Abstract

During acute myocardial infarction, endoplasmic reticulum (ER) stress-induced autophagy and apoptosis have been shown as important pathogeneses of myocardial reconstruction. Importantly, hydrogen sulfide (H₂S), as a third endogenous gas signaling molecule, exerts strong cytoprotective effect on anti-ER stress, autophagy regulation and antiapoptosis. Here, we showed that H₂S treatment inhibits apoptosis by regulating ER stress–autophagy axis and improves myocardial reconstruction after acute myocardial infarction. We found that H₂S intervention improved left ventricle function, reduced glycogen deposition in myocardial tissue mesenchyme, and inhibited apoptosis. Moreover, the expressions of fibrosis indicators (Col3a1 and Col1a2), ER stress-related proteins (CHOP and BIP/ERP78), autophagy-related proteins (Beclin and ATG5), apoptosis protein (Bax), as well as fibrosis protein Col4a3bp were all decreased after treatment with H₂S. H₂S administration also maintained MMP/TIMP balance. Mechanistically, H₂S activated the PI3K/AKT signaling pathway. In addition, H₂S treatment also reduced the expressions of ER stress–related proteins, autophagy-related proteins, and apoptins in in vitro experiments. Interestingly, activation of ER stress–autophagy axis could reverse the inhibitory effect of H₂S on myocardial apoptosis. Altogether, these results suggested that exogenous H₂S suppresses myocardial apoptosis by blocking ER stress–autophagy axis, which in turn reverses cardiac remodeling after myocardial infarction.

中文翻译：

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外源性硫化氢通过调节内质网应激-自噬轴抑制细胞凋亡，并改善急性心肌梗死后的心肌重建

摘要

在急性心肌梗塞期间，内质网（ER）应激诱导的自噬和细胞凋亡已显示为心肌重建的重要病原体。重要的是，硫化氢（H ₂ S）作为第三种内源性气体信号分子，对抗ER应激，自噬调节和抗凋亡具有强大的细胞保护作用。在这里，我们证明了H ₂ S治疗通过调节ER应力-自噬轴抑制细胞凋亡，并改善了急性心肌梗塞后的心肌重建。我们发现H ₂S干预改善了左心室功能，减少了心肌组织间充质中糖原的沉积，并抑制了细胞凋亡。此外，纤维化指标（Col3a1和Col1a2），ER应激相关蛋白（CHOP和BIP / ERP78），自噬相关蛋白（Beclin和ATG5），凋亡蛋白（Bax）以及纤维化蛋白Col4a3bp的表达都用H处理后降低₂ S.H。₂行政体系也保持MMP / TIMP平衡。从机理上讲，H ₂ S激活了PI3K / AKT信号通路。此外，在体外，H ₂ S处理还降低了ER应激相关蛋白，自噬相关蛋白和凋亡素的表达。实验。有趣的是，内质网应激自噬轴的激活可以逆转H ₂ S对心肌细胞凋亡的抑制作用。总而言之，这些结果表明，外源性H ₂ S通过阻断ER应力-自噬轴来抑制心肌细胞凋亡，从而逆转心肌梗塞后的心脏重塑。