Heat-shock-protein 90 protects from downregulation of HIF-1α in calcineurin-induced myocardial hypertrophy
Heat-shock-protein 90 protects from downregulation of HIF-1α in calcineurin-induced myocardial hypertrophy
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DOI：
10.1016/j.yjmcc.2015.05.018
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发表时间：
2015-08-01
影响因子：
5
通讯作者：
Chorianopoulos, Emmanuel
中科院分区：
文献类型：
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作者：
Eschricht, Sabine;Jarr, Kai-Uwe;Chorianopoulos, Emmanuel
研究目的：毛细血管/心肌细胞不匹配是适应性不良心肌肥大的一个特征，但这种现象的确切机制尚不清楚。因此，我们旨在评价钙调神经磷酸酶A在低氧诱导因子-1α(HIF-1α)调节中的作用。方法和结果：钙调神经磷酸酶A(CnATg)过表达的小鼠表现出持续的HIF-1α蛋白上调，尽管进行性心肌肥厚，但没有证据表明毛细血管密度下降。同样，在分离的心肌细胞中过表达钙调神经磷酸酶A可诱导HIF-1α蛋白上调。相反，NFAT过表达没有这样的影响，这意味着NFAT非依赖机制导致HIF-1α水平增加。此外，通过HSP90抑制剂17-AAG或siRNA抑制HSP90可阻断钙调神经磷酸酶A诱导的HIF-1α表达上调。因此，针对HSP90的17-AAG或siRNA也能抑制HIF-1α靶基因如VEGF-A、BNIP-3或PGK-1的上调。最后，当CnATg小鼠接受17-AAG治疗时，他们表现出左心功能和毛细血管密度的降低。结论：我们在这里首次描述了尽管心肌逐渐肥大，但磷酸酶钙调神经磷酸酶A的过度表达防止了毛细血管/心肌细胞不匹配的发展。这种作用是通过HSP-90诱导HIF-1α的稳定来实现的。需要进一步的工作来了解钙调神经磷酸酶A的这种意想不到的心脏保护作用。(C)2015爱思唯尔有限公司。保留所有权利。
Aim of the study: Capillary/myocyte mismatch is a hallmark of maladaptive myocardial hypertrophy, but the exact mechanisms of this phenomenon remain unknown. We therefore aimed to evaluate the role of calcineurin A in the regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in a calcineurin overexpressing mouse model of myocardial hypertrophy.Methods and results: Mice overexpressing calcineurin A (CnATg) showed persistent upregulation of HIF-1 alpha protein without evidence of a reduction in capillary density despite progressive myocardial hypertrophy. Likewise, overexpression of calcineurin A in isolated cardiomyocytes induced upregulation of HIF-1 alpha protein. In contrast, NFAT-overexpression had no such effect, implying that NFAT-independent mechanisms were responsible for increased HIF-1 alpha levels. In addition, inhibition of HSP90 via the HSP90-inhibitor 17-AAG or siRNA abolished calcineurin A-induced upregulation of HIF-1 alpha. Consequently, upregulation of HIF-1 alpha target genes like VEGF-A, BNIP-3 or PGK-1 was also inhibited by either 17-AAG or siRNA directed against HSP90. Finally, when CnATg mice were treated with 17-AAG, they demonstrated reduced left ventricular function and capillary density.Conclusions: We describe here for the first time that overexpression of the phosphatase calcineurin A prevents the development of a capillary/myocyte mismatch despite progressive myocardial hypertrophy. This effect was mediated by HSP-90 induced stabilization of HIF-1 alpha. Further work is needed to understand this unexpected cardioprotective effect of calcineurin A. (C) 2015 Elsevier Ltd. All rights reserved.