determining the susceptibility to chronic liver disease.
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22.
  • Svedlund Eriksson, Elin, et al. (author)
  • Castration of Male Mice Induces Metabolic Remodeling of the Heart
  • 2022
  • In: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 6:11
  • Journal article (peer-reviewed)abstract
    • Androgen deprivation therapy of prostate cancer, which suppresses serum testosterone to castrate levels, is associated with increased risk of heart failure. Here we tested the hypothesis that castration alters cardiac energy substrate uptake, which is tightly coupled to the regulation of cardiac structure and function. Short-term (3-4 weeks) surgical castration of male mice reduced the relative heart weight. While castration did not affect cardiac function in unstressed conditions, we observed reductions in heart rate, stroke volume, cardiac output, and cardiac index during pharmacological stress with dobutamine in castrated vs sham-operated mice. Experiments using radiolabeled lipoproteins and glucose showed that castration shifted energy substrate uptake in the heart from lipids toward glucose, while testosterone replacement had the opposite effect. There was increased expression of fetal genes in the heart of castrated mice, including a strong increase in messenger RNA and protein levels of beta-myosin heavy chain (MHC), the fetal isoform of MHC. In conclusion, castration of male mice induces metabolic remodeling and expression of the fetal gene program in the heart, in association with a reduced cardiac performance during pharmacological stress. These findings may be relevant for the selection of treatment strategies for heart failure in the setting of testosterone deficiency.
  •  
23.
  • Yrlid, Ulf, 1971, et al. (author)
  • Endothelial repair is dependent on CD11c(+) leukocytes to establish regrowing endothelial sheets with high cellular density
  • 2019
  • In: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 105:1, s. 195-202
  • Journal article (peer-reviewed)abstract
    • Endothelial injury makes the vessel wall vulnerable to cardiovascular diseases. Injured endothelium regenerates by collective sheet migration, that is, the endothelial cells coordinate their motion and regrow as a sheet of cells with retained cell-cell contacts into the wounded area. Leukocytes appear to be involved in endothelial repair in vivo; however, little is known about their identity and role in the reparative sheet migration process. To address these questions, we developed a high-quality en face technique that enables visualizing of leukocytes and endothelial cells simultaneously following an endoluminal scratch wound injury of the mouse carotid artery. We discovered that regrowing endothelium forms a broad proliferative front accompanied by CD11c(+) leukocytes. Functionally, the leukocytes were dispensable for the initial migratory response of the regrowing endothelial sheet, but critical for the subsequent formation and maintenance of a front zone with high cellular density. Marker expression analyses, genetic fate mapping, phagocyte targeting experiments, and mouse knock-out experiments indicate that the CD11c(+) leukocytes were mononuclear phagocytes with an origin from both Ly6C(high) and Ly6C(low) monocytes. In conclusion, CD11c(+) mononuclear phagocytes are essential for a proper endothelial regrowth following arterial endoluminal scratch injury. Promoting the endothelial-preserving function of CD11c(+) leukocytes may be a strategy to enhance endothelial repair following surgical and endovascular procedures.
  •  
24.
  • Arif, Muhammad, et al. (author)
  • Integrative transcriptomic analysis of tissue-specific metabolic crosstalk after myocardial infarction
  • 2021
  • In: Elife. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 10
  • Journal article (peer-reviewed)abstract
    • Myocardial infarction (MI) promotes a range of systemic effects, many of which are unknown. Here, we investigated the alterations associated with MI progression in heart and other metabolically active tissues (liver, skeletal muscle, and adipose) in a mouse model of MI (induced by ligating the left ascending coronary artery) and sham-operated mice. We performed a genomewide transcriptomic analysis on tissue samples obtained 6- and 24 hr post MI or sham operation. By generating tissue-specific biological networks, we observed: (1) dysregulation in multiple biological processes (including immune system, mitochondrial dysfunction, fatty-acid beta-oxidation, and RNA and protein processing) across multiple tissues post MI and (2) tissue-specific dysregulation in biological processes in liver and heart post MI. Finally, we validated our findings in two independent MI cohorts. Overall, our integrative analysis highlighted both common and specific biological responses to MI across a range of metabolically active tissues.
  •  
25.
  • Björnson, Elias, 1988, et al. (author)
  • Lipid profiling of human diabetic myocardium reveals differences in triglyceride fatty acyl chain length and degree of saturation.
  • 2020
  • In: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 320, s. 106-111
  • Journal article (peer-reviewed)abstract
    • Type 2 diabetes is a major health problem in the world, and is strongly associated with impaired cardiac function and increased mortality. The causal relationship between type 2 diabetes and impaired cardiac function is still incompletely understood but changes in the cardiac lipid metabolism are believed to be a contributing factor. The objective of this study was to determine the lipid profile in human myocardial biopsies collected in vivo from patients with type 2 diabetes and compare to non-diabetic controls.We conducted full lipidomics analyses, using mass spectrometry, of 85 right atrial biopsies obtained from diabetic and non-diabetic patients undergoing elective cardiac surgery. The patients were characterized clinically and serum was analyzed for lipids and biochemical markers.The groups did not differ in BMI and in circulating triglycerides. We demonstrate that type 2 diabetes is associated with alterations in the cardiac lipidome. Interestingly, the absolute amount of lipids is not altered in the diabetic myocardium. However, triglycerides with longer fatty acyl chains are more abundant and there is a higher degree of unsaturated fatty acid chains in triglycerides in diabetic myocardium.Our study reveals that type 2 diabetes is a relatively strong determinant of the human cardiac lipidome (compared to other clinical variables). Although the total lipid content in the diabetic myocardium is not increased, the lipid composition is markedly affected.
  •  
26.
  •  
27.
  • Fagman, Johan Bourghardt, 1980, et al. (author)
  • The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.
  • 2015
  • In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860 .- 0892-6638. ; 29:4, s. 1540-1550
  • Journal article (peer-reviewed)abstract
    • Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)-dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism.-Fagman, J. B., Wilhelmson, A. S., Motta, B. M., Pirazzi, C., Alexanderson, C., De Gendt, K., Verhoeven, G., Holmäng, A., Anesten, F., Jansson, J. -O., Levin, M., Borén, J., Ohlsson, C., Krettek, A., Romeo, S., Tivesten, A. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.
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28.
  •  
29.
  • Gasim Elsied, Anwar Ali, et al. (author)
  • Sacubitril/valsartan decreases mortality in the rat model of the isoprenaline-induced takotsubo-like syndrome
  • 2021
  • In: ESC Heart Failure. - : Wiley. - 2055-5822. ; 8:5, s. 4130-4138
  • Journal article (peer-reviewed)abstract
    • Aims Takotsubo syndrome (TTS) is an acute potentially reversible cardiac syndrome characterized by variable regional myocardial akinesia that cannot be attributed to a culprit coronary artery occlusion. TTS is an important differential diagnosis of acute heart failure where brain natriuretic peptides are elevated. Sacubitril/valsartan is a novel and effective pharmacological agent for the treatment of patients with heart failure. Our aim was to explore whether treatment with sacubitril/valsartan could prevent isoprenaline-induced takotsubo-like phenotype in rats. Methods and results A total number of 186 Sprague-Dawley male rats were randomized to receive pretreatment with water (CONTROL, n = 62), valsartan (VAL, n = 62), or sacubitril/valsartan (SAC/VAL, n = 62) before receiving isoprenaline for induction of TTS. We recorded heart rate and blood pressure invasively. Cardiac morphology and function were evaluated by high-resolution echocardiography 90 min after the administration of isoprenaline. We documented the survival rate at the time of echocardiography. Compared with the CONTROL group, the SAC/VAL group had less pronounced TTS-like cardiac dysfunction and lower mortality rate, while the VAL group did not differ. Heart rate and blood pressure were not significantly different between the groups. Analysis of cardiac lipids was performed with mass spectrometry. The VAL and SAC/VAL groups had significantly higher levels of lysophosphatidylcholine (LPC), in particular LPC 18:1 and LPC 16:0. Conclusions Pretreatment with sacubitril/valsartan but not with valsartan reduces mortality and attenuates isoprenaline-induced apical akinesia in the TTS-like model in rats. Sacubitril/valsartan could be a potential treatment option in patients with TTS in humans.
  •  
30.
  • Glise, Lars, 1988, et al. (author)
  • Disturbed Laminar Blood Flow Causes Impaired Fibrinolysis and Endothelial Fibrin Deposition In Vivo
  • 2019
  • In: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 119:2, s. 223-233
  • Journal article (peer-reviewed)abstract
    • Endothelial expression of tissue-type plasminogen activator (t-PA) is crucial for maintaining an adequate endogenous fibrinolysis. It is unknown how endothelial t-PA expression and fibrinolysis are affected by blood flow in vivo. In this study, we investigated the impact of different blood flow profiles on endothelial t-PA expression and fibrinolysis in the arterial vasculature. Induction of disturbed laminar blood flow (D-flow) in the mouse carotid artery potently reduced endothelial t-PA messenger ribonucleic acid and protein expression, and caused fibrin deposition. En face immunohistochemistry demonstrated that arterial areas naturally exposed to D-flow had markedly lower endothelial t-PA levels than areas with sustained laminar blood flow (S-flow), and displayed pronounced fibrin deposition despite an intact endothelium. In t-PA and plasminogen-deficient mice, fibrin deposition did not extend into S-flow areas, indicating that areas of D-flow and S-flow differ, not only in fibrinolytic capacity, but also in coagulation. Furthermore, plasminogen accumulation was found at D-flow areas, and infusion of recombinant t-PA activated fibrinolysis and significantly reduced the fibrin deposits. In conclusion, D-flow potently impairs the fibrinolytic capacity and causes endothelial fibrin deposition in vivo. Our data also indicate that t-PA is the limiting factor for efficient fibrinolysis at the thrombosis-prone D-flow areas in the arterial vasculature.
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31.
  • Gustafsson, Maria, 1976, et al. (author)
  • Retention of Low-Density Lipoprotein in Atherosclerotic Lesions of the Mouse. Evidence for a Role of Lipoprotein Lipase
  • 2007
  • In: Circ Res. - 1524-4571. ; 101:8, s. 777-783
  • Journal article (peer-reviewed)abstract
    • Direct binding of apolipoprotein (apo)B-containing lipoproteins to proteoglycans is the initiating event in atherosclerosis, but the processes involved at later stages of development are unclear. Here, we investigated the importance of the apoB-proteoglycan interaction in the development of atherosclerosis over time and investigated the role of lipoprotein lipase (LPL) to facilitate low-density lipoprotein (LDL) retention at later stages of development. Atherosclerosis was analyzed in apoB transgenic mice expressing LDL with normal (control LDL) or reduced proteoglycan-binding (RK3359-3369SA LDL) activity after an atherogenic diet for 0 to 40 weeks. The initiation of atherosclerosis was delayed in mice expressing RK3359-3369SA LDL, but they eventually developed the same level of atherosclerosis as mice expressing control LDL. Retention studies in vivo showed that although higher levels of (131)I-tyramine cellobiose-labeled control LDL ((131)I-TC-LDL) were retained in nonatherosclerotic aortae compared with RK3359-3369SA (131)I-TC-LDL, the retention was significantly higher and there was no difference between the groups in atherosclerotic aortae. Lower levels of control (125)I-TC-LDL and RK3359-3369SA (125)I-TC-LDL were retained in atherosclerotic aortae from ldlr(-/-) mice transplanted with lpl(-/-) compared with lpl(+/+) bone marrow. Uptake of control LDL or RK3359-3369SA LDL into macrophages with specific expression of human catalytically active or inactive LPL was increased compared with control macrophages. Furthermore, transgenic mice expressing catalytically active or inactive LPL developed the same extent of atherosclerosis. Thus, retention of LDL in the artery wall is initiated by direct LDL-proteoglycan binding but shifts to indirect binding with bridging molecules such as LPL.
  •  
32.
  •  
33.
  • Hiukka, A, et al. (author)
  • ApoCIII-Enriched LDL in Type 2 Diabetes Displays Altered Lipid Composition, Increased Susceptibility for Sphingomyelinase and Increased binding to Biglycan.
  • 2009
  • In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 58:9, s. 2018-2026
  • Journal article (peer-reviewed)abstract
    • Objective- Apolipoprotein CIII (apoCIII) is an independent risk factor for cardiovascular disease, but the molecular mechanisms involved are poorly understood. Here, we investigated potential proatherogenic properties of apoCIII-containing LDL from hypertriglyceridemic patients with type 2 diabetes. Research design and methods - LDL was isolated from controls and subjects with type 2 diabetes, and from apoB transgenic mice. LDL-biglycan binding was analyzed with a solid-phase assay using immunoplates coated with biglycan. Lipid composition was analyzed with mass spectrometry. Hydrolysis of LDL by sphingomyelinase was analyzed after labeling plasma LDL with [(3)H]sphingomyelin. ApoCIII isoforms were quantified after isoelectric focusing. Human aortic endothelial cells were incubated with desialylated apoCIII or with LDL enriched with specific apoCIII isoforms. Results- We showed that enriching LDL with apoCIII only induced a small increase in LDL-proteoglycan binding, and this effect was dependent on a functional Site A in apoB100. Our findings indicated that intrinsic characteristics of the diabetic LDL other than apoCIII per se are responsible for further increased proteoglycan binding of diabetic LDL with high endogenous apoCIII, and we showed alterations in the lipid composition of diabetic LDL with high apoCIII. We also demonstrated that high apoCIII increased susceptibility of LDL to hydrolysis and aggregation by SMase. In addition, we demonstrated that sialylation of apoCIII increased with increasing apoCIII content, and that sialylation of apoCIII was essential for its proinflammatory properties. Conclusions- We have demonstrated a number of features of apoCIII-containing LDL from hypertriglyceridemic patients with type 2 diabetes that could explain the proatherogenic role of apoCIII.
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34.
  •  
35.
  • Håversen, Liliana, 1963, et al. (author)
  • Vimentin deficiency in macrophages induces increased oxidative stress and vascular inflammation but attenuates atherosclerosis in mice
  • 2018
  • In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
  • Journal article (peer-reviewed)abstract
    • The aim was to clarify the role of vimentin, an intermediate filament protein abundantly expressed in activated macrophages and foam cells, in macrophages during atherogenesis. Global gene expression, lipid uptake, ROS, and inflammation were analyzed in bone-marrow derived macrophages from vimentin-deficient (Vim(-/-)) and wild-type (Vim(-/-)) mice. Atherosclerosis was induced in Ldlr(-/-) mice transplanted with a PCSK9 gain-of-function virus. The mice were fed an atherogenic diet for 12-15 weeks. We observed impaired uptake of native LDL but increased uptake of oxLDL in Vim(-/-) macrophages. FACS analysis revealed increased surface expression of the scavenger receptor CD36 on Vim(-/-) macrophages. Vim(-/-) macrophages also displayed increased markers of oxidative stress, activity of the transcription factor NF-kappa B, secretion of proinflammatory cytokines and GLUT1-mediated glucose uptake. Vim(-/- )mice displayed decreased atherogenesis despite increased vascular inflammation and increased CD36 expression on macrophages in two mouse models of atherosclerosis. We demonstrate that vimentin has a strong suppressive effect on oxidative stress and that Vim(-/-) mice display increased vascular inflammation with increased CD36 expression on macrophages despite decreased subendothelial lipid accumulation. Thus, vimentin has a key role in regulating inflammation in macrophages during atherogenesis.
  •  
36.
  • Johansson, Maria E, 1977, et al. (author)
  • Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid-rich necrotic cores in hypercholesterolemic mice
  • 2014
  • In: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 44:10, s. 3081-3092
  • Journal article (peer-reviewed)abstract
    • Atherosclerosis is an inflammatory disease associated with the activation of innate immune TLRs and nucleotide-binding oligomerization domain-containing protein (NOD)like receptor pathways. However, the function of most innate immune receptors in atherosclerosis remains unclear. Here, we show that NOD2 is a crucial innate immune receptor influencing vascular inflammation and atherosclerosis severity. 10-week stimulation with muramyl dipeptide (MDP), the NOD2 cognate ligand, aggravated atherosclerosis, as indicated by the augmented lesion burden, increased vascular inflammation and enlarged lipid-rich necrotic cores in Ldlr(-/-) mice. Myeloid-specific ablation of NOD2, but not its downstream kinase, receptor-interacting serine/threonine-protein kinase 2, restrained the expansion of the lipid-rich necrotic core in Ldlr(-/-) chimeric mice. In vitro stimulation of macrophages with MDP enhanced the uptake of oxidized low-density lipoprotein and impaired cholesterol efflux in concordance with upregulation of scavenger receptor A1/2 and downregulation of ATP-binding cassette transporter A1. Ex vivo stimulation of human carotid plaques with MDP led to increased activation of inflammatory signaling pathways p38 MAPK and NF-kappa B-mediated release of proinflammatory cytokines. Altogether, this study suggests that NOD2 contributes to the expansion of the lipid-rich necrotic core and promotes vascular inflammation in atherosclerosis.
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37.
  • Jordal, Malin, 1973-, et al. (author)
  • Swedish Gynecologists’ Positioning in Relation to Clitoral Reconstruction After Female Genital Cutting. A Qualitative Interview Study
  • 2021
  • In: International Journal of Sexual Health. - : Informa UK Limited. - 1931-7611 .- 1931-762X. ; 33, s. 76-87
  • Journal article (peer-reviewed)abstract
    • Background: Clitoral reconstruction (CR) is surgical reparation of the clitoris cut as part of the practice of female genital cutting (FGC) available in a handful of countries, including Sweden. The surgery aims at restoring the clitoris esthetically and functionally, thus has implications for sexual health. Gynaecological examinations can be an opportunity for dialogue regarding women’s sexual health. Gynecologist play a role in referring patients experiencing FGC-related problems, including sexual, to specialist services such as CR. Aim: The aim of this study was to explore how gynecologists position themselves in relation to CR. Method: Eight gynecologists were interviewed using semi-structured interviews. The interviews were tape-recorded, transcribed and analyzed using thematic analysis. Results: The gynecologists positioned themselves in three different ways in relation CR; outright negative, uncertain or positive toward the surgery. Those positioning themselves as negative thought CR was a harmful fraud and denied any possible benefits, at least sufficient for referral for CR. Those positioning themselves as uncertain did not deny possible benefits, but were skeptical toward CR improving cut women’s sexual health and function. Those positioning themselves positive considered the potential physical, psychological/emotional, esthetic, or symbolic aspects of CR as important for general well-being and sexual health. Conclusion: There was a great variety in how the gynecologists positioned themselves toward CR, and many were skeptical toward the functional benefits in relation to sexual health. This is likely to diverge cut women’s access to CR surgery.
  •  
38.
  • Kaya, Ibrahim, et al. (author)
  • Multimodal MALDI Imaging Mass Spectrometry Reveals Spatially Correlated Lipid and Protein Changes in Mouse Heart with Acute Myocardial Infarction
  • 2020
  • In: Journal of the American Society for Mass Spectrometry. - : American Chemical Society (ACS). - 1044-0305 .- 1879-1123. ; 31:10, s. 2133-2142
  • Journal article (peer-reviewed)abstract
    • Acute myocardial infarction (MI) is a cardiovascular disease that remains a major cause of morbidity and mortality worldwide despite advances in its prevention and treatment. During acute myocardial ischemia, the lack of oxygen switches the cell metabolism to anaerobic respiration, with lactate accumulation, ATP depletion, Na+ and Ca2+ overload, and inhibition of myocardial contractile function, which drastically modifies the lipid, protein, and small metabolite profile in the myocardium. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides, and proteins in biological tissue sections. In this work, we demonstrate an application of multimodal chemical imaging using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), which provided comprehensive molecular information in situ within the same mouse heart tissue sections with myocardial infarction. MALDI-IMS (at 30 mu m per pixel) revealed infarct-associated spatial alterations of several lipid species of sphingolipids, glycerophospholipids, lysophospholipids, and cardiolipins along with the acyl carnitines. Further, we performed multimodal MALDI-IMS (IMS3) where dual polarity lipid imaging was combined with subsequent protein MALDI-IMS analysis (at 30 mu m per pixel) within the same tissue sections, which revealed accumulations of core histone proteins H4, H2A, and H2B along with post-translational modification products, acetylated H4 and H2A, on the borders of the infarcted region. This methodology allowed us to interpret the lipid and protein molecular pathology of the very same infarcted region in a mouse model of myocardial infarction. Therefore, the presented data highlight the potential of multimodal MALDI imaging mass spectrometry of the same tissue sections as a powerful approach for simultaneous investigation of spatial infarct-associated lipid and protein changes of myocardial infarction.
  •  
39.
  • Kijani, Siavash, et al. (author)
  • Filter-Dense Multicolor Microscopy
  • 2015
  • In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
  • Journal article (peer-reviewed)abstract
    • Immunofluorescence microscopy is a unique method to reveal the spatial location of proteins in tissues and cells. By combining antibodies that are labeled with different fluorochromes, the location of several proteins can simultaneously be visualized in one sample. However, because of the risk of bleed-through signals between fluorochromes, standard multicolor microscopy is restricted to a maximum of four fluorescence channels, including one for nuclei staining. This is not always enough to address common scientific questions. In particular, the use of a rapidly increasing number of marker proteins to classify functionally distinct cell populations and diseased tissues emphasizes the need for more complex multistainings. Hence, multicolor microscopy should ideally offer more channels to meet the current needs in biomedical science. Here we present an enhanced multi-fluorescence setup, which we call Filter-Dense Multicolor Microscopy (FDMM). FDMM is based on condensed filter sets that are more specific for each fluorochrome and allow a more economic use of the light spectrum. FDMM allows at least six independent fluorescence channels and can be applied to any standard fluorescence microscope without changing any operative procedures for the user. In the present study, we demonstrate an FDMM setup of six channels that includes the most commonly used fluorochromes for histology. We show that the FDMM setup is specific and robust, and we apply the technique on typical biological questions that require more than four fluorescence microscope channels.
  •  
40.
  • Kijani, Siavash, et al. (author)
  • Intimal hyperplasia induced by vascular intervention causes lipoprotein retention and accelerated atherosclerosis
  • 2017
  • In: Physiological Reports. - : Wiley. - 2051-817X. ; 5:14
  • Journal article (peer-reviewed)abstract
    • Accelerated atherosclerosis diminishes the long term patency of vascular interventions, such as percutaneous coronary intervention and implantation of saphenous vein grafts. However, the cause of this accelerated atherosclerosis is unclear. In this study, we tested the hypothesis that intimal hyperplasia formed following vascular intervention promotes retention of atherogenic lipoproteins. Intimal hyperplasia was surgically induced in the mouse common carotid artery. The surgery was combined with different mouse models of hypercholesterolemia to obtain different cholesterol levels and to control the onsets of hypercholesterolemia. Three weeks after surgery, samples were immunostained for apoB lipoproteins, smooth muscle cells and leukocytes. Already at mild hypercholesterolemia (193mg/dL), pronounced apoB lipoprotein retention was found in the extracellular matrix in both intimal hyperplasia and the injured underlying media. In contrast, minimal retention was detected in the uninjured proximal region of the same vessel, or in vessels from mice with normal cholesterol levels (81mg/dL). Induction of aggravated hypercholesterolemia 3weeks after surgery, when a mature intimal hyperplasia had been formed, caused a very rapid development of atherosclerotic lesions. Mechanistically, we show that lipoprotein retention was almost exclusively dependent on electrostatic interactions to proteoglycan glycosaminoglycans, and the lipoprotein retention to intimal hyperplasia could be inhibited invivo using glycosaminoglycan-binding antibodies. Thus, formation of intimal hyperplasia following vascular intervention makes the vessel wall highly susceptible for lipoprotein retention and accelerated atherosclerosis. The increased lipoprotein retention in intimal hyperplasia can be targeted by blocking the interaction between apoB lipoproteins and glycosaminoglycans in the extracellular matrix.
  •  
41.
  • Lantero Rodriguez, Marta, et al. (author)
  • Testosterone reduces metabolic brown fat activity in male mice
  • 2021
  • In: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 251:1, s. 83-96
  • Journal article (peer-reviewed)abstract
    • Brown adipose tissue (BAT) burns substantial amounts of mainly lipids to produce heat. Some studies indicate that BAT activity and core body temperature are lower in males than females. Here we investigated the role of testosterone and its receptor (the androgen receptor; AR) in metabolic BAT activity in male mice. Castration, which renders mice testosterone deficient, slightly promoted the expression of thermogenic markers in BAT, decreased BAT lipid content, and increased basal lipolysis in isolated brown adipocytes. Further, castration increased the core body temperature. Triglyceride-derived fatty acid uptake, a proxy for metabolic BAT activity in vivo, was strongly increased in BAT from castrated mice ( 4.5-fold increase vs sham-castrated mice) and testosterone replacement reversed the castration-induced increase in metabolic BAT activity. BAT-specific AR deficiency did not mimic the castration effects in vivo and AR agonist treatment did not diminish the activity of cultured brown adipocytes in vitro, suggesting that androgens do not modulate BAT activity via a direct, AR-mediated pathway. In conclusion, testosterone is a negative regulator of metabolic BAT activity in male mice. Our findings provide new insight into the metabolic actions of testosterone.
  •  
42.
  • Levin, Malin, 1973, et al. (author)
  • A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure.
  • 2000
  • In: European heart journal. - : Oxford University Press (OUP). - 0195-668X. ; 21:22, s. 1853-8
  • Journal article (peer-reviewed)abstract
    • AIMS: The adrenergic nervous system is of major importance in congestive heart failure. No genetic polymorphism has previously been identified in the beta(1)-adrenergic receptor gene. The aim of this study was to find possible mutations in this gene and to relate such findings to morbidity and prognosis in heart failure. METHODS AND RESULTS: Genomic DNA was extracted from blood leukocytes from patients with congestive heart failure (n=184) and from age-matched controls (n=77). The part of the beta(1)-adrenergic receptor gene corresponding to nucleotide 1-255 was amplified by polymerase chain reaction and analysed by automated sequencing. The patients were investigated by echocardiography and followed regarding symptoms and survival for 5 years. A missense mutation was identified at nucleotide position 145 in the beta(1)-adrenergic receptor gene, which predicted an amino acid substitution at position 49 (Ser49Gly). The allele frequency of the Gly49 variant was 0.13 in controls and 0.18 in patients (P=0.19). At the time of the 5-years follow-up, 62% of the patients with the wild type gene and 39% of the patients with the Ser49Gly variant had died or had experienced hospitalization (P=0.005). Patients without the mutation had significantly poorer survival compared to those with the mutation, risk ratio 2.34 (95% CI 1.30-4.20), P=0.003. In a mulivariate analysis, the risk ratio was 2.03 (95% CI 0.99-4.16) P=0.05. CONCLUSION: A novel missense mution in the beta(1)-adrenergic receptor gene was associated with a decreased mortality risk in patients with congestive heart failure. These data suggest that the beta(1)-receptor Ser49Gly variant might be associated with altered receptor function, resulting in myocardial protection in patients with heart failure.
  •  
43.
  • Levin, Malin, 1973, et al. (author)
  • Evaluation of macrophage-specific promoters using lentiviral delivery in mice.
  • 2012
  • In: Gene therapy. - : Springer Science and Business Media LLC. - 1476-5462 .- 0969-7128. ; 19:11, s. 1041-7
  • Journal article (peer-reviewed)abstract
    • In gene therapy, tissue-specific promoters are useful tools to direct transgene expression and improve efficiency and safety. Macrophage-specific promoters (MSPs) have previously been published using different delivery systems. In this study, we evaluated five different MSPs fused with green fluorescent protein (GFP) to delineate the one with highest specificity using lentiviral delivery. We compared three variants of the CD68 promoter (full length, the 343-bp proximal part and the 150-bp proximal part) and two variants (in forward and reverse orientation) of a previously characterized synthetic promoter derived from elements of transcription factor genes. We transduced a number of cell lines and primary cells in vitro. In addition, hematopoietic stem cells were transduced with MSPs and transferred into lethally irradiated recipient mice. Fluorescence activated cell sorting analysis was performed to determine the GFP expression in different cell populations both in vitro and in vivo. We showed that MSPs can efficiently be used for lentiviral gene delivery and that the 150-bp proximal part of the CD68 promoter provides primarily macrophage-specific expression of GFP. We propose that this is the best currently available MSP to use for directing transgene expression to macrophage populations in vivo using lentiviral vectors.
  •  
44.
  • Levin, Malin, 1973, et al. (author)
  • Rip2 deficiency leads to increased atherosclerosis despite decreased inflammation.
  • 2011
  • In: Circulation research. - 1524-4571. ; 109:11, s. 1210-8
  • Journal article (peer-reviewed)abstract
    • The innate immune system and in particular the pattern-recognition receptors Toll-like receptors have recently been linked to atherosclerosis. Consequently, inhibition of various signaling molecules downstream of the Toll-like receptors has been tested as a strategy to prevent progression of atherosclerosis. Receptor-interacting protein 2 (Rip2) is a serine/threonine kinase that is involved in multiple nuclear factor-κB (NFκB) activation pathways, including Toll-like receptors, and is therefore an interesting potential target for pharmaceutical intervention.
  •  
45.
  • Levin, Malin, 1973, et al. (author)
  • The myocardium-protective Gly-49 variant of the beta 1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation.
  • 2002
  • In: The Journal of biological chemistry. - 0021-9258. ; 277:34, s. 30429-35
  • Journal article (peer-reviewed)abstract
    • The beta(1)-adrenergic receptor (beta(1)AR) is a major mediator of catecholamine effects in human heart. Patients with heart failure who were hetero- or homozygous for the Gly-49 variant of the beta(1)AR (Gly-49-beta(1)AR) showed improved long-term survival as compared with those with the Ser-49 genotype. Here, the functional consequences of this polymorphism were studied in cells expressing either variant. The Gly-49-beta(1)AR demonstrated characteristic features of constitutively active receptors. In cells expressing the Gly-49-beta(1)AR, both basal and agonist-stimulated adenylyl cyclase activities were higher than in cells expressing the Ser-49 variant (Ser-49-beta(1)AR). The Gly-49-beta(1)AR was more sensitive to the inhibitory effect of the inverse agonist metoprolol and displayed increased affinity for agonists. Isoproterenol potency for adenylyl cyclase activation was higher on membranes expressing the Gly-49-beta(1)AR than on those expressing the Ser-49-beta(1)AR. After incubation with saturating concentrations of catecholamines or sustained stimulation, the Gly-49 variant showed a much higher desensitization, which largely prevailed over constitutive activity in terms of cAMP accumulation. The Gly-49-beta(1)AR also displayed a more profound agonist-promoted down-regulation than the Ser-49 variant. The stronger regulation of the Gly-49-beta(1)AR could explain the beneficial effect of the Gly-49 genotypes on survival, further supporting the concept that beta(1)AR desensitization is protective in heart failure.
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46.
  • Levin, Malin, 1973 (author)
  • ß-Adrenergic receptor gene polymorphism in dilated cardiomyopathy. Clinical and functional relevance
  • 2002
  • Doctoral thesis (other academic/artistic)abstract
    • During normal physiological conditions, catecholamines induce positive inotropic and chronotropic responses in the heart through a ß-adrenergic receptor (AR)-activated pathway. The agonist-bound ßAR selectively interacts with the stimulatory Gs-protein, which activates adenylyl cyclase, catalyzing cAMP formation. The adrenergic nervous system is chronically activated in heart failure (HF). This compensatory mechanism helps to preserve cardiac performance temporarily, by increasing contractility and heart rate. However, in due course, this sympathetic drive will be damaging to the failing heart.The aim of this study was to elucidate genetic variance of the ß1AR and further to analyze how possible polymorphisms might affect the pharmacology and function of the receptor and eventually change the prognosis of, or predict the probability for, idiopathic dilated cardiomyopathy (DCM).Sequence analysis of the entire coding region of the ß1AR was performed and two polymorphisms that resulted in amino acid substitutions were identified. At position 49 in the N-terminal domain, either a serine (Ser49-ß1AR) or a glycine (Gly49-ß1AR) was found. At position 389 of the C-terminal region, either a glycine (Gly389) or an arginine (Arg389) was found. Controls and patients with idiopathic HF were genotyped for known polymorphisms in the ß1-, ß2- and ß3ARs. The genetic variants were equally distributed in patients and controls, indicating that neither one is a major determinant for susceptibility for idiopathic HF. However, the Gly49-genotype was associated with an improved long-term survival in patients with idiopathic HF. The pharmacological and functional consequences of the polymorphism in codon 49 of the ß1AR were analyzed using human embryonic kidney 293 cells, expressing the Ser49- or the Gly49-ß1AR. The Gly49-ß1AR demonstrated characteristic features of constitutively activated receptors, displaying increased affinity for agonists, enhanced potency for agonist-activation of adenylyl cyclase and an increased sensitivity to the inhibitory effect of inverse agonists. The Gly49-ß1AR also had a high propensity for desensitization. The stronger regulation of the Gly49-ß1AR could explain the beneficial effect of this genotype on survival, further supporting the concept that desensitization is protective in HF.Furthermore, we aimed to evaluate the influence of the polymorphism in codon 49-ß1AR for MAPK signaling and myocardial apoptosis. We identified myocyte apoptosis in occasional myocardial cells from patients with DCM. However, we did not find any discrepancy in the frequency of apoptotic cells between patients with different genotypes. Cultured cells expressing the Gly49-ß1AR activate ERK1/2, after stimulation with isoproterenol to a significantly higher extent than cells expressing the Ser49-ß1AR. In addition, the Gly49-ß1AR activated the growth and survival signal ERK1/2 to a higher extent than the Ser49-ß1AR in cultured cells. The protective effect of the Gly49-ß1AR in HF patients may, at least in part, be explained by the enhanced protection, at various levels of ß1AR signaling, to high catecholamine levels. These observations may prove useful in follow-up of patients with cardiovascular disease, the selection and timing of pharmacological therapies, and in the prognostic evaluation and selection of such individuals for cardiac transplantation.
  •  
47.
  • Li, Lu, 1964, et al. (author)
  • The Importance of GLUT3 for De Novo Lipogenesis in Hypoxia-Induced Lipid Loading of Human Macrophages
  • 2012
  • In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:8
  • Journal article (peer-reviewed)abstract
    • Atherosclerotic lesions are characterized by lipid-loaded macrophages (foam cells) and hypoxic regions. Although it is well established that foam cells are produced by uptake of cholesterol from oxidized LDL, we previously showed that hypoxia also promotes foam cell formation even in the absence of exogenous lipids. The hypoxia-induced lipid accumulation results from increased triglyceride biosynthesis but the exact mechanism is unknown. Our aim was to investigate the importance of glucose in promoting hypoxia-induced de novo lipid synthesis in human macrophages. In the absence of exogenous lipids, extracellular glucose promoted the accumulation of Oil Red O-stained lipid droplets in human monocyte-derived macrophages in a concentration-dependent manner. Lipid droplet accumulation was higher in macrophages exposed to hypoxia at all assessed concentrations of glucose. Importantly, triglyceride synthesis from glucose was increased in hypoxic macrophages. GLUT3 was highly expressed in macrophage-rich and hypoxic regions of human carotid atherosclerotic plaques and in macrophages isolated from these plaques. In human monocyte-derived macrophages, hypoxia increased expression of both GLUT3 mRNA and protein, and knockdown of GLUT3 with siRNA significantly reduced both glucose uptake and lipid droplet accumulation. In conclusion, we have shown that hypoxia-induced increases in glucose uptake through GLUT3 are important for lipid synthesis in macrophages, and may contribute to foam cell formation in hypoxic regions of atherosclerotic lesions.
  •  
48.
  • Li, Xiujuan, et al. (author)
  • Suppressed Vascular Leakage and Myocardial Edema Improve Outcome From Myocardial Infarction
  • 2020
  • In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 11
  • Journal article (peer-reviewed)abstract
    • Aim: The acute phase of myocardial infarction (MI) is accompanied by edema contributing to tissue damage and disease outcome. Here, we aimed to identify the mechanism whereby vascular endothelial growth factor (VEGF)-A induces myocardial edema in the acute phase of MI to eventually promote development of therapeutics to specifically suppress VEGFA-regulated vascular permeability while preserving collateral vessel formation.Methods and Results: VEGFA regulates vascular permeability and edema by activation of VEGF receptor-2 (VEGFR2), leading to induction of several signaling pathways including the cytoplasmic tyrosine kinase c-Src. The activated c-Src in turn phosphorylates vascular endothelial (VE)-cadherin, leading to dissociation of endothelial adherens junctions. A particular tyrosine at position 949 in mouse VEGFR2 has been shown to be required for activation of c-Src. Wild-type mice and mice with phenylalanine replacing tyrosine (Y) 949 in VEGFR2 (Vegfr2Y949F/Y949F) were challenged with MI through permanent ligation of the left anterior descending coronary artery. The infarct size was similar in wild-type and mutant mice, but left ventricular wall edema and fibrinogen deposition, indicative of vascular leakage, were reduced in the Vegfr2Y949F/Y949F strain. When challenged with large infarcts, the Vegfr2Y949F/Y949F mice survived significantly better than the wild-type strain. Moreover, neutrophil infiltration and levels of myeloperoxidase were low in the infarcted Vegfr2Y949F/Y949F hearts, correlating with improved survival. In vivo tyrosine phosphorylation of VE-cadherin at Y685, implicated in regulation of vascular permeability, was induced by circulating VEGFA in the wild-type but remained at baseline levels in the Vegfr2Y949F/Y949F hearts.Conclusion: Suppression of VEGFA/VEGFR2-regulated vascular permeability leads to diminished edema without affecting vascular density correlating with improved myocardial parameters and survival after MI.
  •  
49.
  • Lindgren, Anna, et al. (author)
  • Adiponectin receptor 2 deficiency results in reduced atherosclerosis in the brachiocephalic artery in apolipoprotein e deficient mice.
  • 2013
  • In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11
  • Journal article (peer-reviewed)abstract
    • Adiponectin has been shown to have beneficial cardiovascular effects and to signal through the adiponectin receptors, AdipoR1 and AdipoR2. The original aim of this study was to investigate the effect of combined AdipoR1 and AdipoR2 deficiency (AdipoR1(-/-)AdipoR2(-/-)) on atherosclerosis. However, we made the interesting observation that AdipoR1 (-/-) AdipoR2 (-/-) leads to embryonic lethality demonstrating the critical importance of the adiponectin signalling system during development. We then investigated the effect of AdipoR2-ablation on the progression of atherosclerosis in apolipoprotein E deficient (ApoE (-/-) ) mice. AdipoR2(-/-)ApoE(-/-) mice fed an atherogenic diet had decreased plaque area in the brachiocephalic artery compared with AdipoR2 (+/+) ApoE(-/-) littermate controls as visualized in vivo using an ultrasound biomicroscope and confirmed by histological analyses. The decreased plaque area in the brachiocephalic artery could not be explained by plasma cholesterol levels or inflammatory status. However, accumulation of neutral lipids was decreased in peritoneal macrophages from AdipoR2(-/-)ApoE(-/-) mice after incubation with oxidized LDL. This effect was associated with lower CD36 and higher ABCA1 mRNA levels in peritoneal macrophages from AdipoR2(-/-)ApoE(-/-) mice compared with AdipoR2(+/+)ApoE(-/-) controls after incubation with oxidized LDL. In summary, we show that adiponectin receptors are crucial during embryonic development and that AdipoR2-deficiency slows down the progression of atherosclerosis in the brachiocephalic artery of ApoE-deficient mice.
  •  
50.
  • Magnusson, Yvonne, 1957, et al. (author)
  • Ser49Gly of beta1-adrenergic receptor is associated with effective beta-blocker dose in dilated cardiomyopathy.
  • 2005
  • In: Clinical pharmacology and therapeutics. - : Springer Science and Business Media LLC. - 0009-9236. ; 78:3, s. 221-31
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: Our objective was to evaluate the influence of polymorphisms at codons 49 and 389 of the beta1-adrenergic receptor (beta1-AR) on the response to beta-blockers and outcome in patients with dilated cardiomyopathy. METHODS: We genotyped both codons of the beta1-AR in 375 patients with dilated cardiomyopathy and 492 control subjects. RESULTS: Neither of the polymorphisms was associated with susceptibility for dilated cardiomyopathy. In a retrospective analysis of patients receiving beta-blockers, there was a significant association between long-term survival rate and codon 49 (P = .014) but not codon 389 (P = .08). Despite a similar mean heart rate (69 beats/min), patients with the Ser49 genotype tended to have higher doses of beta-blockade compared with Gly49 carriers (P = .065). In patients receiving a low dose of beta-blockade (< or = 50% of targeted full dose), the 5-year mortality rate was lower among Gly49 carriers than Ser49 patients (risk ratio [RR], 0.24; 95% confidence interval [CI], 0.07-0.80; P = .020). In patients receiving high doses of beta-blockers, there was no significant difference in outcome between genotypes (P = .20), which was attributable to a better outcome for Ser49 patients treated with a high dose of beta-blockade as compared with a low dose. Gly49 carriers had a similar survival rate with different doses of beta-blockers. With low-dose beta-blockers, both codon 49 (RR, 0.26; 95% CI, 0.08-0.89; P = .029) and codon 389 (RR, 2.42; 95% CI, 1.04-5.63, P = .039) were related to 5-year mortality rate. CONCLUSION: In patients with heart failure, the influence of codon 49 on the outcome and effect of beta-blockers appeared to be more pronounced than that of codon 389. The more common Ser49Ser genotype responded less beneficially to beta-blockade and would motivate genotyping to promote higher doses for the best outcome effect.
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