Fatty acid catalytic enzymes in vascular smooth muscle cells play a crucial role in the pathogenesis of atherosclerosis

Abstract

Purpose: Integrity of vascular smooth muscle cell (SMC) function plays an important role in the development and progression of atherosclerosis. Increasing evidence has given credit to elevated plasma free fatty acids as crucial risk factor for atherosclerotic disease in obese or diabetic patients. However, little is known about the molecular mechanism by which disturbance of fatty acid metabolism in VSMC results in atherosclerosis. In this study, we focused on two fatty acid catalytic enzymes, stearoyl-CoA desaturase 1 (SCD1), that catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acids (SFA), and elongase of long chain fatty acids 6 (Elovl6), that catalyzes the elongation of long-chain SFA and MUFA. Methods and results: We first examined SCD1 and Elovl6 expressions in neointimal hyperplasia by immunohistochemistry. Both SCD1 and Elovl6 were co-localized with smooth muscle alpha-actin-positive cells in medial layer of normal vessels while they were dramatically increased in 14-day balloon-injured rat aortas or intimal thickening area of human coronary artery. Furthermore, SCD1 and Elovl6 mRNA expressions in cultured human aortic SMC (HASMC) were significantly increased by transforming growth factor-beta (TGF-b; 15.2-fold) or platelet-derived growth factor-BB (PDGF-BB; 2.4-fold) which is negative regulator of SMC differentiation. We next examined whether SCD1 or Elovl6 expressions affect cell proliferation in VSMC. Knockdown of SCD1 or Elovl6 expressions in HASMC significantly suppressed DNA synthesis measured by [3H]-thymidine incorporation (63% and 16%, respectively, relative to control, p<0.01). These effects were blunted by adenovirus-mediated overexpression. Furthermore, SCD1 or Elovl6 knockdown markedly induced p21 and p53 expressions, phospholyration of AMP-activated protein kinase (p-AMPK) and suppressed mTOR expression levels, which lead to inhibit cell proliferation. Of importance, analysis of FFA composition in VSMC showed that both SCD1 and Elovl6 knockdown markedly increased the proportion of palmitic acid, while decreased that of MUFAs such as palmitoleic acid or oleic acid. In accordance with these results, palmitic acid substantially suppressed DNA synthesis and induced p21 or p-AMPK expressions. Conclusions: Collectively, our results suggest that perturbation of fatty acid desaturation or elongation in VSMC causes the shift of fatty acid composition and the inhibition of cell proliferation. Therefore, fatty acid metabolism and composition is crucial for SMC proliferation and progression of atherosclerosis.