The anti-apoptotic effect of alpha-lipoic acid against neointimal hyperplasia via induction of Nur77-mediation.

Abstract

e13624 Background: Neointimal hyperplasia of vascular smooth muscle cells (VSMCs) is caused by increased proliferation and decreased apoptosis. We previously reported that alpha-lipoic acid (ALA), a naturally occurring antioxidant, prevents neointimal hyperplasia through its anti-inflammatory property. Nuclear receptor Nur77 (NR4A1; NGFI-B/TR3) induces apoptosis of various cancer cells and also inhibits VSMC proliferation. However, it is unknown whether Nur77-mediated apoptotic pathway is involved in the inhibitory effect of ALA on neointimal hyperplasia. We explored the hypothesis that ALA protects against neointimal hyperplasia through the induction of Nur77-mediated apoptosis in VSMCs. Methods: VSMCs were isolated from the thoracic aorta of 4-week-old male Sprague–Dawley (SD) rats and were treated with ALA (2 mmol/L). Results: ALA treatment induced VSMC apoptosis, as evidenced by increases in Bax expression, cytochrome c release and caspase-3 activation. Also, ALA enhanced the expression and cytoplasmic localization of Nur77, resulting in interaction of Nur77 with Bcl-2, which triggers Nur77-mediated apoptosis. siRNA-mediated downregulation of Nur77 diminished the pro-apoptotic effect of ALA on VSMCs. Moreover, ALA increased p38 MAPK phosphorylation and inhibition of p38 MAPK abolished ALA-induced apoptosis and cytoplasimc localization of Nur77. Adenovirus-mediated transfer of shRNA against Nur77 diminished inhibitory effect of ALA on neointimal hyperplasia. Conclusions: Collectively, these data indicate that ALA induced cell apoptosis through induction of p38 MAPK/Nur77-mediation. This study also suggests that stimulation of Nur77-mediated apoptotic pathway in VSMCs can be a potential therapeutic strategy to treatment of cancer. No significant financial relationships to disclose.