title: Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form.
abstract: Accelerated atherosclerosis is the primary cardiovascular manifestation of diabetes and correlates inversely with levels of circulating adiponectin, an anti-atherosclerotic adipokine that declines in diabetes. We therefore initiated a study to examine the mechanisms by which adiponectin, a hormone released from adipose tissue, influences the proliferation of vascular smooth muscle cells (SMCs). Addition of adiponectin to quiescent porcine coronary artery SMCs increased both protein and DNA synthesis and concurrently activated ERK1/2 and Akt. By contrast, globular adiponectin, a truncated form of this protein, exhibited anti-mitogenic properties as indicated by the inhibition of protein and DNA synthesis in SMCs stimulated with platelet-derived growth factor (PDGF). Whereas globular adiponectin did not stimulate growth-related signal transduction pathways, it was able to block the PDGF-dependent phosphorylation of eukaryotic elongation factor 2 kinase, a regulator of protein synthesis. Proteolysis of adiponectin with trypsin, which produces globular adiponectin, reversed the growth-stimulating actions of the undigested protein. As the existence of globular adiponectin remains controversial, western blotting was used to establish its presence in rat serum. We found that globular adiponectin was detectable in rat serum, but this result was not obtained with all antibodies. The contrasting properties of adiponectin and its globular form with respect to SMC proliferation suggest that protection against atherosclerosis may therefore be mediated, in part, by the level of globular adiponectin.
authors.affiliation: Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2.
authors.forename: Melissa
authors.initials: M
authors.lastname: Fuerst
authors.forename: Carla G
authors.initials: CG
authors.lastname: Taylor
authors.forename: Brenda
authors.initials: B
authors.lastname: Wright
authors.forename: Leslee
authors.initials: L
authors.lastname: Tworek
authors.forename: Peter
authors.initials: P
authors.lastname: Zahradka
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D052242:Adiponectin / Q000097:blood / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013552:Swine
chemical_list: D052242:Adiponectin; D020033:Protein Isoforms; D000263:Adenylate Kinase