ABSTRACT

Accumulating evidence suggests that cardiomyocyte autophagy is relevant to the onset of cardiac hypertrophy (CH). Several miRNAs are involved in the occurrence of heart failure, and relevant therapeutic treatments are currently being developed. MicroRNA-377 (miR-377) is known to correlate with the progression of various cancers, however, its function in CH has not been determined. Therefore, this study aimed to evaluate miR-377 expression in H2C9 hypertrophic cardiomyocytes in vitro and in a murine model of CH. Gene expression changes were verified via qRT-PCR. Western blotting was used for evaluation of alterations in the expression of signaling pathway-related proteins. Our results indicated that miR-377 expression was markedly upregulated in mice with hypertrophic cardiomyopathy. Autophagy markers were downregulated in these mice and in hypertrophic cardiomyocytes following miR-377 transfection. In addition, we demonstrated that miR-377 acts by targeting peroxisome proliferator-activated receptor γ (PPARγ). PPARγ overexpression promoted autophagy and suppressed cyclosporine A-induced CH. In contrast, PPARγ knockdown further suppressed CH and autophagy. In conclusion, our findings indicated that miR-377 accelerates CH by inhibiting autophagy via targeting PPARγ. This newly identified miR-377/PPARγ axis improves our understanding of the molecular mechanisms underlying CH, and provides a potential new therapeutic target for its treatment.

摘要

越来越多的证据表明，心肌细胞自噬与心脏肥大（CH）的发作有关。几种miRNA参与心力衰竭的发生，目前正在开发相关的治疗方法。已知MicroRNA-377（miR-377）与各种癌症的进展相关，但是，尚未确定其在CH中的功能。因此，本研究旨在评估miR-377在体外H2C9肥厚型心肌细胞中的表达并在CH的鼠模型中 基因表达变化通过qRT-PCR验证。Western印迹用于评估信号通路相关蛋白表达的变化。我们的结果表明，miR-377表达在肥厚型心肌病小鼠中明显上调。在miR-377转染后，这些小鼠和肥厚型心肌细胞中的自噬标记被下调。另外，我们证实了miR-377的作用通过靶向过氧化物酶体增殖物激活受体γ（PPAR γ）。PPAR γ表达促进自体吞噬和抑制环孢菌素A诱发的CH。与此相反，PPAR γ击倒进一步抑制了CH和自噬。总之，我们的研究结果表明了miR-377通过经由靶向PPAR抑制自噬加速CH γ。这种新鉴定的miR-377 / PPAR γ轴提高了我们的基本CH的分子机制的理解，并提供了潜在的新的治疗靶标以用于其治疗。