Pioglitazone Ameliorates Smooth Muscle Cell Proliferation in Cuff-Induced Neointimal Formation by Both Adiponectin-Dependent and -Independent Pathways.

Tetsuya Kubota,Naoto Kubota,Kohjiro Ueki,Kazuyuki Tobe,Yasuo Terauchi,Masao Moroi,Mariko Inoue,Takashi Kadowaki,Iseki Takamoto,Hiroyuki Sato,Tsuneo Kobayashi,Hiroki Kumagai,Tomokatsu Iwamura

doi:10.1038/srep34707

Abstract

The aim of this study is to elucidate to what degree adiponectin is involved in TZD-mediated amelioration of neointimal formation. We investigated the effect of 3- or 8-weeks’ pioglitazone on cuff-induced neointimal formation in adiponectin-deficient (APN-KO) and wild-type (WT) mice. Pioglitazone for 3 weeks reduced neointimal formation in the WT mice with upregulation of the plasma adiponectin levels, but failed to reduce neointimal formation in the APN-KO mice, suggesting that pioglitazone suppressed neointimal formation by adiponectin-dependent mechanisms. Pioglitazone for 3 weeks suppressed vascular smooth muscle cell (VSMC) proliferation and increased AdipoR2 expression in the WT mice. In vitro, globular adiponectin activated AMPK through both AdipoR1 and AdipoR2, resulting in the inhibition of VSMC proliferation. Interestingly, 8-weeks’ pioglitazone was reduced neointimal formation in APN-KO mice to degree similar to that seen in the WT mice, suggesting that pioglitazone can also suppress neointimal formation via a mechanism independent of adiponectin. Pioglitazone for 8 weeks completely abrogated the increased VSMC proliferation, along with a reduction of cyclin B1 and cyclin D1 expressions and cardiovascular risk profile in the APN-KO mice. In vitro, pioglitazone suppressed these expressions, leading to inhibition of VSMC proliferation. Pioglitazone suppresses neointimal formation via both adiponectin-dependent and adiponectin-independent mechanisms.

Highlights

Non-fatal myocardial infarction and stroke in patients with type 2 diabetes who are at a high risk of developing macrovascular events[12]
Pioglitazone treatment for 3 weeks suppressed neointimal formation induced by cuff injury in an adiponectin-dependent manner, accompanied by augmentation of AdipoR2 expression
To investigate whether this increase of the plasma adiponectin was associated with suppression of neointimal formation, cuff injury was induced in the femoral artery of the WT and APN-KO mice during 3 weeks the course of pioglitazone treatment

Summary

Introduction

Non-fatal myocardial infarction and stroke in patients with type 2 diabetes who are at a high risk of developing macrovascular events[12]. A recent study revealed that pioglitazone modulated VSMC proliferation via PPARγ18 These data suggest that pioglitazone suppresses atherosclerosis through the PPARγexpressed in VSMCs. In addition to the direct vascular effects of TZDs, TZDs have been shown to upregulate adiponectin expression in white adipose tissue and to increase the plasma adiponectin levels, which is well known to have anti-atherogenic properties[19]. Adiponectin attenuated the VSMC proliferation induced by platelet-derived growth factor (PDGF)-BB through the AdipoR1- and AdipoR2- AMPK pathways in human aortic SMCs (HASMCs) Both WT and APN-KO mice exhibited similar significant improvement of neointimal formation after 8-weeks’ pioglitazone treatment, associated with a reduction of the cardiovascular risk profile. Pioglitazone-induced amelioration of neointimal formation may occur via both adiponectin-dependent and adiponectin-independent mechanisms

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