Lv Lei, Meng Qiurong, Ye Meng, Wang Peng, Xue Guanhua
Department of Vascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
Department of Vascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
J Mol Cell Cardiol. 2014 Sep;74:284-94. doi: 10.1016/j.yjmcc.2014.06.001. Epub 2014 Jun 14.
Signal transducer and activator of transcription 4 (STAT4) has been associated with susceptibility to autoimmune diseases. Intriguingly, we previously reported that STAT4 might play a critical role in vascular smooth muscle cell (VSMC) proliferation. The present study therefore investigated the impact of STAT4 on VSMC migration, apoptosis and neointimal hyperplasia postinjury, as well as the underlying mechanisms. Guide-wire injury was associated with development of intimal neointima, STAT4 and phosphorylated STAT4 (p-STAT4) expressions were apparently up-regulated in the injured arteries. Neointima was greatly blocked in STAT4 knockout (KO) mice compared with wild type (WT) mice. A marked loss of inflammatory cells was identified in the vasculature postinjury in STAT4 KO mice. VSMC apoptosis was enhanced in the vasculature postinjury in STAT4 KO mice compared with WT mice. Cultured primary STAT4 KO VSMCs displayed reduced migration in comparison with WT controls. Mechanically, the deletion of STAT4 potently decreased the level of MCP-1, and its downstream targets MMP1 and MMP2. The effect of STAT4 on VSMC apoptosis was mainly mediated by the activation of the mitochondrial apoptotic pathway, as manifested by increased cytochrome c release and the activation of caspase-3. STAT4 therefore represents a promising molecular target to limit restenosis after artery intervention.
信号转导及转录激活因子4（STAT4）与自身免疫性疾病的易感性相关。有趣的是，我们之前报道过STAT4可能在血管平滑肌细胞（VSMC）增殖中起关键作用。因此，本研究调查了STAT4对VSMC损伤后迁移、凋亡和内膜增生的影响及其潜在机制。导丝损伤与内膜新生内膜的形成有关，在损伤动脉中STAT4和磷酸化STAT4（p-STAT4）的表达明显上调。与野生型（WT）小鼠相比，STAT4基因敲除（KO）小鼠的新生内膜明显受阻。在STAT4 KO小鼠损伤后的脉管系统中发现炎性细胞显著减少。与WT小鼠相比，STAT4 KO小鼠损伤后的脉管系统中VSMC凋亡增强。与WT对照相比，原代培养的STAT4 KO VSMC迁移减少。机制上，STAT4的缺失显著降低了MCP-1及其下游靶点MMP1和MMP2的水平。STAT4对VSMC凋亡的影响主要通过线粒体凋亡途径的激活介导，表现为细胞色素c释放增加和caspase-3激活。因此，STAT4是限制动脉介入后再狭窄的一个有前景的分子靶点。
