Abstract 15372: Inhibition of Fatty Acid Synthase Plays a Protective Role in Vascular Smooth Muscle Cell Proliferation and Neointimal Formation
Backgrounds: Fatty acid synthase (FASN), catalyzing the de novo lipogenesis of fatty acids (FA), is upregulated in several cancer cells and is thought to contribute to their growth and proliferation. Vascular smooth muscle cell (VSMC) proliferation is a crucial event in the development of atherosclerosis. Our recent study showed that Elovl6, elongase of long chain fatty acids 6, which is a responsible for the production of saturated and monounsaturated fatty acids, affects the proliferation of VSMC and contributes to neointimal formation. However, little is known about the role of FASN in vascular smooth muscle cell.
Hypothesis: In this study, we examined whether FASN affects the proliferation of VSMC and contributes to neointimal formation.
Methods and Results: We first examined FASN expression in neointimal hyperplasia by immunohistochemistry. FASN was hardly detected in normal vessels while it was dramatically increased in mice femoral artery at 2 weeks after wire-injury and in intimal thickening lesion of human coronary artery. FASN mRNA and protein expression in cultured human aortic SMC (HASMC) was significantly increased by platelet-derived growth factor-BB (PDGF-BB) which induced growth and dedifferentiation of VSMC. To determine whether de novo lipogenesis in VSMC is relevant to neointimal formation, we generated VSMC specific FASN knockout (SM-FASN-/-) mice by crossing FASN floxed mice with SM22α-Cre transgenic mice. SM-FASN-/- mice at 2 weeks after wire-injury of femoral artery showed markedly suppressed neointimal hyperplasia compared with control mice. Consistent with in vivo data, knockdown of FASN expression using siRNA or treatment with FASN inhibitor, Orlistat or C75, markedly suppressed PDGF-BB-induced cell proliferation and migration in HASMC. Furthermore, disruption of FASN also induced phosphorylation of elF2α, expression of ATF4 and CHOP, which are ER stress-regulated protein, and also induced caspase3/7 activity and PARP cleavage, primary indicators of cell death.
Conclusions: These results demonstrate that proliferation of VSMC in neointima is required for de novo FA supplies by FASN, offering a novel therapeutic target for atherosclerosis and post-angioplasty restenosis.
Author Disclosures: N. Oshima: None. H. Matsui: None. H. Sunaga: None. T. Iso: None. C.F. Semenkovich: None. T. Yokoyama: None. M. Kurabayashi: None.
- © 2016 by American Heart Association, Inc.