Pioglitazone, a PPARγ agonist, attenuates PDGF-induced vascular smooth muscle cell proliferation through AMPK-dependent and AMPK-independent inhibition of mTOR/p70S6K and ERK signaling

摘要: Pioglitazone (PIO), a PPARγ agonist that improves glycemic control in type 2 diabetes through its insulin-sensitizing action, has been shown to exhibit beneficial effects the vessel wall. For instance, it inhibits vascular smooth muscle cell (VSMC) proliferation, major event atherosclerosis and restenosis after angioplasty. Although PPARγ-dependent PPARγ-independent mechanisms have attributed vasoprotective effects, signaling events associated with PIO action VSMCs are not fully understood. To date, likely intermediary role of AMP-activated protein kinase (AMPK) toward inhibition VSMC proliferation examined. Using human aortic VSMCs, present study demonstrates activates AMPK sustained manner thereby contributing part key proliferative events. In particular, at 30μM concentration induce raptor phosphorylation, which diminishes PDGF-induced mTOR activity as evidenced by decreased phosphorylation p70S6K, 4E-BP1, S6 increased accumulation p27(kip1), cycle inhibitor. addition, basal ERK VSMCs. Downregulation endogenous target-specific siRNA reveals an AMPK-independent effect for ERK, contributes diminutions cyclin D1 expression Rb suppression proliferation. Furthermore, AMPK-dependent mTOR/p70S6K occur regardless expression/activation gene silencing pharmacological PPARγ. Strategies utilize nanoparticle-mediated delivery lesion site may limit angioplasty without inducing PPARγ-mediated systemic adverse effects.