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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1631.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Fibrillar Collagen Inhibits Cholesterol Biosynthesis in Human Aortic Smooth Muscle Cells

Nicola Ferri; Elisa Roncalli; Lorenzo Arnaboldi; Simone Fenu; Olena Andrukhova; Seyedhossein Aharinejad; Marina Camera; Elena Tremoli; Alberto Corsini

From the Department of Pharmacological Sciences (N.F., E.R., L.A., M.C., E.T., A.C.), University of Milan, Italy; Axxam (S.F.), San Raffaele Biomedical Science Park, Milan, Italy; the Department of Anatomy and Cell Biology (O.A., S.A.), Vienna Medical University, Austria; and Monzino Cardiology Center IRCCS (M.C., E.T.), Milan, Italy.

Correspondence to Nicola Ferri, Department of Pharmacological Sciences, Via Balzaretti 9, 20133, Milano, Italy. E-mail nicola.ferri{at}unimi.it

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 [¹⁴C]-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 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 2β1 integrin interaction with fibrillar collagen affected the expression of HMG-CoA reductase, which led to the inhibition of cholesterol biosynthesis in human SMCs.

The evaluation of cholesterol biosynthesis in human aortic smooth muscle cells cultured on fibrillar collagen led to the discovery that fibrillar collagen strongly affects the transcription of HMG-CoA reductase by SREBP1a, an effect mediated by 2β1 integrin receptor. This inhibition reduced cholesterol synthesis and Ras prenylation.

Key Words: cholesterol • integrins • HMG-CoA • mevalonate • Ras