Abstract
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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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (grant nos. 82030013, 82070278, 91639204, 81870183), National Key Research and Development Program of China (2019YFA0802704) and China Postdoctoral Science Foundation (2020M681667).
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YJ, LPX and ZRH designed the research; SZ and LPX wrote the paper; SZ, TYS, ZYW, JG and JWC performed the in vitro experiments; SZ, TYS and LLH performed in vivo research and SZ and TYS analyzed data.
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Zhao, S., Song, Ty., Wang, Zy. et al. S-nitrosylation of Hsp90 promotes cardiac hypertrophy in mice through GSK3β signaling. Acta Pharmacol Sin 43, 1979–1988 (2022). https://doi.org/10.1038/s41401-021-00828-9
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DOI: https://doi.org/10.1038/s41401-021-00828-9
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