Inhibiting miR-22 Alleviates Cardiac Dysfunction by Regulating Sirt1 in Septic Cardiomyopathy.

Runze Wang,Yexian Fang,Ting Wei,Tiqun Yang,Zhan-Peng Huang,Wei Zhang,Haijia Zhou,Di Zeng,Jing Liu,Mingming Zhang,Yan Li,Yuerong Xu

doi:10.3389/fcell.2021.650666

Abstract

High morbidity and mortality are the most typical characteristics of septic cardiomyopathy. We aimed to reveal the role of miR-22 in septic cardiomyopathy and to explore the underlying mechanisms. miR-22 cardiac-specific knockout (miR-22cKO) mice and miR-22 cardiac-specific transgenic (miR-22cOE) mice were subjected to a cecal ligation and puncture (CLP) operation, while a sham operation was used in the control group. The echocardiogram results suggested that miR-22cKO CLP mice cardiac dysfunction was alleviated. The serum LDH and CK-MB were reduced in the miR-22cKO CLP mice. As expected, there was reduced apoptosis, increased autophagy and alleviated mitochondrial dysfunction in the miR-22cKO CLP mice, while it had contrary role in the miR-22cOE group. Inhibiting miR-22 promoted autophagy by increasing the LC3II/GAPDH ratio and decreasing the p62 level. Additionally, culturing primary cardiomyocytes with lipopolysaccharide (LPS) simulated sepsis-induced cardiomyopathy in vitro. Inhibiting miR-22 promoted autophagic flux confirmed by an increased LC3II/GAPDH ratio and reduced p62 protein level under bafilomycin A1 conditions. Knocking out miR-22 may exert a cardioprotective effect on sepsis by increasing autophagy and decreasing apoptosis via sirt1. Our results revealed that targeting miR-22 may become a new strategy for septic cardiomyopathy treatment.

Highlights

Sepsis is a serious systemic inflammatory reaction with high mortality caused by bacterial infection
To explored the role of miR-22 in septic cardiomyopathy, the cecal ligation and puncture (CLP) model was established on the miR-22cKO and wild type mice
The HE staining results, the morphology of cardiomyocytes in the miR-22cKO + CLP group was ameliorate compared with the CLP group, suggested that knocking out miR-22 can ameliorate myocardial injury in CLP-induced cardiomyopathy (Figure 1L)

Summary

Introduction

Sepsis is a serious systemic inflammatory reaction with high mortality caused by bacterial infection. The main causes of sepsis include serious complication of severe infection, severe trauma, and major surgery. Further development of this condition can lead to septic shock, serious damage to many organs and death (Semeraro et al, 2012; Kobashi et al, 2013; Martensson and Bellomo, 2015; Wagner et al, 2015). Numerous studies have reported that miRNAs play various roles in Inhibiting miR-22 Alleviates Septic Cardiomyopathy regulating inflammation, apoptosis, necrosis and autophagy in myocardial injury (Ambros, 2004; Condorelli et al, 2014; Pan et al, 2019). MicroRNA-22 (miR-22) is reported to participate in some heart diseases. MiR-22 participates in cardiac hypertrophy and remodeling (Huang et al, 2013)

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