MiR-451 Silencing Inhibited Doxorubicin Exposure-Induced Cardiotoxicity in Mice.

Jun Li,Tao Chen,Suiyang Tong,Weiguo Wan,Xuejun Jiang,Wanli Liu

doi:10.1155/2019/1528278

Abstract

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.

Highlights

Doxorubicin (Dox) is an anthracycline cytostatic agent, which has been commonly used to treat solid tumors, lymphomas, and child leukemias [1]
A previous report demonstrated that miR-451 had a high expression in the hearts, and miR-451 mainly located in the cardiac myocytes [12]
MiR-451 has been shown to play a key role in the pathogenesis of diabetic cardiomyopathy in obese mice [12], miR-451 has not been further investigated for additional function in the hearts, especially in Doxinduced cardiac injury

Summary

Introduction

Doxorubicin (Dox) is an anthracycline cytostatic agent, which has been commonly used to treat solid tumors, lymphomas, and child leukemias [1]. Dox administration resulted in the arrest of cell cycle and inhibited the proliferation of tumor cells [2]. Dox caused cumulative dose-limiting toxicity, which could result in irreversible degenerative cardiomyopathy and heart failure with long-term heart problems [3]. The mechanism of Dox-induced cardiotoxicity involved the generation of oxidative stress, DNA damage, and cardiomyocytes loss [4, 5]. There was no effective approach to prevent Dox-related cardiotoxicity. Development of novel interventions that can inhibit these pathological alterations will reduce or prevent this complication related to Dox in patients with tumor

Objectives

Methods

Conclusion