Therapeutic impact of follistatin-like 1 on myocardial ischemic injury in preclinical models.
Therapeutic impact of follistatin-like 1 on myocardial ischemic injury in preclinical models.
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DOI：
10.1161/circulationaha.112.115089
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发表时间：
2012-10-02
期刊：
影响因子：
37.8
通讯作者：
Murohara T
中科院分区：
文献类型：
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作者：
Ogura Y;Ouchi N;Ohashi K;Shibata R;Kataoka Y;Kambara T;Kito T;Maruyama S;Yuasa D;Matsuo K;Enomoto T;Uemura Y;Miyabe M;Ishii M;Yamamoto T;Shimizu Y;Walsh K;Murohara T
急性冠状动脉综合征是发达国家的主要死亡原因。卵泡抑素样1 （Follistatin-like 1, FSTL1）是一种心肌细胞衍生的分泌蛋白，在心肌缺血损伤时表达上调。本研究通过小型和大型临床前动物缺血/再灌注模型研究FSTL1对急性心脏损伤的治疗作用，并解剖其分子机制。在小鼠或猪缺血/再灌注模型中，给药人FSTL1蛋白显著降低心肌梗死面积，这与缺血心脏细胞凋亡和炎症反应的减少有关。FSTL1可增强缺血/再灌注损伤心脏中amp活化蛋白激酶的磷酸化。在培养的心肌细胞中，FSTL1通过激活amp激活的蛋白激酶的能力抑制缺氧/再氧化和脂多糖刺激的促炎基因表达的凋亡。缺血/再灌注导致心脏骨形态发生蛋白-4表达和Smad1/5/8磷酸化增强，FSTL1抑制缺血心肌Smad1/5/8磷酸化升高。用FSTL1处理心肌细胞，可消除骨形态发生蛋白4刺激的凋亡、Smad1/5/8磷酸化和促炎基因表达的增加。在培养的巨噬细胞中，FSTL1通过激活amp活化的蛋白激酶减少脂多糖刺激的促炎基因表达，并消除骨形态发生蛋白-4依赖性诱导的促炎介质。我们的数据表明，FSTL1可以通过调节amp激活的蛋白激酶和骨形态发生蛋白-4依赖机制，通过抑制细胞凋亡和炎症反应来预防心肌缺血/再灌注损伤，这表明FSTL1可能是心肌梗死后急性冠脉综合征的新治疗靶点。
Acute coronary syndrome is a leading cause of death in developed countries. Follistatin-like 1 (FSTL1) is a myocyte-derived secreted protein that is upregulated in the heart in response to ischemic insult. Here, we investigated the therapeutic impact of FSTL1 on acute cardiac injury in small and large preclinical animal models of ischemia/reperfusion and dissected its molecular mechanism. Administration of human FSTL1 protein significantly attenuated myocardial infarct size in a mouse or pig model of ischemia/reperfusion, which was associated with a reduction of apoptosis and inflammatory responses in the ischemic heart. Administration of FSTL1 enhanced the phosphorylation of AMP-activated protein kinase in the ischemia/reperfusion–injured heart. In cultured cardiac myocytes, FSTL1 suppressed apoptosis in response to hypoxia/reoxygenation and lipopolysaccharide-stimulated expression of proinflammatory genes through its ability to activate AMP-activated protein kinase. Ischemia/reperfusion led to enhancement of bone morphogenetic protein-4 expression and Smad1/5/8 phosphorylation in the heart, and FSTL1 suppressed the increased phosphorylation of Smad1/5/8 in ischemic myocardium. Treating cardiac myocytes with FSTL1 abolished the bone morphogenetic protein-4 –stimulated increase in apoptosis, Smad1/5/8 phosphorylation, and proinflammatory gene expression. In cultured macrophages, FSTL1 diminished lipopolysaccharide-stimulated expression of proinflammatory genes via activation of AMP-activated protein kinase and abolished bone morphogenetic protein-4 – dependent induction of proinflammatory mediators. Our data indicate that FSTL1 can prevent myocardial ischemia/reperfusion injury by inhibiting apoptosis and inflammatory response through modulation of AMP-activated protein kinase– and bone morphogenetic protein-4 – dependent mechanisms, suggesting that FSTL1 could represent a novel therapeutic target for post-myocardial infarction, acute coronary syndrome.