MicroRNA-21 prevents excessive inflammation and cardiac dysfunction after myocardial infarction through targeting KBTBD7

Linshan Yang,Bo Wang,Zhongmin Liu,Xingguang Liu,Zhenzhen Zhan,Qingqing Zhou,Yiru Wang

doi:10.1038/s41419-018-0805-5

Abstract

The excessive inflammation triggered by damage-associated molecular patterns (DAMPs) after myocardial infarction (MI) is responsible for the development of cardiac dysfunction and adverse remodeling, while the mechanisms by which inflammation is fine tuned remain to be fully elucidated. MicroRNA-21 (miR-21) has been shown to function in cardiovascular diseases, while its role in inflammatory responses and cardiac function post MI in mice remains unknown. Here, we found that miR-21 expression was markedly increased in border and infarct areas of cardiac tissues during the early inflammatory phase of MI model established by ligating the left-anterior descending coronary artery. MiR-21 knockout mice had decreased survival rates, worse cardiac dysfunction, and increased infarct and scar areas after MI compared with WT mice. MiR-21 knockout mice showed significantly higher levels of inflammatory cytokines including IL-1β, IL-6, and TNF-α in cardiac tissues, as well as infiltration of CD11b+ monocytes/macrophages with higher expression level of inflammatory cytokines. MI induced the great release of high mobility group protein B1 (HMGB1) and heat shock protein 60 (HSP60) in cardiac tissue. MiR-21 deficiency significantly promoted the inflammatory cytokine production triggered by DAMPs in macrophages, whereas, miR-21 overexpression markedly inhibited the inflammatory cytokine production. Mechanistically, miR-21 deficiency enhanced p38 and NF-κB signaling activation in cardiac tissue post MI and macrophages treated with DAMPs. MiR-21 was found to directly target kelch repeat and BTB (POZ) domain containing 7 (KBTBD7), which promoted DAMP-triggered inflammatory responses in macrophages. Furthermore, KBTBD7 interacted with MKK3/6 and promoted their activation, which in turn enhanced the activation of downstream p38 and NF-κB signaling induced by DAMPs. Therefore, our findings demonstrate that miR-21 attenuates inflammation, cardiac dysfunction, and maladaptive remodeling post MI through targeting KBTBD7 and inhibiting p38 and NF-κB signaling activation, suggesting that miR-21 may function as a novel potential therapeutic target for MI.

Highlights

Myocardial infarction (MI) resulting from coronary artery occlusion causes ischemic death of cardiac tissue
damage-associated molecular patterns (DAMPs) can be recognized by Toll like receptors (TLRs) such as TLR4 mainly expressed on macrophages which are abundant in cardiac tissue, which in turn activates downstream MAPK and NF-κB signaling, resulting in the production of inflammatory cytokines such as IL-1β, IL-6, and TNF-α by macrophages[4,5]
Since inflammatory cytokines are predominantly produced by monocytes and macrophages in cardiac tissue following MI3,5,7, and the highest increased level of miR-21 was showed in CD11b+ monocytes/macrophages as compared with that in cardiomyocytes or fibroblasts isolated from cardiac tissue of sham or MI group (Fig. S1B), we explored the effects of miR-21 deficiency on inflammatory cytokine production in these two types of immune cells

Summary

Introduction

Myocardial infarction (MI) resulting from coronary artery occlusion causes ischemic death of cardiac tissue. The pathological changes post MI in cardiac tissue can be divided into three overlapping phases: inflammatory phase, proliferative phase, and maturation phase[1,2]. Official journal of the Cell Death Differentiation Association. DAMPs can be recognized by Toll like receptors (TLRs) such as TLR4 mainly expressed on macrophages which are abundant in cardiac tissue, which in turn activates downstream MAPK and NF-κB signaling, resulting in the production of inflammatory cytokines such as IL-1β, IL-6, and TNF-α by macrophages[4,5]. During the proliferative phase, macrophages phagocytose the apoptotic or necrotic cells and activate an anti-inflammatory program through the release of TGF-β and IL-105. Post-infarction inflammation is a double-edged sword, and how to control inflammation to prevent pathological remodeling is an important issue, which remains to be fully elucidated

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Results

Conclusion