A role for caspase-1 in heart failure
A role for caspase-1 in heart failure
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DOI：
10.1161/01.res.0000260203.55077.61
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发表时间：
2007-03-16
影响因子：
20.1
通讯作者：
Engelhardt, Stefan
中科院分区：
文献类型：
--
作者：
Merkle, Sabine;Frantz, Stefan;Engelhardt, Stefan
心力衰竭时心肌细胞凋亡增加，并且与疾病进展有关。 “促凋亡”半胱天冬酶的激活代表心肌细胞凋亡的关键步骤。相反，“促炎”半胱天冬酶（半胱天冬酶 1、4、5、11、12）的作用尚不清楚。在这里，我们研究了 caspase-1 的心脏功能。小鼠心力衰竭模型中的基因阵列分析显示心肌 caspase-1 上调。此外，我们发现小鼠和人类心力衰竭中 caspase-1 蛋白的表达增加。心肌细胞特异性过度表达 caspase-1 的小鼠在没有可检测到的白细胞介素 (IL)-1 β 或 IL-18 形成和炎症的情况下发生心力衰竭。转基因 caspase-1 在心肌重塑的结构和分子迹象出现之前诱导原代心肌细胞凋亡。相比之下，内源性 caspase-1 的缺失对于心肌梗塞诱发的心力衰竭是有益的。此外，caspase-1缺陷型小鼠可以免受缺血/再灌注诱导的心肌细胞凋亡的影响。对原代大鼠心肌细胞的研究表明，caspase-1 主要通过激活 caspase-3 和 -9 诱导心肌细胞凋亡。与之前的发现（暗示 caspase-1 具有促炎作用）相反，这些数据表明 caspase-1 在心肌细胞中具有主要的促凋亡作用。我们的研究结果支持 caspase-1 介导的心肌细胞凋亡在心力衰竭进展中的功能作用。
Apoptosis of cardiomyocytes is increased in heart failure and has been implicated in disease progression. The activation of "proapoptotic" caspases represents a key step in cardiomyocyte apoptosis. In contrast, the role of "proinflammatory" caspases (caspases 1, 4, 5, 11, 12) is unclear. Here, we study the cardiac function of caspase-1. Gene array analysis in a murine heart failure model showed upregulation of myocardial caspase-1. In addition, we found increased expression of caspase-1 protein in murine and human heart failure. Mice with cardiomyocyte-specific overexpression of caspase-1 developed heart failure in the absence of detectable formation of interleukin (IL)-1 beta or IL-18 and inflammation. Transgenic caspase-1 induced primary cardiomyocyte apoptosis before structural and molecular signs of myocardial remodeling occurred. In contrast, deletion of endogenous caspase-1 was beneficial in the setting of myocardial infarction-induced heart failure. Furthermore, caspase-1-deficient mice were protected from ischemia/reperfusion-induced cardiomyocyte apoptosis. Studies in primary rat cardiomyocytes indicated that caspase-1 induces cardiomyocyte apoptosis primarily through activation of caspases-3 and -9. In contrast to previous findings, which imply a proinflammatory role of caspase-1, these data suggest a primary proapoptotic role for caspase-1 in cardiomyocytes. Our findings support a functional role for caspase-1-mediated myocardial apoptosis contributing to the progression of heart failure.