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...

Objective-Vascular calcification which refers to ectopic mineralization in vascular cells is associated with several conditions, such as chronic kidney disease, atherosclerosis, and diabetes mellitus. Estrogen-related receptor (ERR)γ is a member of the orphan nuclear receptor superfamily, which plays diverse roles in regulating homeostatic and metabolic processes. However, the role of ERRγ in vascular calcification has not been investigated to date. The aim of the present study was to examine the role of ERRγ in vascular calcification. Approach and Results-Vascular calcification was induced by treating rat aortic vascular smooth muscle cells with calcification medium. ERRγ expression in vascular smooth muscle cells was induced during calcification mediuminduced vascular calcification. Adenovirus-mediated overexpression of ERRγ in vascular smooth muscle cells resulted in the upregulation of the expression of osteogenic genes, including runt-related transcription factor 2, osteopontin, and Msx2, and the downregulation of α-smooth muscle actin. Adenovirus-mediated overexpression of ERRγ induced bone morphogenetic protein 2 (BMP2) expression, leading to increased phosphorylation of the intracellular BMP2 effector proteins SMAD1/5/8. Collectively, these data suggested that ERRγ promotes dedifferentiation of vascular smooth muscle cells to an osteogenic phenotype during the vascular calcification process. Inhibition of endogenous ERRγ expression or activity using a specific siRNA or the selective inverse agonist GSK5182 attenuated vascular calcification and osteogenic gene expression in vitro and in vivo. 14 In a recent study, pharmacological inhibition of BMP signaling inhibited atheroma development and vascular calcification in high fat diet-fed low-density lipoprotein receptor −/− mice, suggesting a potential benefit of BMP inhibition in the treatment of vascular calcification. 8 The development of novel agents against these targets with the capacity to modulate signaling pathways would be beneficial for the treatment of patients with atherosclerosis and vascular calcification. Conclusions-The present results indicate that ERRγ plays a key role in vascular calcificationEstrogen-related receptors (ERRs) are closely related to estrogen receptors, sharing high homology in the DNAbinding domain, although they do not bind estrogen. 15 The estrogen receptor-related receptor subfamily consists of 3 members, ERRα, ERRβ, and ERRγ (NR3B1-3), which bind to classic estrogen response elements and to extended halfsite core sequences (TNAAGGTCA; ERR response element [ERRE]) as either monomers or dimers. 16 ERRα is strongly expressed throughout osteoblast differentiation and regulates osteopontin expression through a noncanonical ERRα response element.17,18 Previously, we reported that ERRγ is expressed in osteoblast progenitors and negatively regulates BMP2-induced osteoblast differentiation and bone formation. 19 However, the role of ERRγ in vascular calcification remains to be determined.The aim of the present study was to cla...