1. Hydrogen sulfide regulates SERCA2a SUMOylation by S-Sulfhydration of SENP1 to ameliorate cardiac systole-diastole function in diabetic cardiomyopathy.
- Author
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Peng S, Wang M, Zhang S, Liu N, Li Q, Kang J, Chen L, Li M, Pang K, Huang J, Lu F, Zhao D, and Zhang W
- Subjects
- Animals, Mice, Rats, Calcium metabolism, Cysteine Endopeptidases metabolism, Diastole, Endopeptidases metabolism, Mammals, Myocytes, Cardiac metabolism, Peptide Hydrolases metabolism, Sumoylation, Systole, Diabetes Mellitus, Type 2 metabolism, Diabetic Cardiomyopathies drug therapy, Diabetic Cardiomyopathies metabolism, Hydrogen Sulfide pharmacology, Hydrogen Sulfide metabolism
- Abstract
Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus that eventually progresses to heart failure. The sarco(endo)plasmic reticulum calcium ATPase 2a (SERCA2a), an important calcium pump in cardiomyocytes, is closely related to myocardial systolic-diastolic function. In mammalian cells, hydrogen sulfide (H
2 S), as a second messenger, antioxidant, and sulfurizing agent, is involved in diverse biological processes. Despite the importance of H2 S for protection against DCM, the mechanisms remain poorly understood. The aim of the present study was to determine whether H2 S regulates intracellular calcium homeostasis by acting on SERCA2a to reduce cardiomyocyte apoptosis during DCM. Db/db mice were injected with NaHS for 18 weeks. Neonatal rat cardiomyocytes (NRCMs) were treated with high glucose, palmitate, oleate, and NaHS for 48 h. Compared to the NaHS-treated groups, in vivo and in vitro type 2 diabetic models both showed reduced intracellular H2 S content, reduced cystathionine γ-lyase (CSE) expression, impaired cardiac function, decreased SERCA2a expression and decreased SERCA2a activity, reduced SUMOylation of SERCA2a, increased sentrin-specific protease 1 (SENP1) expression, and disruption of calcium homeostasis leading to activation of the mitochondrial apoptosis pathway. Compared to the NaHS-treated type 2 diabetes cellular model, overexpression of SENP1 C683A reduced the S-sulfhydration of SENP1, reduced the SUMOylation of SERCA2a, reduced the increased expression and activity of SERCA2a, and induced mitochondrial apoptosis in cardiomyocytes. These results suggested that exogenous H2 S elevates SENP1 S-sulfhydration to increase SERCA2a SUMOylation, improve myocardial systolic-diastolic function, and decrease cardiomyocyte apoptosis in DCM., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Masson SAS.)- Published
- 2023
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