Pioglitazone Ameliorates Smooth Muscle Cell Proliferation in Cuff-Induced Neointimal Formation by Both Adiponectin-Dependent and -Independent Pathways.
Pioglitazone Ameliorates Smooth Muscle Cell Proliferation in Cuff-Induced Neointimal Formation by Both Adiponectin-Dependent and -Independent Pathways.
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DOI：
10.1038/srep34707
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发表时间：
2016-10-05
影响因子：
4.6
通讯作者：
Kadowaki T
中科院分区：
文献类型：
--
作者：
Kubota T;Kubota N;Sato H;Inoue M;Kumagai H;Iwamura T;Takamoto I;Kobayashi T;Moroi M;Terauchi Y;Tobe K;Ueki K;Kadowaki T
本研究的目的是阐明脂联素在多大程度上参与TZD介导的新生内膜形成的改善。我们研究了3周或8周吡格列酮对脂联素缺陷（APN-KO）和野生型（WT）小鼠袖套诱导的新生内膜形成的影响。吡格列酮给药3周可减少WT小鼠的新生内膜形成，并上调血浆脂联素水平，但未能减少APN-KO小鼠的新生内膜形成，表明吡格列酮通过脂联素依赖性机制抑制新生内膜形成。吡格列酮3周可抑制WT小鼠的血管平滑肌细胞（VSMC）增殖并增加AdipoR 2表达。在体外，球状脂联素通过AdipoR 1和AdipoR 2激活AMPK，导致VSMC增殖抑制。有趣的是，8周的吡格列酮减少了APN-KO小鼠中的新生内膜形成，其程度与WT小鼠中观察到的相似，表明吡格列酮也可以通过不依赖于脂联素的机制抑制新生内膜形成。吡格列酮8周完全消除了APN-KO小鼠中VSMC增殖的增加，沿着细胞周期蛋白B1和细胞周期蛋白D1表达的减少以及心血管风险特征。在体外，吡格列酮抑制这些表达，导致抑制VSMC增殖。吡格列酮通过脂联素依赖性和非脂联素依赖性机制抑制新生内膜形成。
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.
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影响因子：
168.9
作者：
Dormandy, JA;Charbonnel, B;Taton, J
通讯作者：
Taton, J
影响因子：
8.3
作者：
Ishibashi, M;Egashira, K;Takeshita, A
通讯作者：
Takeshita, A
影响因子：
37.8
作者：
Arita, Y;Kihara, S;Matsuzawa, Y
通讯作者：
Matsuzawa, Y
影响因子：
37.8
作者：
Kubota, T;Kubota, N;Yamaguchi, T
通讯作者：
Yamaguchi, T
影响因子：
5.9
作者：
Bruemmer, D;Law, RE
通讯作者：
Law, RE