Abstract 12854: Long-Chain Fatty Acid Elongase, Elovl6, is Crucial for Vascular Smooth Muscle Cell Proliferation Underlying Neointimal Hyperplasia

Abstract

Background: Vascular smooth muscle cell (VSMC) proliferation is a crucial event in the development of atherosclerosis. The elongase of long chain fatty acids family 6 (Elovl6) is a central lipogenic enzyme that catalyzes the elongation of saturated (SFA) and monounsaturated (MUFA) long-chain fatty acids. However, little is known about the role of Elovl6 in atherosclerosis.

Methods and Results: We first examined Elovl6 expression in neointimal hyperplasia by immunohistochemistry. Elovl6 was co-localized with SMα-actin-positive cells in medial layer of normal vessels while it was dramatically increased in 14-day balloon-injured rat aortas or intimal thickening area of human coronary artery. Furthermore, Elovl6 mRNA expression in cultured human aortic SMC (HASMC) was significantly increased by platelet-derived growth factor-BB (2.4-fold) or hypoxic stress (6.7-fold) which is negative regulator of SMC differentiation. However, adenovirus-mediated Elovl6 overexpression or knockdown of Elovl6 using siRNA transfection did not affect SMC marker genes such as SM-MHC and SM22α. Thus, Elovl6 did not affect VSMC differentiation. We next examined whether Elovl6 affects cell proliferation in VSMC. Knockdown of Elovl6 expression in HASMC significantly suppressed DNA synthesis measured by [3H]-thymidine incorporation (16%, relative to control, p<0.01). These effects were blunted by Elovl6-overexpression. Furthermore, Elovl6 knockdown markedly induced p21and p53 expression, phospholyration of AMP-activated protein kinase (AMPK) and suppressed mTOR expression levels, which lead to inhibit cell proliferation. Of importance, analysis of FFA composition showed that 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 p53 expressions.

Conclusions: Given that reduced-Elovl6 expression in HASMC causes the shift of fatty acid composition from MUFA to SFA and the inhibition of cell proliferation, these results suggest that fatty acid elongation and composition is crucial for SMC proliferation and progression of atherosclerosis in injured aorta.