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Hormones and Vasculature (K.H., S.L., M.R.I.W., P.A.K., K.S.) and Cell Biology of Diabetes Laboratories (J.N., P.J.L.), Baker Heart Research Institute, and Department of Medicine, Monash University (J.N., P.J.L.), The Alfred Hospital, Melbourne, Victoria 8008, Australia; and Stanford University Medical Center (K.S.), Stanford, California 94304-5637
Address all correspondence and requests for reprints to: Dr. Peter J. Little, Cell Biology of Diabetes Laboratory, Baker Heart Research Institute, St. Kilda Road Central, P.O. Box 6492, Melbourne, Victoria 8008, Australia. E-mail: peter.little{at}baker.edu.au.
Vascular smooth muscle cell (VSMC) proliferation and proteoglycan biosynthesis are two critical contributors to the development of atherosclerosis. We investigated the effects of specific androgens, androstenedione, dihydrotestosterone, and testosterone, on proteoglycan biosynthesis in human VSMC derived from internal mammary arteries. Vascular SMCs were metabolically labeled with [35S]sulfate or [35S]methionine/cysteine to assess glycosaminoglycans (GAGs) or proteoglycan core protein, respectively. The electrophoretic migration of radiolabeled proteoglycans was assessed by SDS-PAGE. Proteoglycan-low density lipoprotein (LDL) interactions were assessed using LDL affinity columns. Treatment of VSMCs with androstenedione (100 nM), dihydrotestosterone (10 nM), or testosterone (100 nM) increased [35S]sulfate incorporation into GAGs by 24.8% (P < 0.05), 22% (P < 0.05), and 32.5% (P < 0.05), respectively. Treatment of VSMCs with testosterone did not alter [35S]methionine/cysteine incorporation into proteoglycan core protein, suggesting that the effect of testosterone was associated with an increase in GAG length. Dihydrotestosterone (10 nM) and testosterone (100 nM) treatment of VSMCs resulted in the synthesis of biglycan and decorin that showed reduced electrophoretic mobility by SDS-PAGE, indicating an increase in GAG length. The effect of testosterone treatment on [35S]sulfate incorporation and GAG length was reversed by pretreatment of VSMCs with flutamide (1 µM), an androgen receptor antagonist. Proteoglycans from VSMCs treated with testosterone showed 11% (P < 0.01) higher binding capacity to LDL compared with proteoglycans from untreated cells. These results suggest a possible proatherogenic action of androgens through an elongation of GAG chains on proteoglycans in an androgen receptor-dependent manner.
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