S-nitrosylation of Hsp90 promotes cardiac hypertrophy in mice through GSK3β signaling
S-nitrosylation of Hsp90 promotes cardiac hypertrophy in mice through GSK3β signaling
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Hsp90 的 S-亚硝基化通过 GSK3β 信号促进小鼠心脏肥大
DOI：
10.1038/s41401-021-00828-9
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发表时间：
2021-12
影响因子：
8.2
通讯作者：
Yong Ji
中科院分区：
文献类型：
--
作者：
Shuang Zhao;Tian-yu Song;Zi-yu Wang;Jie Gao;Jia-wei Cao;Lu-lu Hu;Zheng-rong Huang;Li-ping Xie;Yong Ji
心脏肥厚是慢性心力衰竭的主要诱发因素之一，缺乏有效的干预措施。探讨心肌肥厚的发病机制将揭示潜在的治疗靶点。s -亚硝基化是发生在蛋白质活性半胱氨酸上的一种翻译后修饰，介导多种细胞过程。我们在这里发现热休克蛋白90 （Hsp90）是肥厚啮齿类动物心脏中高度s -亚硝基化的靶标，Hsp90在心脏肥厚中的作用尚不明确。体外血管紧张素II （Ang II）或苯肾上腺素（PE）处理的新生大鼠心肌细胞（NRCMs）以及体内横断主动脉收缩（TAC）小鼠分离的心肌细胞中，Hsp90的s -亚硝基化（SNO-Hsp90）水平升高。结果表明，心肌肥厚过程中s -亚硝基谷胱甘肽还原酶（GSNOR）表达的降低介导了SNO-Hsp90水平的升高，GSNOR腺相关病毒表达载体（AAV9-GSNOR）的传递降低了SNO-Hsp90水平，从而减轻了心肌肥厚。质谱分析显示，半胱氨酸589 （Cys589）可能是Hsp90的s -亚硝基化位点。传递突变的AAV9-Hsp90-C589A抑制SNO-Hsp90水平并减轻心脏肥厚。我们进一步发现，SNO-Hsp90导致糖原合成酶激酶3β (GSK3β)与Hsp90的相互作用增加，导致GSK3β磷酸化升高，eIF2Bε磷酸化降低，从而加重心肌肥厚。应用GSK3β抑制剂TWS119消除了Hsp90-C589A突变对angii处理的nrcm的保护作用。总之，本研究表明SNO-Hsp90在心肌肥厚中起关键作用，可能是心肌肥厚治疗的一个治疗靶点。
Cardiac hypertrophy, as one of the major predisposing factors for chronic heart failure, lacks effective interventions. Exploring the pathogenesis of cardiac hypertrophy will reveal potential therapeutic targets. S-nitrosylation is a kind of posttranslational modification that occurs at active cysteines of proteins to mediate various cellular processes. We here identified heat shock protein 90 (Hsp90) as a highly S-nitrosylated target in the hearts of rodents with hypertrophy, and the role of Hsp90 in cardiac hypertrophy remains undefined. The S-nitrosylation of Hsp90 (SNO-Hsp90) levels were elevated in angiotensin II (Ang II)- or phenylephrine (PE)-treated neonatal rat cardiomyocytes (NRCMs) in vitro as well as in cardiomyocytes isolated from mice subjected to transverse aortic constriction (TAC) in vivo. We demonstrated that the elevated SNO-Hsp90 levels were mediated by decreased S-nitrosoglutathione reductase (GSNOR) expression during cardiac hypertrophy, and delivery of GSNOR adeno-associated virus expression vectors (AAV9-GSNOR) decreased the SNO-Hsp90 levels to attenuate cardiac hypertrophy. Mass spectrometry analysis revealed that cysteine 589 (Cys589) might be the S-nitrosylation site of Hsp90. Delivery of the mutated AAV9-Hsp90-C589A inhibited SNO-Hsp90 levels and attenuated cardiac hypertrophy. We further revealed that SNO-Hsp90 led to increased interaction of glycogen synthase kinase 3β (GSK3β) and Hsp90, leading to elevated GSK3β phosphorylation and decreased eIF2Bε phosphorylation, thereby aggravating cardiac hypertrophy. Application of GSK3β inhibitor TWS119 abolished the protective effect of Hsp90-C589A mutation in Ang II-treated NRCMs. In conclusion, this study demonstrates a critical role of SNO-Hsp90 in cardiac hypertrophy, which may be of a therapeutic target for cardiac hypertrophy treatment.
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影响因子：
20.1
作者：
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影响因子：
3
作者：
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通讯作者：
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影响因子：
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作者：
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