Exogenous H2S Protects Against Diabetic Cardiomyopathy by Activating Autophagy via the AMPK/mTOR Pathway
Exogenous H2S Protects Against Diabetic Cardiomyopathy by Activating Autophagy via the AMPK/mTOR Pathway
复制标题
外源性 H2S 通过 AMPK/mTOR 途径激活自噬来预防糖尿病心肌病
DOI：
10.1159/000481758
复制
发表时间：
2017-01-01
影响因子：
--
通讯作者：
Lu, Fanghao
中科院分区：
文献类型：
--
作者：
Yang, Fan;Zhang, Linxue;Lu, Fanghao
背景/目的：自噬通过对细胞成分的处理和再循环在细胞内环境稳定中起重要作用。硫化氢（H2S）是第三种被证明具有心脏保护作用的内源性气体。鉴于自噬在心脏保护中的调节作用，本研究旨在研究高糖处理期间H2S通过自噬的保护作用。方法：本研究观察了血浆和心肌组织中H2S含量、线粒体和自噬体超微结构的变化。本研究还研究了使用Hoechst/PI的凋亡率以及用或不用GYY 4137处理的H9 C2细胞中自噬相关蛋白和线粒体凋亡蛋白的表达。分离心肌线粒体，测定RCR和ADP/O比值。用siRNA转染进行AMPK敲低。结果如下：在STZ诱导的糖尿病模型中，NaHS处理不仅增加糖尿病组p-AMPK的表达，而且进一步激活细胞自噬。高糖48小时后，自噬体和细胞活力减少。自噬细胞超微结构观察和LC 3-I/LC 3-II转化证实了H2S可诱导细胞自噬。此外，线粒体膜电位（MMP）显著降低。自噬相关蛋白的表达水平显著升高。此外，H2S激活AMPK/雷帕霉素（mTOR）信号通路。结论：我们的研究结果表明，H2S降低氧化应激，保护线粒体免受损伤，激活自噬，并最终通过AMPK/mTOR途径导致心脏保护。
Background/Aim: Autophagy plays an important role in cellular homeostasis through the disposal and recycling of cellular components. Hydrogen sulphide (H2S) is the third endogenous gas that has been shown to confer cardiac protective effects. Given the regulation of autophagy in cardioprotection, this study aimed to investigate the protective effects of H2S via autophagy during high glucose treatment. Methods: This study investigated the content of H2S in the plasma as well as myocardial, ultrastructural changes in mitochondria and autophagosomes. This study also investigated the apoptotic rate using Hoechst/PI as well as expression of autophagy-associated proteins and mitochondrial apoptotic proteins in H9C2 cells treated with or without GYY4137. Mitochondria of cardiac tissues were isolated and RCR and ADP/O were also detected. AMPK knockdown was performed with siRNA transfection. Results: In a STZ-induced diabetic model, NaHS treatment not only increased the expression of p-AMPK in diabetic group but further activated cell autophagy. Following 48h high glucose, autophagosomes and cell viability were reduced. The present results showed that autophagy could be induced by H2S, which was verified by autophagic ultrastructural observation and LC3-I/LC3-II conversion. In addition, the mitochondrial membrane potential (MMP) was significantly decreased. The expressions levels of autophagic-related proteins were significantly elevated. Moreover, H2S activated the AMPK/rapamycin (mTOR) signalling pathway. Conclusions: Our findings demonstrated that H2S decreases oxidative stress and protects against mitochondria injury, activates autophagy, and eventually leads to cardiac protection via the AMPK/mTOR pathway.