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Submitted on September 20, 2004
Accepted on January 7, 2005
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, Melbourne, VIC, Australia, 8008; Monash University, Department of Medicine (J.N., P.J.L.), The Alfred Hospital, Melbourne, VIC, Australia, 8008; Rm H3554, Stanford University Medical Center, 300 Pasteur Dr, Stanford, CA 94304-5637 (K.S.)
* To whom correspondence should be addressed. 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 effect 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 radiolabled proteoglycans was assessed by SDS-PAGE. Proteoglycan-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 synthesis 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 the pre-treatment 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 pro-atherogenic action of androgens through an elongation of GAG chains on proteoglycans in an androgen receptor dependent manner.
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