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

作者：Osman Islam; Segar Lakshman^*

来源：Biochemical Pharmacology, 2016, 101: 54-70.

DOI：10.1016/j.bcp.2015.11.026

• Vascular smooth muscle cells
• Pioglitazone
• AMPK
• p70S6K
• ERK

Pioglitazone (PIO), a PPAR gamma agonist that improves glycemic control in type 2 diabetes through its insulin sensitizing action, has been shown to exhibit beneficial effects in the vessel wall. For instance, it inhibits vascular smooth muscle cell (VSMC) proliferation, a major event in atherosclerosis and restenosis after angioplasty. Although PPAR gamma-dependent and PPAR gamma-independent mechanisms have been attributed to its vasoprotective effects, the signaling events associated with PIO action in VSMC5 are not fully understood. To date, the likely intermediary role of AMP-activated protein kinase (AMPIC) toward PIO inhibition of VSMC proliferation has not been examined. Using human aortic VSMCs, the present study demonstrates that PIO activates AMPIC in a sustained manner thereby contributing in part to inhibition of key proliferative signaling events. In particular, PIO at 30 mu M concentration activates AMPK to induce raptor phosphorylation, which diminishes PDGF-induced mTOR activity as evidenced by decreased phosphorylation of p70S6K, 4E-BP1, and S6 and increased accumulation of p27(kip1), a cell cycle inhibitor. In addition, PIO inhibits the basal phosphorylation of ERK in VSMCs. Downregulation of endogenous AMPK by target-specific siRNA reveals an AMPK-independent effect for PIO inhibition of ERK, which contributes in part to diminutions in cyclin D1 expression and Rb phosphorylation and the suppression of VSMC proliferation. Furthermore, AMPK-dependent inhibition of mTOR/p70S6K and AMPK-independent inhibition of ERK signaling occur regardless of PPAR gamma expression/activation in VSMC5 as evidenced by gene silencing and pharmacological inhibition of PPAR gamma. Strategies that utilize nanoparticle-mediated PIO delivery at the lesion site may limit restenosis after angioplasty without inducing PPAR gamma-mediated systemic adverse effects.

• 出版日期2016-2-1