Abstract 13688: Long Chain Fatty Acid Composition Modulated by Elovl6 Plays a Critical Role in Vascular Smooth Muscle Cell Proliferation and Neointimal Formation
Introduction: Elovl6, the elongase of long chain fatty acids 6, is a rate-limiting enzyme catalyzing the elongation of saturated and monounsaturated fatty acids with 12, 14 and 16 carbons. Our recent study showed that Elovl6 is abundantly expressed in vascular smooth muscle cells (VSMC) and is dramatically induced in neointima in rat.
Hypothesis: In this study, we tested the hypothesis that changes of fatty acid (FA) composition by Elovl6 affects the proliferation of VSMC and contributes to neointimal formation in vivo.
Methods and Results: Abundant Elovl6 expression was observed in mice femoral artery at 2 weeks after wire-injury and in intimal thickening lesion 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, p<0.05) or hypoxic stress (6.7-fold, p<0.01) in a dose- or time-dependent manner. Furthermore, knockdown of Elovl6 expression in HASMC markedly suppressed cell proliferation (16%, relative to control, p<0.01) and migration, concomitantly induced the expression of p21 and phospholyration of AMP-activated protein kinase (p-AMPK) and suppressed mTOR expression. Consistent with in vitro data, Elovl6 deficient (Elovl6 -/-) mice at 2 weeks after injury showed markedly suppressed neointimal formation compared with wild-type (WT) mice (intima/media ratio: WT, 1.4 ± 0.6; Elovl6 -/-, 0.5 ± 0.2; Ki67-positive cells: 0.2 fold relative to WT mice; N=6-7, p<0.05). Of an importance, analysis of FA composition in SMC isolated from Elovl6 -/- mice showed that high levels of palmitic acid and low levels of oleic acid were detected as compared with that from WT mice. In accordance with these results, exogenous treatment of palmitic acid in SMC substantially suppressed cell proliferation (42%, relative to control, p<0.01) and migration, induced p21 and p-AMPK expressions. Conversely, these effects were blunted by adenovirus-mediated Elovl6-overexpression or exogenous oleic acid treatment.
Conclusions: Collectively, our study demonstrates that proliferation of VSMC is tightly regulated by FA composition modulated by Elvlo6, offering a novel therapeutic target for arterial proliferative disease in which VSMC plays a key role.
Author Disclosures: H. Matsui: None. H. Sunaga: None. S. Anjo: None. M.A. Syamsunarno: None. T. Iso: None. T. Matsuzaka: None. H. Shimano: None. T. Yokoyama: None. M. Kurabayashi: None.
- © 2014 by American Heart Association, Inc.