Vascular peroxidase 1 is a novel regulator of cardiac fibrosis after myocardial infarction
Vascular peroxidase 1 is a novel regulator of cardiac fibrosis after myocardial infarction
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血管过氧化物酶1是心肌梗死后心脏纤维化的新型调节剂
DOI：
10.1016/j.redox.2019.101151
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发表时间：
2019-04-01
期刊：
影响因子：
11.4
通讯作者：
Zhang, Guogang
中科院分区：
文献类型：
--
作者：
Liu, Zhaoya;Xu, Qian;Zhang, Guogang
心肌纤维化是心肌梗死后心脏重构的重要机制。VPO 1是一种血红素酶，使用过氧化氢（H2 O2）产生次氯酸（HOCl）。我们前期的研究表明VPO 1对心肌缺血再灌注和肾纤维化有调节作用。我们研究了VPO 1在MI后心脏纤维化中的作用。结果表明，在缺血性心肌病衰竭的人类心脏和伴有严重心脏纤维化的MI小鼠模型中，VPO 1表达强烈上调。最重要的是，通过尾静脉注射VPO 1 siRNA敲低VPO 1显著减少心脏纤维化，改善心脏功能和存活率。在VPO 1敲除小鼠模型和TGF-131培养的心脏成纤维细胞中，VPO 1有助于心脏成纤维细胞的分化、迁移、I型胶原合成和增殖。从机制上讲，VPO 1 MI后的纤维化作用部分通过HOCl形成激活Smad 2/3和ERK 1/2来表现。因此，我们的结论是，VPO 1是一个重要的调节心肌梗死后的心脏纤维化，通过介导HOCl/Smad 2/3和ERK 1/2信号通路，这意味着一个有前途的治疗靶点在缺血性心肌病。
Cardiac fibrosis is the most important mechanism contributing to cardiac remodeling after myocardial infarction (MI). VPO1 is a heme enzyme that uses hydrogen peroxide (H2O2) to produce hypochlorous acid (HOCl). Our previous study has demonstrated that VPO1 regulates myocardial ischemic reperfusion and renal fibrosis. We investigated the role of VPO1 in cardiac fibrosis after MI. The results showed that VPO1 expression was robustly upregulated in the failing human heart with ischemic cardiomyopathy and in a murine model of MI accompanied by severe cardiac fibrosis. Most importantly, knockdown of VPO1 by tail vein injection of VPO1 siRNA significantly reduced cardiac fibrosis and improved cardiac function and survival rate. In VPO1 knockdown mouse model and cardiac fibroblasts cultured with TGF-131, VPO1 contributes to cardiac fibroblasts differentiation, migration, collagen I synthesis and proliferation. Mechanistically, the fibrotic effects following MI of VPO1 manifested partially through HOCl formation to activate Smad2/3 and ERK1/2. Thus, we conclude that VPO1 is a crucial regulator of cardiac fibrosis after MI by mediating HOCl/Smad2/3 and ERK1/2 signaling pathways, implying a promising therapeutic target in ischemic cardiomyopathy.