Hydrogen Sulfide Regulates SERCA2a Ubiquitylation via Muscle RING Finger-1 S-Sulfhydration to Affect Cardiac Contractility in db/db Mice.
Hydrogen Sulfide Regulates SERCA2a Ubiquitylation via Muscle RING Finger-1 S-Sulfhydration to Affect Cardiac Contractility in db/db Mice.
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作者：
硫化氢（H2S）作为一种气体递质，参与多种病理生理过程。糖尿病性心肌病（DCM）是糖尿病（DM）的主要并发症，可导致心肌结构和功能异常，最终导致心力衰竭（HF）。收缩和舒张功能障碍是心力衰竭的基本特征。SERCA2a作为内质网钙转运的关键酶，影响心肌舒张和收缩过程。H2S可以保护心脏功能免受糖尿病心脏的影响，但其机制尚不清楚。本研究发现，外源性H2S通过调控H2S/MuRF1/SERCA2a/心脏收缩通路影响细胞钙转运。我们的研究结果显示，与db/db小鼠相比，外源H2S恢复了CSE和SERCA2a的蛋白表达水平以及SERCA2a的活性，同时降低了胞质钙浓度和MuRF1的表达。我们证明了MuRF1可以通过共免疫沉淀与SERCA2a相互作用。通过LC-MS/MS蛋白泛素化分析，我们发现与nahs处理的db/db小鼠相比，db/db小鼠心脏组织中147种泛素化水平升高的蛋白，包括SERCA2a。我们的研究进一步发现，NaHS修饰了MuRF1 s -巯基化，增强了SERCA2a的活性和表达。在高血糖和高脂血症下，MuRF1- cys44突变质粒的过表达降低了MuRF1的s -巯基化水平，降低了SERCA2a的泛素化水平和细胞内Ca2+浓度。这些发现表明H2S通过Cys44的MuRF1 s -巯基化调节SERCA2a泛素化，以防止因胞质钙增加而导致的心肌收缩能力下降。
Hydrogen sulfide (H2S), as a gasotransmitter, is involved in various pathophysiological processes. Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus (DM), which leads to structural and functional abnormalities of the myocardium and eventually causes heart failure (HF). Systolic and diastolic dysfunction are fundamental features of heart failure. SERCA2a, as a key enzyme for calcium transport in the endoplasmic reticulum (ER), affects the process of myocardial relaxation and contraction. H2S can protect the cardiac function against diabetic hearts, however, its mechanisms are unclear. This study found that exogenous H2S affects cellular calcium transport by regulating the H2S/MuRF1/SERCA2a/cardiac contractile pathway. Our results showed that, compared with the db/db mice, exogenous H2S restored the protein expression levels of CSE and SERCA2a, and the activity of SERCA2a, while reducing cytosolic calcium concentrations and MuRF1 expression. We demonstrated that MuRF1 could interact with SERCA2a via co-immunoprecipitation. Using LC-MS/MS protein ubiquitylation analysis, we identified 147 proteins with increased ubiquitination levels, including SERCA2a, in the cardiac tissues of the db/db mice compared with NaHS-treated db/db mice. Our studies further revealed that NaHS administration modified MuRF1 S-sulfhydration and enhanced the activity and expression of SERCA2a. Under hyperglycemia and hyperlipidemia, overexpression of the MuRF1-Cys44 mutant plasmid reduced the S-sulfhydration level of MuRF1 and decreased the ubiquitination level of SERCA2a and the intracellular Ca2+ concentration. These findings suggested that H2S modulates SERCA2a ubiquitination through MuRF1 S-sulfhydration of Cys44 to prevent decreased myocardial contractility due to increased cytosolic calcium.
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