Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Department of Pediatric Cardiovascular Medicine, Woman and Child Hospital of Hubei Province, Wuhan, Hubei, 430060, China.
Biomed Res Int. 2019 Jul 4;2019:1528278. doi: 10.1155/2019/1528278. eCollection 2019.
Oxidative stress and cardiomyocytes apoptosis were closely involved in the pathological process of doxorubicin- (Dox-) induced cardiac injury. MicroRNA-451 (miR-451) was mainly expressed in cardiomyocytes. However, the role of miR-451 in Dox-induced cardiac injury remained unclear. Our study aimed to investigate the effect of miR-451 on Dox-induced cardiotoxicity in mice. We established a Dox-induced cardiotoxicity model in the mice and manipulated miR-451 expression in the heart using a miR-451 inhibitor, which was injected every other day beginning at one day before Dox injection. Oxidative stress and apoptosis in the hearts were evaluated. miR-451 levels were significantly increased in Dox-treated mice or cardiomyocytes. miR-451 inhibition attenuated Dox-induced whole-body wasting and heart atrophy, reduced cardiac injury, restored cardiac function, and improved cardiomyocyte contractile function. Moreover, miR-451 inhibition reduced oxidative stress and cardiomyocytes apoptosis in vivo and in vitro. miR-451 inhibition increased the expression of calcium binding protein 39 (Cab39) and activated adenosine monophosphate activated protein kinase (AMPK) signaling pathway. A specific inhibitor of AMPK abolished the protection provided by miR-451 inhibition against cell injury in vitro. In conclusion, miR-451 inhibition protected against Dox-induced cardiotoxicity via activation of AMPK signaling pathway.
氧化应激和心肌细胞凋亡与阿霉素（Dox）诱导的心脏损伤的病理过程密切相关。miR-451（miR-451）主要在心肌细胞中表达。然而，miR-451 在 Dox 诱导的心脏损伤中的作用尚不清楚。本研究旨在探讨 miR-451 对小鼠 Dox 诱导的心脏毒性的影响。我们建立了小鼠 Dox 诱导的心脏毒性模型，并使用 miR-451 抑制剂在心脏中操纵 miR-451 的表达，该抑制剂从 Dox 注射前一天开始每隔一天注射一次。评估心脏中的氧化应激和细胞凋亡。Dox 处理的小鼠或心肌细胞中 miR-451 水平显着升高。miR-451 抑制减轻了 Dox 诱导的全身消瘦和心脏萎缩，减少了心脏损伤，恢复了心脏功能，并改善了心肌细胞的收缩功能。此外，miR-451 抑制减轻了体内和体外的氧化应激和心肌细胞凋亡。miR-451 抑制增加了钙结合蛋白 39（Cab39）的表达并激活了 AMP 激活的蛋白激酶（AMPK）信号通路。AMPK 的特异性抑制剂消除了 miR-451 抑制在体外对细胞损伤的保护作用。总之，miR-451 抑制通过激活 AMPK 信号通路来保护 Dox 诱导的心脏毒性。
