title: Adipokines enhance oleic acid-induced proliferation of vascular smooth muscle cells by inducing CD36 expression.
abstract: Adipose tissue is not only releasing lipids but also various adipokines that are both dysregulated in the obese state and may contribute to obesity-associated vascular dysfunction and cardiovascular risk. We have previously shown that the combination of adipocyte-conditioned medium (CM) and oleic acid (OA) increases proliferation of human vascular smooth muscle cells (VSMC) in a synergistic way. We identified vascular endothelial growth factor (VEGF) as a component within CM that is responsible for most of the observed effects. In this study, we investigate novel mechanisms that underlie the combined effects of adipokine and oleic acid-induced proliferation of VSMC. Oleic acid leads to significant lipid accumulation in VSMC that is further enhanced by the combined treatment with CM. Accordingly CM stimulates CD36 expression in VSMC while OA is not affecting CD36. Silencing of CD36 was established and prevents lipid accumulation in all tested conditions. CD36 silencing also abrogates CM- and OA-induced proliferation and considerably reduces proliferation induced by the combination of CM and OA. At the same time, VEGF secretion and VEGF-receptor 1 (VEGF-R1) by VSMC was not affected by CD36 silencing. However, VEGF was not able to induce any proliferation in VSMC after CD36 silencing that also blunted VEGF-induced extracellular signal-regulated kinase (ERK) activation. Finally, combined silencing of CD36 together with a blocking antibody against VEGF prevented most of CMOA-induced proliferation. In conclusion, our results demonstrate that CD36 is mediating CM-induced proliferation of VSMC. Induction of CD36 by adipokines enhances the response of VSMC towards VEGF and OA.
authors.affiliation: Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center , Düsseldorf , Germany.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Schlich
authors.forename: Daniela
authors.initials: D
authors.lastname: Lamers
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eckel
authors.forename: Henrike
authors.initials: H
authors.lastname: Sell
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D054392:Adipokines / Q000378:metabolism / Q000494:pharmacology*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000328:Adult; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D018955:CD36 Antigens / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology*; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D054392:Adipokines; D057134:Antibodies, Neutralizing; D018955:CD36 Antigens; D017077:Culture Media, Conditioned; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019301:Oleic Acid; D040281:Vascular Endothelial Growth Factor Receptor-1; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Adipokines; CD36; VEGF; oleic acid; proliferation; smooth muscle cells