Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice
Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice
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DOI：
10.1172/jci39896
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发表时间：
2010-06-01
影响因子：
15.9
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Ueda, Kazutaka;Takano, Hiroyuki;Komuro, Issei
据报道，促红细胞生成素对心肌梗死后的心脏有有益作用，但这些作用的潜在机制尚不清楚。我们在这里证明，音刺猬是一个关键的调解人促红细胞生成素诱导的小鼠心脏保护。用促红细胞生成素治疗小鼠可抑制心肌梗死后左心室重塑并改善心功能，这与红细胞生成和骨髓源性细胞动员无关。促红细胞生成素通过上调心肌细胞中血管生成细胞因子如VEGF和促血管生成素-1的表达来防止心肌细胞凋亡，并增加梗死心脏中毛细血管和成熟血管的数量。促红细胞生成素也增加了心肌细胞中音刺猬的表达，抑制音刺猬信号抑制促红细胞生成素诱导的血管生成细胞因子表达增加。此外，促红细胞生成素对梗死心脏的有益作用被心肌细胞特异性的音刺猬基因缺失所消除。这些结果表明，促红细胞生成素保护心肌梗死后的心脏通过诱导血管生成通过音刺猬信号。
Erythropoietin reportedly has beneficial effects on the heart after myocardial infarction, but the underlying mechanisms of these effects are unknown. We here demonstrate that sonic hedgehog is a critical mediator of erythropoietin-induced cardioprotection in mice. Treatment of mice with erythropoietin inhibited left ventricular remodeling and improved cardiac function after myocardial infarction, independent of erythropoiesis and the mobilization of bone marrow-derived cells. Erythropoietin prevented cardiomyocyte apoptosis and increased the number of capillaries and mature vessels in infarcted hearts by upregulating the expression of angiogenic cytokines such as VEGF and angiopoietin-1 in cardiomyocytes. Erythropoietin also increased the expression of sonic hedgehog in cardiomyocytes, and inhibition of sonic hedgehog signaling suppressed the erythropoietin-induced increase in angiogenic cytokine expression. Furthermore, the beneficial effects of erythropoietin on infarcted hearts were abolished by cardiomyocyte-specific deletion of sonic hedgehog. These results suggest that erythropoietin protects the heart after myocardial infarction by inducing angiogenesis through sonic hedgehog signaling.