| 1. |
- Andersson, Linda, 1973, et al.
(författare)
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Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking
- 2021
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 42:43, s. 4481-4492
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Rip2 modifies VEGF-induced signalling and vascular permeability in myocardial ischemia
- 2015
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 107:4, s. 478-486
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Cardiac Plin5 interacts with SERCA2 and promotes calcium handling and cardiomyocyte contractility
- 2023
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Ingår i: Life Science Alliance. - : Life Science Alliance, LLC. - 2575-1077. ; 6:4
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Tidskriftsartikel (refereegranskat)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. |
- Klevstig, Martina, et al.
(författare)
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Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia
- 2019
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Ingår i: Journal of Molecular and Cellular Cardiology. - : Elsevier BV. - 0022-2828 .- 1095-8584. ; 137, s. 1-8
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Laudette, Marion, et al.
(författare)
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Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function
- 2023
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 119:7, s. 1537-1552
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Tidskriftsartikel (refereegranskat)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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| 6. |
- Yrlid, Ulf, 1971, et al.
(författare)
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Endothelial repair is dependent on CD11c(+) leukocytes to establish regrowing endothelial sheets with high cellular density
- 2019
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 105:1, s. 195-202
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Tidskriftsartikel (refereegranskat)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.
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| 7. |
- Lindbom, Malin, 1976
(författare)
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Myocardial creatine metabolism in experimental infarction and heart failure
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The failing heart is characterized by changes in structure, function and metabolism. All these changes are usually defined as pathologic remodelling. An important part of this negative remodelling process is disturbances in the myocardial energy metabolism. It has been demonstrated both in clinical and experimental studies that the failing heart contains low levels of creatine(Cr), phosphocreatine (PCr) and adenosine-triphosphate (ATP). For the heart to be able to function and contract normally, it needs energy in the form of ATP. ATP needs to be transported from sites of energy production to the sites of energy utilization in the myocyte. The Creatine-kinas (CK) system is responsible for this energy transport. Previous studies have shown that Cr depletion results in disturbed energy metabolism, which is associated with decreased PCr content, decreased CK activity and compromised left ventricular dysfunction. But there is still limited knowledge about the role of creatine and myocardial energy metabolism in the diseased heart. It is known that the heart that depends on exogenous lipids for the oxidative production of ATP, and thereby for maintenance of normal cellular energy homeostasis. Recent studies have however, reported that the heart synthesizes and releases its own endogenous apolipoprotein B (apoB). It has been proposed that apoB may be involved in cardioprotection by means of elimination of toxic intracellular lipids. The aim of this thesis were ? To investigate whether measures of intensive cardiac care applied to rats with acute myocardial infarction (MI) would reduce mortality in this small animal model. ? To investigate in vivo the effects of Cr depletion in rats on left ventricular function and morphology, energy metabolism, catecholamines and incidence of malignant ventricular arrhythmias during acute myocardial infarction. ? To investigate in vivo the effects of Cr depletion in mice on left ventricular function and morphology, energy metabolism and myocardial lipids. ? To investigate importance of endogenous lipoproteins in the heart for cardiac function, morphology and survival in the settings of acute and chronic myocardial infarction. ? To investigate acute and chronic effects of complete heart block (CHB) on cardiac function, morphology and energy metabolism in a rat model. In paper I we show that by applying simple methods like pre-treatment with anti-arrhythmia, prolonged respiratory support, use of isoflurane gas anaesthesia, and treatment of MVA with electrical cardioversion, the mortality in the rat model of acute MI is decreased by ~70 %. In the rat model of Cr depletion we show that lack of myocardial Cr leads to disturbances in metabolism, morphology and function of the heart, similar to those found in HF patients. The animals suffering from CR depletion show increased incidence of arrhythmias and increased mortality in the setting of acute MI. We also showed that Cr depletion in mice leads to similar disturbances as in the rat model. One very interesting new finding was the increased accumulation of triglycerides. The most important finding in the mouse model was that the disturbances in the metabolism, structure and function of the heart are completely reversible upon the normalization of the Cr levels. These findings indicate that Cr metabolism may be an important target for pharmacological interventions in order to increase myocardial efficiency and structural integrity of the failing heart. In paper IV we showed that the over-expression of apolipoprotein B (apoB) in mice increased the survival post-MI, 2-fold. This was associated with improved myocardial function in the apoB mice. It was also determined that the production of endogenous apoB was increased acutely post-ischemia injury, but in long term it decreases to subnormal levels. These findings indicate that the myocardial apoB system may be important in cardioprotection in pathophysiologic settings as myocardial ischemia and HF. CHB in rats lead to early, pronounced and sustained cardiac remodelling with the development of eccentric hypertrophy. Howevere they did not develop left ventricular dysfunction and showed no signs of disturbed energy metabolism. Future studies are needed here to elucidate the mechanism behind the beneficial cardiac remodelling post-CHB.
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| 8. |
- Omerovic, Elmir, 1968, et al.
(författare)
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Aqueous fish extract increases survival in the mouse model of cytostatic toxicity
- 2008
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Ingår i: Journal of Experimental & Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966 .- 0392-9078. ; 4:27
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Tidskriftsartikel (refereegranskat)abstract
- Background: Treatment of cancer patients with anthracycline antibiotic doxorubicin (DOX) may be complicated by development of acute and chronic congestive heart failure (CHF), malignant arrhythmias and death. The aim of this study was to test whether an aqueous low molecular weight (LMW) extract from cod muscle decreases acute mortality in the mouse model of acute CHF caused by DOX. Methods: A LMW fraction (< 500 Da) of the aqueous phase of cod light muscle (AOX) was used for treatment of male BALB/c mice (similar to 25 g, n = 70). The animals were divided into four groups, DOX + AOX (n = 20), DOX + saline (NaCl) (n = 30), NaCl + AOX (n = 10) and NaCl only (n = 10). Echocardiography was performed in the separate subgroups (DOX treated n = 6 and controls n = 6) to verify the presence and the grade of acute CHF. The cod extract was delivered by subcutaneously implanted osmotic minipumps over the period of 2 weeks. High-dose injection of DOX was administered to randomly selected animals. The animals received single intraperitoneal injection of DOX (25 mg/kg) and were followed over two weeks for mortality. Results: Mortality rate was 68% lower (p < 0.05) in the mice treated with the extract. The analyses of cod extract have shown strong antioxidative effect in vitro. Conclusion: The aqueous LMW cod muscles extract decreases mortality in the mouse model of DOX induced acute CHF. This effect may be mediated by cardioprotection through antioxidative mechanisms.
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| 9. |
- Perman, Jeanna, 1981, et al.
(författare)
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The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction.
- 2011
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Ingår i: The Journal of clinical investigation. - : American Society for Clinical Investigation. - 1558-8238 .- 0021-9738. ; 121:7, s. 2625-40
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Tidskriftsartikel (refereegranskat)abstract
- Impaired cardiac function is associated with myocardial triglyceride accumulation, but it is not clear how the lipids accumulate or whether this accumulation is detrimental. Here we show that hypoxia/ischemia-induced accumulation of lipids in HL-1 cardiomyocytes and mouse hearts is dependent on expression of the VLDL receptor (VLDLR). Hypoxia-induced VLDLR expression in HL-1 cells was dependent on HIF-1α through its interaction with a hypoxia-responsive element in the Vldlr promoter, and VLDLR promoted the endocytosis of lipoproteins. Furthermore, VLDLR expression was higher in ischemic compared with nonischemic left ventricles from human hearts and was correlated with the total lipid droplet area in the cardiomyocytes. Importantly, Vldlr-/- mice showed improved survival and decreased infarct area following an induced myocardial infarction. ER stress, which leads to apoptosis, is known to be involved in ischemic heart disease. We found that ischemia-induced ER stress and apoptosis in mouse hearts were reduced in Vldlr-/- mice and in mice treated with antibodies specific for VLDLR. These findings suggest that VLDLR-induced lipid accumulation in the ischemic heart worsens survival by increasing ER stress and apoptosis.
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| 10. |
- Redfors, Björn, et al.
(författare)
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Effects of doxorubicin on myocardial expression of apolipoprotein-B.
- 2012
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Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1651-2006 .- 1401-7431. ; 46:2
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Doxorubicin (DOX) is an effective antitumor agent against a variety of human malignancies but is associated with deleterious side effects, including myocardial damage and heart failure. Myocardial apoB-containing lipoprotein (apoB) is upregulated post myocardial infarction and has been shown to be cardioprotective in this setting by unloading excessive lipid. The aim of this study was to investigate whether apoB expression is increased also in DOX-induced heart failure and whether apoB overexpression protects the heart in DOX-induced myocardial injury. Design: Cardiac function and energy metabolism was studied in mice and rats 24 hours after intraperitoneally administered DOX. Results: We found that the content of apoB was decreased in rat myocardium 24 hours after DOX injection. In contrast, apoB content was increased in the infarcted myocardium of rats 24 hours post ischemia-reperfusion. Moreover, transgenic mice overexpressing apoB had better cardiac function and lower intracellular lipid accumulation compared to wild type mice 24h post DOX. Conclusions: Our findings indicate that depression of the myocardial apoB system may contribute to DOX-induced cardiac injury and that overexpression of apoB is protective, not only in ischemically damaged myocardium, but also in DOX-induced heart failure.
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