Rosuvastatin exerts cardioprotective effect in lipopolysaccharide-mediated injury of cardiomyocytes in an MG53-dependent manner

Jiawei Zhuang,Jian Huang,Yiquan Lai,Jiamao Wang,Gangyi Cheng,Shaoyi Zheng,Hongwei Guo,Zhonggui Shan

doi:10.1186/s12872-022-02458-3

Abstract

BackgroundMyocarditis is a cardiomyopathy associated with the inflammatory response. Rosuvastatin (RS) demonstrates cardioprotective effect in the clinical setting, although its cellular and molecular mechanisms in ameliorating myocarditis are largely unknown. MG53 (muscle-specific E3 ligase Mitsugumin 53), a newly identified striated muscle-specific protein, is involved in skeletal muscle membrane repair. We aimed to explore whether RS mediated the repair of cardiomyocytes in an MG53-dependent manner.MethodsThe RS-induced upregulation of MG53 was determined using RT-qPCR and western blotting. A lipopolysaccharide (LPS)-induced cell inflammatory model was constructed using rat cardiac muscle cell H9C2. Inflammatory injury was evaluated according to the alterations of cell viability, mitochondrial membrane potential, cell apoptosis, and expression of pro-inflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1). Small interfering RNAs (siRNAs) were used to silence MG53. The cardioprotective effect of RS and the inhibition of this protection by MG53 silence were evaluated in the forementioned in vitro model. The underlying mechanism was finally investigated using western blotting to detected the expressions of apoptotic markers (Bcl-2, Bax, Cleaved caspase-9, Cleaved caspase-3), cell cycle regulatory factors (Cyclin A, Cyclin E1, Cyclin D1, CDK2), and components involved in NF-κB signaling pathway (p-IκBa, Iκba, p-p65, p65).ResultsRS ameliorated LPS-induced inflammatory injury. RS upregulated the expression of MG53. MG53 was crucial for the RS-mediated repair response in vitro. Ablation of MG53 inhibited the RS-mediated protective effect. Furthermore, RS and MG53 interact in multiple signaling pathways to modulate recovery.ConclusionRS exerts cardioprotective effect in an MG53-dependent manner. MG53 may serve as a novel drug target for myocarditis treatment.

Highlights

Myocarditis, an infectious disease, is commonly caused by Type B Coxsackievirus (CVB) and characterized by myocardial inflammatory cell infiltration and nonischemic myocytic necrosis
Development of in vitro myocarditis model of LPS‐treated H9C2 cells To mimic the conditions of myocarditis, H9C2 cells were treated with different concentrations of LPS for 24 h
We found that the mRNA levels of IL-1β, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1), as assessed using RTqPCR, were significantly increased by LPS stimulation (Fig. 1F, G)

Summary

Introduction

Myocarditis, an infectious disease, is commonly caused by Type B Coxsackievirus (CVB) and characterized by myocardial inflammatory cell infiltration and nonischemic myocytic necrosis. The severe symptoms can vary from a mild infection to sudden cardiac arrest in young and healthy individuals [3]. Myocarditis contributes much to the mortality of people less than 40 years old and constitutes approximately 20% of cardiovascular disease (CVD) events. The dilated cardiomyopathy caused by myocarditis can progress to cardiac arrest, whose 10-year survival probability is < 40% [5]. Myocarditis is a cardiomyopathy associated with the inflammatory response. MG53 (muscle-specific E3 ligase Mitsugumin 53), a newly identified striated musclespecific protein, is involved in skeletal muscle membrane repair. We aimed to explore whether RS mediated the repair of cardiomyocytes in an MG53-dependent manner

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