Simvastatin attenuates the c-Raf/Erk and calcineurin-NFATc2 pathways via inhibition of Hsp90 activity during the development of heart failure
Simvastatin attenuates the c-Raf/Erk and calcineurin-NFATc2 pathways via inhibition of Hsp90 activity during the development of heart failure
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辛伐他汀通过抑制心力衰竭发展过程中的 Hsp90 活性来减弱 c-Raf/Erk 和钙调神经磷酸酶-NFATc2 通路
DOI：
10.1016/j.jphs.2022.11.002
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发表时间：
2023
影响因子：
3.5
通讯作者：
Tanonaka Kouichi
中科院分区：
文献类型：
--
作者：
Marunouchi Tetsuro;Fujita Kyo;Takahashi Kirara;Namiki Shunsuke;Kyo Lina;Uchida Manami;Yano Emi;Tanonaka Kouichi
Hsp90是一种分子伴侣，有助于客户蛋白的激活和稳定。在我们之前的研究中，我们发现在慢性心力衰竭动物模型的发展过程中，抑制Hsp90可以延缓心脏重塑。辛伐他汀是一种HMG-CoA还原酶抑制剂，已被证明可以抑制Hsp90。然而，辛伐他汀是否可以通过抑制Hsp90来预防心脏重构尚不清楚。因此，辛伐他汀对心肌梗死后慢性心力衰竭大鼠模型的影响进行了研究。结果显示辛伐他汀通过抑制心脏纤维化来减少心脏重塑。此外，辛伐他汀降低了心肌重构过程中参与细胞内信号传导的c-Raf和钙调磷酸酶的表达。在体外，我们发现在辛伐他汀存在下培养的成纤维细胞中，Hsp90与c-Raf和钙调磷酸酶的相互作用减少，这些客户蛋白的表达水平降低。此外，辛伐他汀还能减少成纤维细胞的增殖、迁移和胶原蛋白的产生。这些结果提示，抑制Hsp90是辛伐他汀抑制心肌重构发展的部分原因。
Hsp90 is a molecular chaperone that contributes to the activation and stabilization of client proteins. In our previous studies, we found that inhibition of Hsp90 delayed cardiac remodeling during the development of chronic heart failure in animal models. Simvastatin, an inhibitor of HMG-CoA reductase, has been shown to inhibit Hsp90. However, it is unclear whether simvastatin can prevent cardiac remodeling by inhibiting Hsp90. Therefore, the effects of simvastatin were examined in a rat model of chronic heart failure following myocardial infarction. The results showed that simvastatin reduced cardiac remodeling by inhibiting cardiac fibrosis. Furthermore, simvastatin decreased the expression of c-Raf and calcineurin, which are involved in intracellular signaling during the development of myocardial remodeling.In vitro, we found that the interaction of Hsp90 with c-Raf and calcineurin was reduced and the expression levels these client proteins were decreased in fibroblasts cultured in the presence of simvastatin. In addition, simvastatin also reduced proliferation, migration, and collagen production of fibroblasts. These results suggest that Hsp90 inhibition is partly responsible for the inhibitory effect of simvastatin on the development of myocardial remodeling.