Fibrillar Collagen Inhibits Cholesterol Biosynthesis in Human Aortic Smooth Muscle Cells

Objective-Integrin-mediated cell adhesion to type I fibrillar collagen regulates gene and protein expression, whereas little is known of its effect on lipid metabolism. In the present study, we examined the effect of type I fibrillar collagen on cholesterol biosynthesis in human aortic smooth muscle cells (SMCs). Methods and Results-SMCs were cultured on either fibrillar or monomer collagen for 48 hours and [(14)C]-acetate incorporation into cholesterol was evaluated. Fibrillar collagen reduced by 72.9 +/- 2.6% cholesterol biosynthesis without affecting cellular cholesterol levels. Fibrillar collagen also reduced 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) promoter activity (-72.6 +/- 7.3%), mRNA (-58.7 +/- 6.4%), protein levels (-35.5 +/- 8.5%), and enzyme activity (-37.7 +/- 2.2%). Intracellular levels of the active form of sterol regulatory element binding proteins (SREBP) 1a was decreased by 60.7 +/- 21.7% in SMCs cultured on fibrillar collagen, whereas SREBP2 was not significantly affected (+12.1 +/- 7.1%). The overexpression of the active form of SREBP1a rescued the downregulation of fibrillar collagen on HMG-CoA reductase levels. Blocking antibody to alpha 2 integrin partially reversed the downregulation of HMG-CoA reductase mRNA expression. Finally, fibrillar collagen led to an intracellular accumulation of unprenylated Ras. Conclusions-Our study demonstrated that alpha 2 beta 1 integrin interaction with fibrillar collagen affected the expression of HMG-CoA reductase, which led to the inhibition of cholesterol biosynthesis in human SMCs. (Arterioscler Thromb Vasc Biol. 2009;29:1631-1637.)