Induction of autophagy markers is associated with attenuation of miR-133a in diabetic heart failure patients undergoing mechanical unloading.
Induction of autophagy markers is associated with attenuation of miR-133a in diabetic heart failure patients undergoing mechanical unloading.
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发表时间：
2015-04
影响因子：
2.2
通讯作者：
S. Nandi;M. Duryee;Hamid R. Shahshahan;G. Thiele;D. Anderson;P. Mishra
中科院分区：
文献类型：
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作者：
S. Nandi;M. Duryee;Hamid R. Shahshahan;G. Thiele;D. Anderson;P. Mishra
自噬在所有形式的心力衰竭中普遍存在，心脏保护性miR-133a在人类心力衰竭中减弱。先前关于心力衰竭患者接受左心室辅助装置(LVAD)植入的报道表明，自噬在衰竭的人的心脏的左心室中上调。在小鼠模型中的研究表明，糖尿病下调miR-133a的表达。然而，miR-133a在糖尿病心脏自噬调节中的作用尚不清楚。我们测试了这样一种假设，即糖尿病通过抑制心力衰竭患者接受LVAD植入的miR-133a而加剧心脏自噬。对15例糖尿病(D)心力衰竭患者和6例非糖尿病(ND)心力衰竭患者进行了左心内膜微核糖核酸(MiRNA)检测。对4例高度上调的ND和5例高度下调miR-133a的ND进行自噬标志物(Beclin1、LC3B、ATG3)及其上游调节因子(mTOR和AMPK)和肥大标志物(β-肌球蛋白重链)的RT-qPCR、Western blotting和免疫荧光分析。我们的结果表明，糖尿病心脏中miR-133a的减弱与自噬和肥大的诱导以及mTOR的抑制有关，而AMPK活性没有明显的差异。综上所述，miR-133a的减弱是糖尿病引起的心脏自噬和心脏肥厚的加重的原因之一。
Autophagy is ubiquitous in all forms of heart failure and cardioprotective miR-133a is attenuated in human heart failure. Previous reports from heart failure patients undergoing left ventricular assist device (LVAD) implantation demonstrated that autophagy is upregulated in the LV of the failing human heart. Studies in the murine model show that diabetes downregulates miR-133a. However, the role of miR-133a in the regulation of autophagy in diabetic hearts is unclear. We tested the hypothesis that diabetes exacerbates cardiac autophagy by inhibiting miR-133a in heart failure patients undergoing LVAD implantation. The miRNA assay was performed on the LV of 15 diabetic (D) and 6 non-diabetic (ND) heart failure patients undergoing LVAD implantation. Four ND with highly upregulated and 5 D with highly downregulated miR-133a were analyzed for autophagy markers (Beclin1, LC3B, ATG3) and their upstream regulators (mTOR and AMPK), and hypertrophy marker (beta-myosin heavy chain) by RT-qPCR, Western blotting and immunofluorescence. Our results demonstrate that attenuation of miR-133a in diabetic hearts is associated with the induction of autophagy and hypertrophy, and suppression of mTOR without appreciable difference in AMPK activity. In conclusion, attenuation of miR-133a contributes to the exacerbation of diabetes mediated cardiac autophagy and hypertrophy in heart failure patients undergoing LVAD implantation.