α-Lipoic Acid Prevents Neointimal Hyperplasia Via Induction of p38 Mitogen-Activated Protein Kinase/Nur77-Mediated Apoptosis of Vascular Smooth Muscle Cells and Accelerates Postinjury Reendothelialization

Abstract

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...

Dipeptidyl peptidase-4 inhibition by gemigliptin prevents abnormal vascular remodeling via NF-E2-related factor 2 activation

“…A number of molecules including α-lipoic acid, caffeic acid phenethyl ester, and nifedipine have been recognized for their anti-proliferative effects on VSMCs mediated by ROS reduction [20][21][22][23]. DPP-4 inhibitors such as sitagliptin, anagliptin, and alogliptin have been shown to reduce atherosclerotic lesions in apoE−/− mice by inhibiting proinflammatory responses and endothelial cell apoptosis, thereby preventing the cardiac malfunction associated with ROS production [9,10,24,25].…”

“…Previously, we reported that various types of drugs such as α-lipoic acid and dimethyl fumarate have been identified as Nrf2 activators with protective effects against abnormal vascular remodeling via restoration of mitochondrial function [20,37]. In many studies, cardiovascular diseases such as hypertension, atherosclerosis, and heart failure have been shown to be associated with abnormal vascular remodeling following vascular damage to the fundamental interactions between endothelial cells and VSMCs.…”

NR4All in the vessel wall

“…Most recently, it has been demonstrated that ␣-lipoic acid inhibits neointima formation in rat carotid arteries after ballooninjury, involving enhanced SMC apoptosis. In this study it is shown that ␣-lipoic acid enhances the expression and cytoplasmic, rather than nuclear, localization of Nur77 in the cell, which triggered apoptosis [11]. Knockdown experiments both in cultured SMCs and in the rat model revealed crucial involvement of Nur77 in ␣-lipoic acid-induced SMC apoptosis.…”

“…Knockdown experiments both in cultured SMCs and in the rat model revealed crucial involvement of Nur77 in ␣-lipoic acid-induced SMC apoptosis. Interestingly, it was also shown that ␣-lipoic acid enhances endothelial cell proliferation [11].…”

Effect of stents coated with a combination of sirolimus and alpha-lipoic acid in a porcine coronary restenosis model

“…Moreover, ALA inhibits neointimal proliferation and late stent thrombosis after percutaneous transluminal coronary angioplasty [40,41]. ALA-coated stents suppress neointimal proliferation in a porcine coronary restenosis model [42].…”