Abstract-Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are important pathogenic mechanisms in atherosclerosis and restenosis after vascular injury. In this study, we investigated the effects of

Objective-To explore whether ␣-lipoic acid (ALA), a naturally occurring antioxidant, inhibits neointimal hyperplasia by inducing apoptosis of vascular smooth muscle cells and to examine its potential effects on reendothelialization and platelet aggregation. Methods and Results-Restenosis and late stent thrombosis, caused by neointimal hyperplasia and delayed reendothelialization, are significant clinical problems of balloon angioplasty and drug-eluting stents. ALA treatment strongly induced apoptosis of vascular smooth muscle cells and enhanced the expression and cytoplasmic localization of Nur77, which triggers intrinsic apoptotic events. Small interfering RNA-mediated downregulation of Nur77 diminished this proapoptotic effect of ALA. Moreover, ALA increased p38 mitogen-activated protein kinase phosphorylation, and inhibition of p38 mitogen-activated protein kinase completely blocked ALA-induced vascular smooth muscle cell apoptosis and Nur77 induction and cytoplasmic localization. In balloon-injured rat carotid arteries, ALA enhanced Nur77 expression and increased TUNEL-positive apoptotic cells in the neointima, leading to inhibition of neointimal hyperplasia. This preventive effect of ALA was significantly reduced by infection of an adenovirus encoding Nur77 small hairpin (sh)RNA. Furthermore, ALA reduced basal apoptosis of human aortic endothelial cells and accelerated reendothelialization after balloon injury. ALA also suppressed arachidonic acid-induced platelet aggregation. Conclusion-ALA could be a promising therapeutic agent to prevent restenosis and late stent thrombosis after angioplasty and drug-eluting stent implantation. Key Words: apoptosis Ⅲ ␣-lipoic acid Ⅲ Nur77 Ⅲ VSMC Ⅲ neointimal hyperplasia R estenosis caused by neointimal hyperplasia is a main obstacle in the long-term success of percutaneous coronary intervention, such as balloon angioplasty and stenting. Neointimal hyperplasia is characterized by diffuse intimal thickening, resulting from uncontrolled proliferation of vascular smooth muscle cells (VSMCs). [1][2][3] Along with excessive proliferation of VSMCs, decreased VSMC apoptosis also plays a crucial role in the development and progression of neointimal hyperplasia. 4 -6 The intrinsic antiapoptotic phenotype, leading to diabetic vasculopathy, was observed in neointimal VSMCs isolated from patients with diabetes mellitus. 4 Inhibition of antiapoptotic B cell lymphoma-x (Bcl-x) expression induces VSMC apoptosis and reduces neointimal hyperplasia and intimal lesion formation. 5,6 Drug-eluting stents (DESs), which locally release antiproliferative drugs, profoundly reduce the rate of in-stent restenosis. 3 However, late stent thrombosis (LST) associated with delayed reendothelialization remains a major problem, limiting the long-term efficacy and safety of DESs. 3,7 Delayed or incomplete reendothelialization contributes to neointimal hyperplasia, and accelerated reendothelialization inhibits restenosis and LST. 7-9 Therefore, pharmacological agents that inhibit proliferation and inc...