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Sökning: WFRF:(Dunér Pontus)

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1.
  • Al-Amily, Israa Mohammad, et al. (författare)
  • The functional impact of G protein-coupled receptor 142 (Gpr142) on pancreatic -cell in rodent
  • 2019
  • Ingår i: Pflugers Archiv-European Journal of Physiology. - : Springer Science and Business Media LLC. - 0031-6768 .- 1432-2013. ; 471:4, s. 633-645
  • Tidskriftsartikel (refereegranskat)abstract
    • We have recently shown that the G protein-coupled receptor 142 (GPR142) is expressed in both rodent and human pancreatic -cells. Herein, we investigated the cellular distribution of GPR142 within islets and the effects of selective agonists of GPR142 on glucose-stimulated insulin secretion (GSIS) in the mouse islets and INS-1832/13 cells. Double-immunostaining revealed that GPR142 immunoreactivity in islets mainly occurs in insulin-positive cells. Potentiation of GSIS by GPR142 activation was accompanied by increased cAMP content in INS-1832/13 cells. PKA/Epac inhibition markedly suppressed the effect of GPR142 activation on insulin release. Gpr142 knockdown (Gpr142-KD) in islets was accompanied by elevated release of MCP-1, IFN, and TNF during culture period and abolished the modulatory effect of GPR142 activation on the GSIS. Gpr142-KD had no effect on Ffar1, Ffar2, or Ffar3 mRNA while reducing Gpr56 and increasing Tlr5 and Tlr7 mRNA expression. Gpr142-KD was associated with an increased expression of Chrebp, Txnip, RhoA, and mitochondrial Vdac1 concomitant with a reduced Pdx1, Pax6, and mitochondrial Vdac2 mRNA levels. Long-term exposure of INS-1832/13 cells to hyperglycemia reduced Gpr142 and Vdac2 while increased Chrebp, Txnip, and Vdac1 mRNA expression. GPR142 agonists or Bt(2)-cAMP counteracted this effect. Glucotoxicity-induced decrease of cell viability in Gpr142-KD INS-1 cells was not affected by GPR142-agonists while Bt(2)-cAMP prevented it. The results show the importance of Gpr142 in the maintenance of pancreatic -cell function in rodents and that GPR142 agonists potentiate GSIS by an action, which most likely is due to increased cellular generation of second messenger molecule cAMP.
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2.
  • Amisten, Stefan, et al. (författare)
  • Activation of imidazoline receptor I-2, and improved pancreatic beta-cell function in human islets
  • 2018
  • Ingår i: Journal of Diabetes and Its Complications. - : Elsevier BV. - 1056-8727. ; 32:9, s. 813-818
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: The impact of BL11282, an imidazoline receptor (NISCH) agonist, on potentiation of glucose-stimulated insulin secretion (GSIS) from isolated human non-diabetic (ND) and type 2 diabetic (T2D) islets was investigated. Methods: Analysis of mRNA was performed by RNA-sequencing and qPCR Insulin and cAMP by RIA and EUSA respectively. Results: RNA-sequencing data revealed that NISCH is highly expressed in fat tissues, islets, liver and muscles, with eight detectable splice variants of transcripts in islets. NISCH had a positive correlation with GLP-1 (GLP1R) and GIP (GIPR) receptor transcripts. The expression of NISCH was confirmed by qPCR in human islets. NISCH and GLP1R were comparably higher expressed in mouse islets compared to human islets. GSIS was dose-dependently potentiated by BL11282 from incubated islets of ND and T2D human islet donors. The insulinotropic action of BL11282 was associated with increased cAMP. While the harmful effect of high glucose on reductive capacity of islet cells was enhanced by glibenclamide during long-term culture, it was counteracted by BL11282 or Bt2-cAMP. BL11282 also increased proliferation of INS-1 cells during long-time culture. Conclusion: Our data suggest that BL11282 potentiates GSIS by an action involving cAMP/PKA system and BL11282 could be an attractive insulinotropic and beta-cell protective agent. (C) 2018 Elsevier Inc. All rights reserved.
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3.
  • Asciutto, Giuseppe, et al. (författare)
  • Low elastin content of carotid plaques is associated with increased risk of ipsilateral stroke.
  • 2015
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Atherosclerotic plaques with a low content of connective tissue proteins are believed to have an increased risk of rupture and to give rise to clinical events. The aim of the present study was to investigate if the content of elastin, collagen and of the matrix metalloproteinase (MMP) -1, -3, -9 and -12 in plaques removed at surgery can be associated with the occurrence of ipsilateral symptoms.
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4.
  • Bengtsson, Eva, et al. (författare)
  • ADAMTS-7 is associated with a high-risk plaque phenotype in human atherosclerosis
  • 2017
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Several large-scale genome-wide association studies have identified single-nucleotide polymorphisms in the genomic region of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats (ADAMTS)-7 and associations to coronary artery disease. Experimental studies have provided evidence for a functional role of ADAMTS-7 in both injury-induced vascular neointima formation and development of atherosclerotic lesions. However, whether ADAMTS-7 is associated with a specific plaque phenotype in humans has not been investigated. Carotid plaques (n = 206) from patients with and without cerebrovascular symptoms were analyzed for expression of ADAMTS-7 by immunohistochemistry and correlated to components associated with plaque vulnerability. Plaques from symptomatic patients showed increased levels of ADAMTS-7 compared with lesions from asymptomatic patients. High levels of ADAMTS-7 correlated with high levels of CD68-staining and lipid content, but with low smooth muscle cell and collagen content, which together are characteristics of a vulnerable plaque phenotype. ADAMTS-7 levels above median were associated with increased risk for postoperative cardiovascular events. Our data show that ADAMTS-7 is associated with a vulnerable plaque phenotype in human carotid lesions. These data support previous observations of a potential proatherogenic role of ADAMTS-7.
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5.
  • Berglund, Lisa, et al. (författare)
  • Glucose-Dependent Insulinotropic Polypeptide (GIP) Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB.
  • 2016
  • Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 65:1, s. 239-254
  • Tidskriftsartikel (refereegranskat)abstract
    • Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the pro-atherogenic cytokine osteopontin (OPN) in mouse arteries, via local release of endothelin-1 (ET-1) and activation of cAMP response element binding protein (CREB). Infusion of GIP increases plasma OPN levels in healthy individuals. Plasma ET-1 and OPN levels are positively correlated in patients with critical limb ischemia. Fasting GIP levels are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared to controls. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients; and expression associates to parameters characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from human, mouse, rat and pig; remarkable up-regulation is observed in endothelial and smooth muscle cells upon culture conditions yielding a "vascular disease-like" phenotype. Moreover, a common variant rs10423928 in the GIPR gene associated with increased risk of stroke in type 2 diabetes patients.
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6.
  • Chen, Yihong, et al. (författare)
  • Identification of an osteopontin-derived peptide that binds neuropilin-1 and activates vascular repair responses and angiogenesis
  • 2024
  • Ingår i: Pharmacological Research. - 1096-1186. ; 205
  • Tidskriftsartikel (refereegranskat)abstract
    • The osteopontin-derived peptide FOL-005 stimulates hair growth. Using ligand-receptor glyco-capture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005 and the more stable analogue FOL-026. X-ray diffraction and microscale thermophoresis analysis revealed that FOL-026 shares binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of VEGFR-2, ERK1/2 and AKT, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro. FOL-026 also promoted angiogenesis in vivo as assessed by subcutaneous Matrigel plug and hind limb ischemia models. NRP-1 knock-down or treatment of NRP-1 antagonist EG00229 blocked the stimulatory effects of FOL-026 on endothelial cells. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell growth, migration, inhibited apoptosis, and induced VEGF gene expression and VEGFR-2/AKT phosphorylation by an NRP-1-dependent mechanism. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. These findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and/or enhanced angiogenesis.
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7.
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8.
  • Dunér, Pontus, et al. (författare)
  • Adhesion G Protein-Coupled Receptor G1 (ADGRG1/GPR56) and Pancreatic beta-Cell Function
  • 2016
  • Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 101:12, s. 4637-4645
  • Tidskriftsartikel (refereegranskat)abstract
    • Context: Adhesion G protein-coupled receptor (GPCR)-G1 (ADGRG1) is the most abundant GPCR in human pancreatic islets, but its role in islet function is unclear. Objective: Investigate how ADGRG1 expression and activation by its ligand, collagen III, impacts beta-cell function in normal and type 2 diabetic (T2D) islets. Design: Genes associated with the ADGRG1 in human islets was probed by RNA-sequencing of human pancreatic islet isolated from cadaveric donors, followed by functional studies on beta-cell proliferation, apoptosis, and insulin secretion in human and mouse islets and in INS-1 cells. Main Outcome Measures: Changes in beta-cell gene expression, proliferation, apoptosis, and insulin secretion were quantified by RNA-sequencing, qPCR, Thymidine incorporation, Western blotting, and RIA, respectively. Results: ADGRG1 is the most abundant GPCR mRNA in both human and mouse islets, and its expression in human islets strongly correlates with genes important for beta-cell function and T2D risk. The expression of ADGRG1 was reduced in islets of T2D donors, in db/db mouse islets, and in isolated human islets exposed to chronic hyperglycemia. Beneficial effects of collagen type III on beta-cell function via activation of the cAMP/protein kinase A pathway, suppression of RhoA and caspase-3 activity, increased beta-cell viability, and proliferation were abolished when ADGRG1 was down-regulated in beta-cells. Conclusions: We demonstrate a mechanistic link between ADGRG1 expression and beta-cell function. Pharmacological agents that promote expression or activation of the ADGRG1 receptor may represent a novel approach for the treatment of T2D.
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9.
  • Dunér, Pontus, et al. (författare)
  • Antibodies against apoB100 peptide 210 inhibit atherosclerosis in apoE(-/-) mice
  • 2021
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Atherosclerotic plaques are characterized by an accumulation and subsequent oxidation of LDL, resulting in adaptive immune responses against formed or exposed neoepitopes of the LDL particle. Autoantibodies against native p210, the 3136-3155 amino acid sequence of the LDL protein apolipoprotein B-100 (apoB100) are common in humans and have been associated with less severe atherosclerosis and decreased risk for cardiovascular events in clinical studies. However, whether apoB100 native p210 autoantibodies play a functional role in atherosclerosis is not known. In the present study we immunized apoE(-/-) mice with p210-PADRE peptide to induce an antibody response against native p210. We also injected mice with murine monoclonal IgG against native p210. Control groups were immunized with PADRE peptide alone or with control murine monoclonal IgG. Immunization with p210-PADRE induced an IgG1 antibody response against p210 that was associated with reduced atherosclerotic plaque formation in the aorta and reduced MDA-LDL content in the lesions. Treatment with monoclonal p210 IgG produced a similar reduction in atherosclerosis as immunization with p210-PADRE. Our findings support an atheroprotective role of antibodies against the apoB100 native p210 and suggest that vaccines that induce the expression of native p210 IgG represent a potential therapeutic strategy for lowering cardiovascular risk.
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10.
  • Dunér, Pontus, et al. (författare)
  • Immune responses against aldehyde-modified laminin accelerate atherosclerosis in Apoe(-/-) mice.
  • 2010
  • Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 212:2, s. 457-465
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: LDL oxidation in the vascular wall is associated with aldehyde modification of surrounding extracellular matrix proteins that may target autoimmune responses against vascular tissues. Here we investigated the possible influence of immunity against a malondialdehyde (MDA)-modified form of the basement membrane protein laminin on atherosclerosis. METHODS AND RESULTS: IgM and IgG autoantibodies were present in human plasma and a prospective clinical study demonstrated that individuals who later suffered from acute cardiovascular events had lower levels of MDA-laminin antibodies compared to those in the control group. Immunohistochemical analysis of atherosclerotic plaques from Apoe(-/-) mice demonstrated co-localization between laminin and MDA epitopes, however MDA-laminin IgG was absent in mouse plasma. To determine the effect of MDA-laminin immunity, Apoe(-/-) mice were immunized with MDA-laminin. Analysis of circulating leukocytes at 12 weeks demonstrated increased T-cell activation, expansion of Th17 cells and a lower fraction of regulatory T cells (Tregs) in mice immunized with MDA-laminin. At 25 weeks, aortic atherosclerosis was increased by more than 60% in mice immunized with MDA-laminin, together with increased levels of MDA-laminin IgG1 and MDA-laminin-specific T-cells expressing IL-2, IL-4 and IL-6 in the spleen. CONCLUSION: The clinical observations suggest that immune responses against MDA-laminin may be involved in the development of cardiovascular disease in humans. Furthermore, observations in mice provide evidence for the presence of aldehyde-modified laminin in atherosclerotic lesions and demonstrate that induction of an immune response against these structures is associated with activation of Th17 cells, reduced fraction of Tregs and a more aggressive development of atherosclerosis.
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11.
  • Dunér, Pontus, et al. (författare)
  • Immune responses against fibronectin modified by lipoprotein oxidation and their association with cardiovascular disease.
  • 2009
  • Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; Feb 14., s. 593-603
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract. Dunér P, To F, Alm R, Gonçalves I, Fredrikson GN, Hedblad B, Berglund G, Nilsson J, Bengtsson E (Malmö University Hospital, Lund University, Lund, Sweden). Immune responses against fibronectin modified by lipoprotein oxidation and their association with cardiovascular disease. J Intern Med 2009; doi: 10.1111/j.1365-2796.2008.02067.xObjectives. Accumulation and subsequent oxidation of LDL in the arterial wall are considered as key events in the development of atherosclerosis. We have investigated the possibility that LDL oxidation results in release of aldehydes that modify surrounding matrix proteins and that this may target immune responses against the plaque extracellular matrix and modulate the disease progression. Results. Using custom-made ELISAs we demonstrate that human plasma contains autoantibodies against aldehyde-modified fibronectin (FN) and to a lesser extent also other extracellular matrix proteins including collagen type I, type III, and tenascin-C. Immunohistochemistry and western blot analysis showed that aldehyde-modified FN is present in human atherosclerotic plaques and that aldehydes generated by oxidation of LDL formed adducts with FN in vitro. We also demonstrate that aldehyde-modification of FN results in a loss of its ability to promote basal secretion of cytokines and growth factors from cultured macrophages without affecting the ability of the cells to respond to stimulation with LPS. A prospective clinical study demonstrated that subjects that subsequently developed acute myocardial infarction or sudden cardiac death had lower baseline levels of autoantibodies against aldehyde-modified FN than matched controls. Conclusions. These observations demonstrate that oxidation of LDL in the arterial wall may lead to aldehyde-modification of surrounding extracellular matrix proteins and that these modifications may affect macrophage function and activate autoimmune responses of pathophysiological importance for the development of atherosclerosis.
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12.
  • Dunér, Pontus (författare)
  • Immune Responses Aginst Aldehyde Modified Extracellular Matrix in Atherosclerosis
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Atherosclerosis is a chronic inflammatory disease and the leading cause of myocardial infarction and stroke. Accumulation, aggregation and subsequent oxidation of LDL in the arterial wall are considered as key events in the development of atherosclerosis. The oxidation of LDL generates reactive aldehydes, including malondialdehyde (MDA) that modifies ApoB in LDL. Immune responses against MDA-modified epitopes on ApoB have been shown to be linked to atherosclerotic disease. This thesis is focused on the possibility that LDL oxidation result in the release of MDA that modified surrounding extracellular matrix (ECM) proteins. These modifications may subsequently target immune responses against the plaque ECM and influence the atherosclerotic process. Our studies provide evidence for the presence of MDA-modifications on ECM proteins during atherosclerosis. We also show that antibodies against several MDA-modified ECM proteins are present in human plasma. A prospective clinical study showed that subjects that later suffered from acute cardiovascular events had significantly lower IgG and IgM antibody levels against MDA-modified fibronectin. These epidemiological results indicate that immune responses against MDA-modified fibronectin may have protective effects in atherosclerotic disease. To investigate the functional role of immune responses against modified matrix proteins in atherosclerosis, we immunized Apoe-/- mice with two different MDA-modified matrix proteins to which we had found antibodies in human plasma. MDA-modified fibronectin immunization significantly decreased the atherosclerotic plaque development in both aorta and in subvalvular lesions, while MDA-modified laminin resulted in increased plaque development. Finally we show that injection of Alum, an adjuvant commonly used in vaccines, results in LDL oxidation and aldehyde generation at the injection site.
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13.
  • Dunér, Pontus, et al. (författare)
  • Immunization of apoE-/- mice with aldehyde-modified fibronectin inhibits the development of atherosclerosis.
  • 2011
  • Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 91, s. 528-536
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims. Oxidation of LDL in the extracellular matrix of the arterial wall results in formation of malondialdehyde (MDA) that modifies surrounding matrix proteins. This is associated with activation of an immune response against modified extracellular matrix proteins present in atherosclerotic plaques. Clinical studies have revealed an inverse association between antibodies to MDA-modified fibronectin and risk for development of cardiovascular events. To determine the functional role of these immune responses in atherosclerosis we performed studies in which apoE-deficient mice were immunized with MDA-modified fibronectin. Methods and Results. Immunization of apoE-deficient mice with MDA-modified fibronectin resulted in a 70% decrease in plaque area and a less inflammatory phenotype of remaining plaques. Immunization shifted a weak naturally occurring Th1 antibody response against MDA-fibronectin into a Th2 antibody response. Cytokine expression and flow cytometry analyses of spleen cells from immunized mice showed an activation of regulatory T cells. Immunization with MDA-fibronectin was also found to reduce plasma fibronectin levels. Conclusions. Immunization with MDA-fibronectin significantly reduces the development of atherosclerosis in apoE-deficient mice suggesting that the immune response observed in humans may have a protective effect. MDA-fibronectin represents a possible novel target for immunomodulatory therapy in atherosclerosis.
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14.
  • Dunér, Pontus, et al. (författare)
  • Increased aldehyde-modification of collagen type IV in symptomatic plaques - A possible cause of endothelial dysfunction.
  • 2015
  • Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 240:1, s. 26-32
  • Tidskriftsartikel (refereegranskat)abstract
    • Subendothelial LDL-adhesion and its subsequent oxidation are considered as key events in the development of atherosclerotic lesions. During oxidation of LDL, reactive aldehydes such as malondialdehyde (MDA) are formed, which modify apolipoprotein B100. However, the possibility that these reactive aldehydes could leak out of the LDL-particle and modify surrounding extracellular matrix proteins has been largely unexplored. We have investigated if aldehyde-modification of collagen type IV, one of the major basement membrane components, in plaques is associated with cardiovascular events.
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15.
  • Edsfeldt, Andreas, et al. (författare)
  • High Plasma Levels of Galectin-3 Are Associated with Increased Risk for Stroke after Carotid Endarterectomy.
  • 2016
  • Ingår i: Cerebrovascular Diseases. - : S. Karger AG. - 1421-9786 .- 1015-9770. ; 41:3-4, s. 199-203
  • Tidskriftsartikel (refereegranskat)abstract
    • Galectin-3 (Gal-3) has been suggested to have both pro- and anti-atherogenic properties. High plasma Gal-3 levels are associated with increased risk for cardiovascular (CV) death. However, it has so far not been investigated if plasma Gal-3 levels can predict the risk for future stroke in patients suffering from carotid atherosclerosis. The aim of this study was to investigate whether Gal-3 could be used as a marker to predict postoperative cerebrovascular ischemic events among patients who underwent carotid endarterectomy (CEA).
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16.
  • Edsfeldt, Andreas, et al. (författare)
  • Impaired Fibrous Repair: A Possible Contributor to Atherosclerotic Plaque Vulnerability in Patients With Type II Diabetes.
  • 2014
  • Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 34:9, s. 2143-2150
  • Tidskriftsartikel (refereegranskat)abstract
    • Diabetes mellitus (DM) type II is increasing rapidly worldwide. Patients with DM II have a greater atherosclerotic burden and higher risk of developing cardiovascular complications. Inflammation has been proposed as the main cause for the high risk of atherosclerotic disease in DM II. In this study, we compared markers of inflammation and fibrous repair in plaques from subjects with and without DM II.
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17.
  • Edsfeldt, Andreas, et al. (författare)
  • Proinflammatory Role of Sphingolipids and Glycosphingolipids in the Human Atherosclerotic Plaque
  • 2016
  • Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 36:6, s. 1132-1140
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Lipids are central to the development of atherosclerotic plaques. Specifically, which lipids are culprits remains controversial, and promising targets have failed in clinical studies. Sphingolipids are bioactive lipids present in atherosclerotic plaques, and they have been suggested to have both proatherogenic and antiatherogenic. However, the biological effects of these lipids remain unknown in the human atherosclerotic plaque. The aim of this study was to assess plaque levels of sphingolipids and investigate their potential association with and contribution to plaque vulnerability.APPROACH AND RESULTS: Glucosylceramide, lactosylceramide, ceramide, dihydroceramide, sphingomyelin, and sphingosine-1-phosphate were analyzed in homogenates from 200 human carotid plaques using mass spectrometry. Inflammatory activity was determined by analyzing plaque levels of cytokines and plaque histology. Caspase-3 was analyzed by ELISA technique. Expression of regulatory enzymes was analyzed with RNA sequencing. Human coronary artery smooth muscle cells were used to analyze the potential role of the 6 sphingolipids as inducers of plaque inflammation and cellular apoptosis in vitro. All sphingolipids were increased in plaques associated with symptoms and correlated with inflammatory cytokines. All sphingolipids, except sphingosine-1-phosphate, also correlated with histological markers of plaque instability. Lactosylceramide, ceramide, sphingomyelin, and sphingosine-1-phosphate correlated with caspase-3 activity. In vitro experiments revealed that glucosylceramide, lactosylceramide, and ceramide induced cellular apoptosis. All analyzed sphingolipids induced an inflammatory response in human coronary artery smooth muscle cells.CONCLUSIONS: This study shows for the first time that sphingolipids and particularly glucosylceramide are associated with and are possible inducers of plaque inflammation and instability, pointing to sphingolipid metabolic pathways as possible novel therapeutic targets.
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18.
  • Edsfeldt, Andreas, et al. (författare)
  • Transforming growth factor-β2 is associated with atherosclerotic plaque stability and lower risk for cardiovascular events
  • 2023
  • Ingår i: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 119:11, s. 2061-2073
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: Transforming growth factor-beta (TGF-β) exists in three isoforms TGF-β1, -β2, and -β3. TGF-β1 has been suggested to be important for maintaining plaque stability, yet the role of TGF-β2 and -β3 in atherosclerosis remains to be investigated. This study explores the association of the three isoforms of TGF-β with plaque stability in the human atherosclerotic disease. Methods and results: TGF-β1, -β2, and -β3 proteins were quantified in 223 human carotid plaques by immunoassays. Indications for the endarterectomy were: symptomatic carotid plaque with stenosis >70% or without symptoms and >80% stenosis. Plaque mRNA levels were assessed by RNA sequencing. Plaque components and extracellular matrix were measured histologically and biochemically. Matrix metalloproteinases and monocyte chemoattractant protein-1 (MCP-1) was measured with immunoassays. The effect of TGF-β2 on inflammation and protease activity was investigated in vitro using THP-1 and RAW264.7 macrophages. Patients were followed longitudinally for cardiovascular (CV) events. TGF-β2 was the most abundant isoform and was increased at both protein and mRNA levels in asymptomatic plaques. TGF-β2 was the main determinant separating asymptomatic plaques in an Orthogonal Projections to Latent Structures Discriminant Analysis. TGF-β2 correlated positively to features of plaque stability and inversely to markers of plaque vulnerability. TGF-β2 was the only isoform inversely correlated to the matrix-degrading matrix metalloproteinase-9 and inflammation in the plaque tissue. In vitro, TGF-β2 pre-treatment reduced MCP-1 gene and protein levels as well as matrix metalloproteinase-9 gene levels and activity. Patients with plaques with high TGF-β2 levels had a lower risk to suffer from future CV events. Conclusions: TGF-β2 is the most abundant TGF-β isoform in human plaques and may maintain plaque stability by decreasing inflammation and matrix degradation.
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19.
  • Engelbertsen, Daniel, et al. (författare)
  • Increased Inflammation in Atherosclerotic Lesions of Diabetic Akita-LDLr(-/-) Mice Compared to Nondiabetic LDLr(-/-) Mice.
  • 2012
  • Ingår i: Experimental Diabetes Research. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2012:Nov.,28
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. Diabetes is associated with increased cardiovascular disease, but the underlying cellular and molecular mechanisms are poorly understood. One proposed mechanism is that diabetes aggravates atherosclerosis by enhancing plaque inflammation. The Akita mouse has recently been adopted as a relevant model for microvascular complications of diabetes. Here we investigate the development of atherosclerosis and inflammation in vessels of Akita mice on LDLr(-/-) background. Methods and Results. Akita-LDLr(-/-) and LDLr(-/-) mice were fed high-fat diet from 6 to 24 weeks of age. Blood glucose levels were higher in both male and female Akita-LDLr(-/-) mice (137% and 70%, resp.). Male Akita-LDLr(-/-) mice had markedly increased plasma cholesterol and triglyceride levels, a three-fold increase in atherosclerosis, and enhanced accumulation of macrophages and T-cells in plaques. In contrast, female Akita-LDLr(-/-) mice demonstrated a modest 29% increase in plasma cholesterol and no significant increase in triglycerides, atherosclerosis, or inflammatory cells in lesions. Male Akita-LDLr(-/-) mice had increased levels of plasma IL-1β compared to nondiabetic mice, whereas no such difference was seen between female diabetic and nondiabetic mice. Conclusion. Akita-LDLr(-/-) mice display considerable gender differences in the development of diabetic atherosclerosis. In addition, the increased atherosclerosis in male Akita-LDLr(-/-) mice is associated with an increase in inflammatory cells in lesions.
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20.
  • Goncalves, Isabel, et al. (författare)
  • Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes.
  • 2015
  • Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 35:7, s. 1723-1731
  • Tidskriftsartikel (refereegranskat)abstract
    • Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus.
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21.
  • Goncalves, Isabel, et al. (författare)
  • High levels of cathepsin D and cystatin B are associated with increased risk of coronary events.
  • 2016
  • Ingår i: Open Heart. - : BMJ. - 2053-3624. ; 3:1, s. 000353-000353
  • Tidskriftsartikel (refereegranskat)abstract
    • The majority of acute coronary syndromes are caused by plaque ruptures. Proteases secreted by macrophages play an important role in plaque ruptures by degrading extracellular matrix proteins in the fibrous cap. Matrix metalloproteinases have been shown to be markers for cardiovascular disease whereas the members of the cathepsin protease family are less studied.
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22.
  • Herum, Kate M., et al. (författare)
  • Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin
  • 2020
  • Ingår i: Journal of the American Heart Association. - 2047-9980. ; 9:3, s. 013518-013518
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Pressure overload of the heart occurs in patients with hypertension or valvular stenosis and induces cardiac fibrosis because of excessive production of extracellular matrix by activated cardiac fibroblasts. This initially provides essential mechanical support to the heart, but eventually compromises function. Osteopontin is associated with fibrosis; however, the underlying signaling mechanisms are not well understood. Herein, we examine the effect of thrombin-cleaved osteopontin on fibrosis in the heart and explore the role of syndecan-4 in regulating cleavage of osteopontin. Methods and Results: Osteopontin was upregulated and cleaved by thrombin in the pressure-overloaded heart of mice subjected to aortic banding. Cleaved osteopontin was higher in plasma from patients with aortic stenosis receiving crystalloid compared with blood cardioplegia, likely because of less heparin-induced inhibition of thrombin. Cleaved osteopontin and the specific osteopontin peptide sequence RGDSLAYGLR that is exposed after thrombin cleavage both induced collagen production in cardiac fibroblasts. Like osteopontin, the heparan sulfate proteoglycan syndecan-4 was upregulated after aortic banding. Consistent with a heparan sulfate binding domain in the osteopontin cleavage site, syndecan-4 was found to bind to osteopontin in left ventricles and cardiac fibroblasts and protected osteopontin from cleavage by thrombin. Shedding of the extracellular part of syndecan-4 was more prominent at later remodeling phases, at which time levels of cleaved osteopontin were increased. Conclusions: Thrombin-cleaved osteopontin induces collagen production by cardiac fibroblasts. Syndecan-4 protects osteopontin from cleavage by thrombin, but this protection is lost when syndecan-4 is shed in later phases of remodeling, contributing to progression of cardiac fibrosis.
  •  
23.
  • Hsiung, Sabrina, et al. (författare)
  • Hyperglycemia does not affect tissue repair responses in shear stress-induced atherosclerotic plaques in ApoE-/-mice
  • 2018
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The mechanisms responsible for macrovascular complications in diabetes remain to be fully understood. Recent studies have identified impaired vascular repair as a possible cause of plaque vulnerability in diabetes. This notion is supported by observations of a reduced content of fibrous proteins and smooth muscle cell mitogens in carotid endarterectomy from diabetic patients along with findings of decreased circulating levels of endothelial progenitor cells. In the present study we used a diabetic mouse model to characterize how hyperglycemia affects arterial repair responses. We induced atherosclerotic plaque formation in ApoE-deficient (ApoE-/-) and heterozygous glucokinase knockout ApoE-deficient mice (ApoE-/-GK+/-) mice with a shear stress-modifying cast. There were no differences in cholesterol or triglyceride levels between the ApoE-/-A nd ApoE-/-GK+/-mice. Hyperglycemia did not affect the size of the formed atherosclerotic plaques, and no effects were seen on activation of cell proliferation, smooth muscle cell content or on the expression and localization of collagen, elastin and several other extracellular matrix proteins. The present study demonstrates that hyperglycemia per se has no significant effects on tissue repair processes in injured mouse carotid arteries, suggesting that other mechanisms are involved in diabetic plaque vulnerability.
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24.
  • Hultman, Karin, et al. (författare)
  • Cartilage Oligomeric Matrix Protein Associates With a Vulnerable Plaque Phenotype in Human Atherosclerotic Plaques
  • 2019
  • Ingår i: Stroke. - 1524-4628. ; 50:11, s. 3289-3292
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose- Extracellular matrix proteins are important in atherosclerotic disease by influencing plaque stability and cellular behavior but also by regulating inflammation. COMP (cartilage oligomeric matrix protein) is present in healthy human arteries and expressed by smooth muscle cells. A recent study showed that transplantation of COMP-deficient bone marrow to apoE-/- mice increased atherosclerotic plaque formation, indicating a role for COMP also in bone marrow-derived cells. Despite the evidence of a role for COMP in murine atherosclerosis, knowledge is lacking about the role of COMP in human atherosclerotic disease. Methods- In the present study, we investigated if COMP was associated with a stable or a vulnerable human atherosclerotic plaque phenotype by analyzing 211 carotid plaques for COMP expression using immunohistochemistry. Results- Plaque area that stained positive for COMP was significantly larger in atherosclerotic plaques associated with symptoms (n=110) compared with asymptomatic plaques (n=101; 9.7% [4.7-14.3] versus 5.6% [2.8-9.8]; P=0.0002). COMP was positively associated with plaque lipids (r=0.32; P=0.000002) and CD68 cells (r=0.15; P=0.036) but was negatively associated with collagen (r=-0.16; P=0.024), elastin (r=-0.14; P=0.041), and smooth muscle cells (r=-0.25; P=0.0002). COMP was positively associated with CD163 (r=0.37; P=0.00000006), a scavenger receptor for hemoglobin/haptoglobin and a marker of Mhem macrophages, and with intraplaque hemorrhage, measured as glycophorin A staining (r=0.28; P=0.00006). Conclusions- The present study shows that COMP is associated to symptomatic carotid atherosclerosis, CD163-expressing cells, and a vulnerable atherosclerotic plaque phenotype in humans.
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25.
  • Knutsson, Anki, et al. (författare)
  • Associations of Interleukin-5 With Plaque Development and Cardiovascular Events
  • 2019
  • Ingår i: JACC: Basic to Translational Science. - : Elsevier BV. - 2452-302X. ; 4:8, s. 891-902
  • Tidskriftsartikel (refereegranskat)abstract
    • Experimental studies have suggested an atheroprotective role of interleukin (IL)-5 through the stimulation of natural immunoglobulin M antibody expression. In the present study we show that there are no associations between baseline levels of IL-5 and risk for development of coronary events or stroke during a 15.7 ± 6.3 years follow-up of 696 subjects randomly sampled from the Malmö Diet and Cancer study. However, presence of a plaque at the carotid bifurcation was associated with lower IL-5 and IL-5 deficiency resulted in increased plaque development at sites of oscillatory blood flow in Apoe−/− mice suggesting a protective role for IL-5 in plaque development.
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26.
  • Lyssenko, Valeriya, et al. (författare)
  • Pleiotropic Effects of GIP on Islet Function Involve Osteopontin
  • 2011
  • Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 60:9, s. 2424-2433
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE-The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic beta-cell function by potentiating insulin secretion and beta-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS-Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies.Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of beta-cell viability and proliferation. RESULTS-The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. CONCLUSIONS-These findings support beta-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional beta-cell mass in humans. Diabetes 60:2424-2433, 2011
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27.
  • Mantani, Polyxeni, et al. (författare)
  • IL-25 Inhibits Atherosclerosis Development in Apolipoprotein E Deficient Mice
  • 2015
  • Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective IL-25 has been implicated in the initiation of type 2 immunity and in the protection against autoimmune inflammatory diseases. Recent studies have identified the novel innate lymphoid type 2 cells (ILC2s) as an IL-25 target cell population. The purpose of this study was to evaluate if IL-25 has any influence on atherosclerosis development in mice. Methods and Results Administration of 1 mu g IL-25 per day for one week to atherosclerosis-prone apolipoprotein (apo) E deficient mice, had limited effect on the frequency of T cell populations, but resulted in a large expansion of ILC2s in the spleen. The expansion was accompanied by increased levels of anti-phosphorylcholine (PC) natural IgM antibodies in plasma and elevated levels of IL-5 in plasma and spleen. Transfer of ILC2s to apoE deficient mice elevated the natural antibody-producing B1a cell population in the spleen. Treatment of apoE/Rag-1 deficient mice with IL-25 was also associated with extensive expansion of splenic ILC2s and increased plasma IL-5, suggesting ILC2s to be the source of IL-5. Administration of IL-25 in IL-5 deficient mice resulted in an expanded ILC2 population, but did not stimulate generation of anti-PC IgM, indicating that IL-5 is not required for ILC2 expansion but for the downstream production of natural antibodies. Additionally, administration of 1 mu g IL-25 per day for 4 weeks in apoE deficient mice reduced atherosclerosis in the aorta both during initiation and progression of the disease. Conclusions The present findings demonstrate that IL-25 has a protective role in atherosclerosis mediated by innate responses, including ILC2 expansion, increased IL-5 secretion, B1a expansion and natural anti-PC IgM generation, rather than adaptive Th2 responses.
  •  
28.
  • Mantani, Polyxeni T, et al. (författare)
  • ILC2 transfers to apolipoprotein E deficient mice reduce the lipid content of atherosclerotic lesions
  • 2019
  • Ingår i: BMC Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 20
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Expansion of type 2 innate lymphoid cells (ILC2s) in hypercholesterolaemic mice protects against atherosclerosis while different ILC2 subsets have been described (natural, inflammatory) based on their suppression of tumorigenicity 2 (ST2) and killer-cell lectin like receptor G1 (KLRG1) expression. The aim of the current study is to characterize the interleukin 25 (IL25)-induced splenic ILC2 population (Lin-CD45+IL17RB+ICOS+IL7raintermediate) and address its direct role in experimental atherosclerosis by its adoptive transfer to hypercholesterolaemic apolipoprotein E deficient (apoE-/-) mice.RESULTS: Immunomagnetically enriched, FACS-sorted ILC2s from the spleens of IL-25 treated apoE-/- mice were stained for KLRG1 and ST2 directly upon cell obtainment or in vitro cell expansion for flow cytometric analysis. IL25-induced splenic ILC2s express high levels of both KLRG1 and ST2. However, both markers are downregulated upon in vitro cell expansion. In vitro expanded splenic ILC2s were intraperitoneally transferred to apoE-/- recipients on high fat diet. ApoE-/- mice that received in vitro expanded splenic ILC2s had decreased lipid content in subvalvular heart and brachiocephalic artery (BCA) plaques accompanied by increased peritoneal B1 cells, activated eosinophils and alternatively activated macrophages (AAMs) as well as anti-phosphorylcholine (PC) immunoglobulin (Ig) M in plasma.CONCLUSIONS: With the current data we designate the IL25-induced ILC2 population to decrease the lipid content of atherosclerotic lesions in apoE-/- mice and we directly link the induction of B1 cells and the atheroprotective anti-PC IgM antibodies with ILC2s.
  •  
29.
  • Mantani, Polyxeni T., et al. (författare)
  • Interleukin-25 (IL-25) has a protective role in atherosclerosis development in the aortic arch in mice
  • 2018
  • Ingår i: Journal of Biological Chemistry. - 0021-9258. ; 293:18, s. 6791-6801
  • Tidskriftsartikel (refereegranskat)abstract
    • Atherosclerosis is a chronic inflammatory disease characterized by the entrapment of apolipoprotein B– containing lipoproteins in the arterial intima, leading to local inflammation. T helper (Th) cell 1–mediated immune responses have been associated with atherosclerosis, and the cytokine interleukin-25 (IL-25 or IL-17E) has been reported to potentially regulate Th1 cell– and Th17 cell–related immune responses. In this study, we evaluated the effects of complete IL-25 deficiency or of a temporal IL-25 blockade on atherosclerosis development in apolipoprotein E– deficient (Apoe/) mice. Mice deficient in both apolipoprotein E and IL-25 (Apoe//IL-25/) had more Th1 cells in the spleen, along with elevated plasma levels of IL-17 and an increased release of splenic interferon- (INF-). In support of this observation, a 4-week-long treatment of young Apoe/ mice (at 10 –14 weeks of age) with an IL-25– blocking antibody increased the release of Th1/Th17-associated cytokines in the spleen. In both mouse models, these findings were associated with increased atherosclerotic plaque formation in the aortic arch. We conclude that complete IL-25 deficiency and a temporal IL-25 blockade during early plaque development aggravate atherosclerosis development in the aortic arch of Apoe/ mice, accompanied by an increase in Th1/Th17-mediated immune responses. Our finding that endogenous IL-25 has an atheroprotective role in the murine aortic arch has potential implications for atherosclerosis development and management in humans.
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30.
  • Mohammad Al-Amily, Israa, et al. (författare)
  • Ablation of GPR56 Causes β-Cell Dysfunction by ATP Loss through Mistargeting of Mitochondrial VDAC1 to the Plasma Membrane
  • 2023
  • Ingår i: Biomolecules. - : MDPI AG. - 2218-273X. ; 13:3
  • Tidskriftsartikel (refereegranskat)abstract
    • The activation of G Protein-Coupled Receptor 56 (GPR56), also referred to as Adhesion G-Protein-Coupled Ceceptor G1 (ADGRG1), by Collagen Type III (Coll III) prompts cell growth, proliferation, and survival, among other attributes. We investigated the signaling cascades mediating this functional effect in relation to the mitochondrial outer membrane voltage-dependent anion Channel-1 (VDAC1) expression in pancreatic β-cells. GPR56KD attenuated the Coll III-induced suppression of P70S6K, JNK, AKT, NFκB, STAT3, and STAT5 phosphorylation/activity in INS-1 cells cultured at 20 mM glucose (glucotoxicity) for 72 h. GPR56-KD also increased Chrebp, Txnip, and Vdac1 while decreasing Vdac2 mRNA expression. In GPR56-KD islet β-cells, Vdac1 was co-localized with SNAP-25, demonstrating its plasma membrane translocation. This resulted in ATP loss, reduced cAMP production and impaired glucose-stimulated insulin secretion (GSIS) in INS-1 and human EndoC βH1 cells. The latter defects were reversed by an acute inhibition of VDAC1 with an antibody or the VDAC1 inhibitor VBIT-4. We demonstrate that Coll III potentiates GSIS by increasing cAMP and preserving β-cell functionality under glucotoxic conditions in a GPR56-dependent manner by attenuating the inflammatory response. These results emphasize GPR56 and VDAC1 as drug targets in conditions with impaired β-cell function.
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31.
  • Murugesan, Vignesh, et al. (författare)
  • β-Sarcoglycan Deficiency Reduces Atherosclerotic Plaque Development in ApoE-Null Mice
  • 2017
  • Ingår i: Journal of Vascular Research. - : S. Karger AG. - 1423-0135 .- 1018-1172. ; 54, s. 235-245
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Smooth muscle cells are important for atheroscleroticplaque stability. Their proper ability to communicatewith the extracellular matrix is crucial for maintainingthe correct tissue integrity. In this study, we have investigatedthe role of β-sarcoglycan within the matrix-binding dystrophin-glycoproteincomplex in the development of atherosclerosis.Results: Atherosclerotic plaque developmentwas significantly reduced in ApoE-deficient mice lackingβ-sarcoglycan, and their plaques contained an increase indifferentiated smooth muscle cells. ApoE-deficient micelacking β-sarcoglycan showed a reduction in ovarian adiposetissue and adipocyte size, while the total weight of theanimals was not significantly different. Western blot analysisof adipose tissues showed a decreased activation of proteinkinase B, while that of AMP-activated kinase was increasedin mice lacking β-sarcoglycan. Analysis of plasma in β-sarcoglycan-deficientmice revealed reduced levels of leptin,adiponectin, insulin, cholesterol, and triglycerides but in-creased levels of IL-6, IL-17, and TNF-α. Conclusions: Our resultsindicate that the dystrophin-glycoprotein complex andβ-sarcoglycan can affect the atherosclerotic process. Furthermore,the results show the effects of β-sarcoglycan deficiencyon adipose tissue and lipid metabolism, which mayalso have contributed to the atherosclerotic plaque reduction.
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32.
  • Nyström, Tobias, et al. (författare)
  • A constitutive endogenous osteopontin production is important for macrophage function and differentiation.
  • 2007
  • Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 313:6, s. 1149-1160
  • Tidskriftsartikel (refereegranskat)abstract
    • Macrophages are involved in the pathological process underlying atherosclerosis and constitutively express the multifunctional protein osteopontin which has important exogenous effects on these cells. However, the effect of the endogenous osteopontin expression on macrophage function has been sparsely studied. To shed light on the importance of the endogenous osteopontin expression, RAW 264.7 macrophage-like cells were silenced in osteopontin expression using RNAi. The cells were analysed for basic functions including attachment, migration, apoptosis and for the expression of macrophage differentiation markers and cytokines. The macrophages with silenced osteopontin expression showed impaired migration and an increased rate of serum starvation-induced apoptosis as compared to osteopontin-producing control cells. Furthermore, the cells with silence osteopontin expression had an altered phenotype with monocyte-like characteristics, including decreased expression of macrophage scavenger receptor A type 1. The altered phenotype of these cells could not be reversed by presence of extracellular osteopontin. In addition the cells with silenced osteopontin expression had a lower expression of IL-12 mRNA and the anti-apoptotic Flip mRNA. We conclude that a constitutive endogenous osteopontin production is important for proper basic functions of macrophages and our study indicates that the constitutive osteopontin production is involved in maintaining macrophages in a differentiated phenotype.
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33.
  • Parandeh, Fariborz, et al. (författare)
  • Inhibitory effect of UDP-glucose on cAMP generation and insulin secretion
  • 2020
  • Ingår i: The Journal of biological chemistry. - 1083-351X. ; 295:45, s. 15245-15252
  • Tidskriftsartikel (refereegranskat)abstract
    • Type-2 diabetes (T2D) is a global disease caused by the inability of pancreatic β-cells to secrete adequate insulin. However, the molecular mechanisms underlying the failure of β-cells to respond to glucose in T2D remains unknown. Here, we investigated the relative contribution of UDP-glucose (UDP-G), a P2Y14-specific agonist, in the regulation of insulin release using human isolated pancreatic islets and INS-1 cells. P2Y14 was expressed in both human and rodent pancreatic β-cells. Dose-dependent activation of P2Y14 by UDP-G suppressed glucose-stimulated insulin secretion (GSIS) and knockdown of P2Y14 abolished the UDP-G effect. 12-h pretreatment of human islets with pertussis-toxin (PTX) improved GSIS and prevented the inhibitory effect of UDP-G on GSIS. UDP-G on GSIS suppression was associated with suppression of cAMP in INS-1 cells. UDP-G decreased the reductive capacity of nondiabetic human islets cultured at 5 mm glucose for 72 h and exacerbated the negative effect of 20 mm glucose on the cell viability during culture period. T2D donor islets displayed a lower reductive capacity when cultured at 5 mm glucose for 72 h that was further decreased in the presence of 20 mm glucose and UDP-G. Presence of a nonmetabolizable cAMP analog during culture period counteracted the effect of glucose and UDP-G. Islet cultures at 20 mm glucose increased apoptosis, which was further amplified when UDP-G was present. UDP-G modulated glucose-induced proliferation of INS-1 cells. The data provide intriguing evidence for P2Y14 and UDP-G's role in the regulation of pancreatic β-cell function.
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34.
  • Rattik, Sara, et al. (författare)
  • High Plasma Levels of Heparin-Binding Epidermal Growth Factor Are Associated With a More Stable Plaque Phenotype and Reduced Incidence of Coronary Events
  • 2015
  • Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 35:1, s. 222-228
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective-Rupture of atherosclerotic plaques is the major cause of acute coronary events (CEs). Plaque destabilization is the consequence of an imbalance between inflammatory-driven degradation of fibrous tissue and smooth muscle cell-dependent tissue repair. Proinflammatory factors have been documented extensively as biomarkers of cardiovascular risk but factors that contribute to stabilization of atherosclerotic plaques have received less attention. The present study aimed to investigate whether plasma levels of the smooth muscle cell growth factor epidermal growth factor (EGF), heparin-binding-EGF (HB-EGF), and platelet-derived growth factor correlate with plaque phenotype and incidence of CEs. Approach and Results-HB-EGF, EGF and platelet-derived growth factor were measured in plasma from 202 patients undergoing carotid endarterectomy and in 384 incident CE cases and 409 matched controls recruited from the Malmo Diet and Cancer cohort. Significant positive associations were found between the plasma levels of all 3 growth factors and the collagen and elastin contents of the removed plaques. CE cases in the Malmo Diet and Cancer cohort had lower levels of HB-EGF in plasma, whereas no significant differences were found for EGF and platelet-derived growth factor. After adjusting for cardiovascular risk factors in a Cox proportional hazard model, the hazard ratio for the highest HB-EGF tertile was 0.61 (95% confidence interval, 0.47-0.82; P<0.001). Conclusions-The associations between high levels of smooth muscle cell growth factors in plasma and a more fibrous plaque phenotype as well as the association between low levels of HB-EGF and incident CEs point to a potential clinically important role for factors that contribute to plaque stabilization by stimulating smooth muscle cells.
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35.
  • Rohwedder, Ina, et al. (författare)
  • Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation
  • 2012
  • Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 4:7, s. 564-576
  • Tidskriftsartikel (refereegranskat)abstract
    • Atherosclerotic lesions are asymmetric focal thickenings of the intima of arteries that consist of lipids, various cell types and extracellular matrix (ECM). These lesions lead to vascular occlusion representing the most common cause of death in the Western world. The main cause of vascular occlusion is rupture of atheromatous lesions followed by thrombus formation. Fibronectin (FN) is one of the earliest ECM proteins deposited at atherosclerosis-prone sites and was suggested to promote atherosclerotic lesion formation. Here, we report that atherosclerosis-prone apolipoprotein E-null mice lacking hepatocyte-derived plasma FN (pFN) fed with a pro-atherogenic diet display dramatically reduced FN depositions at atherosclerosis-prone areas, which results in significantly smaller and fewer atherosclerotic plaques. However, the atherosclerotic lesions from pFN-deficient mice lacked vascular smooth muscle cells and failed to develop a fibrous cap. Thus, our results demonstrate that while FN worsens the course of atherosclerosis by increasing the atherogenic plaque area, it promotes the formation of the protective fibrous cap, which in humans prevents plaques rupture and vascular occlusion. See accompanying article http://dx.doi.org/10.1002/emmm.201200238
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36.
  • Shami, Annelie, et al. (författare)
  • Dystrophin deficiency reduces atherosclerotic plaque development in ApoE-null mice.
  • 2015
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
  • Tidskriftsartikel (refereegranskat)abstract
    • Dystrophin of the dystrophin-glycoprotein complex connects the actin cytoskeleton to basement membranes and loss of dystrophin results in Duchenne muscular dystrophy. We have previously shown injury-induced neointima formation of the carotid artery in mice with the mdx mutation (causing dystrophin deficiency) to be increased. To investigate the role of dystrophin in intimal recruitment of smooth muscle cells (SMCs) that maintains plaque stability in atherosclerosis we applied a shear stress-modifying cast around the carotid artery of apolipoprotein E (ApoE)-null mice with and without the mdx mutation. The cast induces formation of atherosclerotic plaques of inflammatory and SMC-rich/fibrous phenotypes in regions of low and oscillatory shear stress, respectively. Unexpectedly, presence of the mdx mutation markedly reduced the development of the inflammatory low shear stress plaques. Further characterization of the low shear stress plaques in ApoE-null mdx mice demonstrated reduced infiltration of CD3(+) T cells, less laminin and a higher SMC content. ApoE-null mdx mice were also found to have a reduced fraction of CD3(+) T cells in the spleen and lower levels of cytokines and monocytes in the circulation. The present study is the first to demonstrate a role for dystrophin in atherosclerosis and unexpectedly shows that this primarily involves immune cells.
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37.
  • Taneera, Jalal, et al. (författare)
  • Orphan G-protein coupled receptor 183 (GPR183) potentiates insulin secretion and prevents glucotoxicity-induced β-cell dysfunction
  • 2020
  • Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 499
  • Tidskriftsartikel (refereegranskat)abstract
    • The expression and functional impact of most expression orphan G-protein coupled receptors (GPCRs) in β-cell is not fully understood. Microarray expression indicated that 36 orphan GPCRs are restricted in human islets, while 55 receptors overlapped between human islets and INS-1 cells. GPR183 showed higher expression in diabetic compared to non-diabetic human islets. GPR183 expression co-localized with β-cells while it was lacking in α-cells in human islets. The GPR183 agonist (7α-25-DHC) potentiated insulin secretion and protected against glucotoxicity-induced β-cell damage in human islets. Silencing of GPR183 in INS-1 cells decreased the expression of proinsulin genes, Pdx1, Mafa and impaired insulin secretion with a concomitant decrease in cAMP generation. Cultured INS-1 cells with 7α-25-DHC were associated with increased proliferation and expression of GPR183, INS2, PDX1, NeuroD, and INSR. In conclusion, the beneficial impact of GPR183 activation on β-cell function makes it a potential therapeutic target to prevent or reverse β-cell dysfunction.
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38.
  • Tengryd, Christoffer, et al. (författare)
  • The proteoglycan mimecan is associated with carotid plaque vulnerability and increased risk of future cardiovascular death
  • 2020
  • Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150. ; 313, s. 88-95
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and aims: A vulnerable plaque is an atherosclerotic plaque that is rupture-prone with a higher risk to cause cardiovascular symptoms such as myocardial infarction or stroke. Mimecan or osteoglycin is a small leucine-rich proteoglycan, important for collagen fibrillogenesis, that has been implicated in atherosclerotic disease, yet the role of mimecan in human atherosclerotic disease remains unknown. Methods: 196 human atherosclerotic carotid plaques were immunostained for mimecan. Smooth muscle cells, macrophages and intraplaque haemorrhage were also measured with immunohistochemistry. Neutral lipids were stained with Oil Red O and calcium deposits were quantified. Plaque homogenate levels of MCP-1, IL-6 and MIP-1β were measured using a Proximity Extension Assay and MMP-9 levels were measured using Mesoscale. Glycosaminoglycans, collagen and elastin were assessed by colorimetric assays and TGF-β1, β2 and β3 were measured using a multiplex assay. Mimecan gene expression in THP-1 derived macrophages was quantified by qPCR and protein expression in vitro was visualized with immunofluorescence. Cardiovascular events were registered using medical charts and national registers during follow-up. Results: Mimecan correlated positively with plaque area of lipids, macrophages, intraplaque haemorrhage and inversely with smooth muscle cell staining. Mimecan also correlated positively with plaque levels of MMP-9 and MCP-1. Mimecan was upregulated in THP-1 derived macrophages upon stimulation with MCP-1. Patients with high levels of mimecan (above median) had higher risk for cardiovascular death. Conclusions: This study indicates that mimecan is associated with a vulnerable plaque phenotype, possibly regulated by plaque inflammation. In line, plaque levels of mimecan independently predict future cardiovascular death.
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39.
  • Wigren, Maria, et al. (författare)
  • Atheroprotective effects of Alum are associated with capture of oxidized LDL antigens and activation of regulatory T cells
  • 2009
  • Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 104:12, s. e62-70
  • Tidskriftsartikel (refereegranskat)abstract
    • The immune system represents a promising novel target for prevention of atherosclerosis. Several pilot vaccines that reduce atherosclerosis in experimental animals have been developed. The aluminum hydroxide adjuvant Alum has been shown to have antiatherogenic properties in itself, suggesting that it may be a suitable adjuvant in possible future atherosclerosis vaccines. To characterize the immune pathways mediating this protection, we treated wild-type C57BL/6 and Apoe(-)(/)(-) mice with Alum or PBS. Analyses of splenocytes isolated from 12-week-old mice demonstrated that Alum increased the presence of CD4(+)CD25(+)FoxP3(+) regulatory T cells and downregulated the expression of T cell activation markers CD28 and ICOS in Apoe(-)(/)(-) mice but not in C57BL/6 wild-type mice. A similar immunosuppressive phenotype was found also in 25-week-old Apoe(-)(/)(-) mice and was associated with reduced atherosclerosis. Alum precipitates recovered from the injection site of Apoe(-)(/)(-) mice contained antigens derived from oxidized LDL. These findings demonstrate that treatment of Apoe(-)(/)(-) mice with Alum results in an increase of regulatory T cells and suggest that these are activated by tolerogenic antigen-presenting cells presenting oxidized LDL antigens. Our findings provide improved mechanistic understanding of the atheroprotective properties of aluminum hydroxide adjuvants but also point to the importance of determining if hypercholesterolemia may compromise the efficacy of Alum-containing vaccines used clinically today.
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40.
  • Wigren, Maria, et al. (författare)
  • Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine.
  • 2011
  • Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 269, s. 546-556
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract. Wigren M, Kolbus D, Dunér P, Ljungcrantz I, Söderberg I, Björkbacka H, Fredrikson GN, Nilsson J. (Malmö University Hospital, Lund University; Malmö University, Malmo; Sweden) Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine. J Intern Med 2010; doi: 10.1111/j.13 65-2796.2010.02311.x. Objectives. Autoimmune responses against oxidized low-density lipoprotein are considered to play an important pro-inflammatory role in atherosclerosis and to promote disease progression. T-regulatory cells (Tregs) are immunosuppressive cells that have an important part in maintaining self-tolerance and protection against autoimmunity. We investigated whether aBp210, a prototype atherosclerosis vaccine based on a peptide sequence derived from apolipoprotein B, inhibits atherosclerosis through the activation of Tregs. Design. Six-week-old Apoe(-/-) mice were immunized with aBp210 and received booster immunizations 3 and 5 weeks later, as well as 1 week before being killed at 25 weeks of age. Results. At 12 weeks, immunized mice had increased expression of the Treg marker CD25 on circulating CD4 cells, and concanavalin A (Con A)-induced interferon-γ, interleukin (IL)-4, and IL-10 release from splenocytes was markedly depressed. At 25 weeks, there was a fivefold expansion of splenic CD4+ CD25+ Foxp3 Tregs, a 65% decrease in Con A-induced splenic T-cell proliferation and a 37% reduction in the development of atherosclerosis in immunized mice. Administration of blocking antibodies against CD25 neutralized aBp210-induced Treg activation as well as the reduction of atherosclerosis. Conclusions. The present findings demonstrate that immunization of Apoe(-/-) mice with the apolipoprotein B peptide vaccine aBp210 is associated with activation of Tregs. Administration of antibodies against CD25 results in depletion of Tregs and blocking of the atheroprotective effect of the vaccine. Modulation in atherosclerosis-related autoimmunity by antigen-specific activation of Tregs represents a novel approach for treatment of atherosclerosis.
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41.
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42.
  • Zetterqvist, Anna, et al. (författare)
  • Inhibition of nuclear factor of activated T-cells (NFAT) suppresses accelerated atherosclerosis in diabetic mice.
  • 2013
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis.
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43.
  • Zhao, Ming, et al. (författare)
  • Fc{gamma}RIIB Inhibits the Development of Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice.
  • 2010
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 184:5, s. 2253-2260
  • Tidskriftsartikel (refereegranskat)abstract
    • The immune processes associated with atherogenesis have received considerable attention during recent years. IgG FcRs (FcgammaR) are involved in activating the immune system and in maintaining peripheral tolerance. However, the role of the inhibitory IgG receptor FcgammaRIIB in atherosclerosis has not been defined. Bone marrow cells from FcgammaRIIB-deficient mice and C57BL/6 control mice were transplanted to low-density lipoprotein receptor-deficient mice. Atherosclerosis was induced by feeding the recipient mice a high-fat diet for 8 wk and evaluated using Oil Red O staining of the descending aorta at sacrifice. The molecular mechanisms triggering atherosclerosis was studied by examining splenic B and T cells, as well as Th1 and Th2 immune responses using flow cytometry and ELISA. The atherosclerotic lesion area in the descending aorta was approximately 5-fold larger in mice lacking FcgammaRIIB than in control mice (2.75 +/- 2.57 versus 0.44 +/- 0.42%; p < 0.01). Moreover, the FcgammaRIIB deficiency resulted in an amplified splenocyte proliferative response to Con A stimulation (proliferation index 30.26 +/- 8.81 versus 2.96 +/- 0.81%, p < 0.0001) and an enhanced expression of MHC class II on the B cells (6.65 +/- 0.64 versus 2.33 +/- 0.25%; p < 0.001). In accordance, an enlarged amount of CD25-positive CD4 T cells was found in the spleen (42.74 +/- 4.05 versus 2.45 +/- 0.31%; p < 0.0001). The plasma Ab and cytokine pattern suggested increased Th1 and Th2 immune responses, respectively. These results show that FcgammaRIIB inhibits the development of atherosclerosis in mice. In addition, they indicate that absence of the inhibiting IgG receptor cause disease, depending on an imbalance of activating and inhibiting immune cells.
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