Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype

doi:10.1007/s13238-020-00750-6

Protein Cell

2021, Vol. 12

Issue (3) : 194-212 https://doi.org/10.1007/s13238-020-00750-6

RESEARCH ARTICLE

Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype

Yiteng Liao^1,², Hao Li^1,², Hao Cao³, Yun Dong⁴, Lei Gao¹, Zhongmin Liu^1,³(

), Junbo Ge⁵(

), Hongming Zhu¹(

)

¹. 1Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
². Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
³. Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
⁴. Department of Ultrasound in Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
⁵. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China

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Abstract

Fibrotic remodeling is an adverse consequence of immune response-driven phenotypic modulation of cardiac cells following myocardial infarction (MI). MicroRNA-146b (miR-146b) is an active regulator of immunomodulation, but its function in the cardiac inflammatory cascade and its clinical implication in fibrotic remodeling following MI remain largely unknown. Herein, miR-146b-5p was found to be upregulated in the infarcted myocardium of mice and the serum of myocardial ischemia patients. Gain- and loss-of-function experiments demonstrated that miR-146b-5p was a hypoxia-induced regulator that governed the pro-fibrotic phenotype transition of cardiac cells. Overexpression of miR-146b-5p activated fibroblast proliferation, migration, and fibroblast-to-myofibroblast transition, impaired endothelial cell function and stress survival, and disturbed macrophage paracrine signaling. Interestingly, the opposite effects were observed when miR-146b-5p expression was inhibited. Luciferase assays and rescue studies demonstrated that the miR-146b-5p target genes mediating the above phenotypic modulations included interleukin 1 receptor associated kinase 1 (IRAK1) and carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1). Local delivery of a miR-146b-5p antagomir significantly reduced fibrosis and cell death, and upregulated capillary and reparative macrophages in the infarcted myocardium to restore cardiac remodeling and function in both mouse and porcine MI models. Local inhibition of miR-146b-5p may represent a novel therapeutic approach to treat cardiac fibrotic remodeling and dysfunction following MI.

Keywords cardiac fibrosis microRNA porcine model myocardial infarction

Corresponding Author(s): Zhongmin Liu,Junbo Ge,Hongming Zhu

Online First Date: 22 September 2020 Issue Date: 26 March 2021

Cite this article:

Yiteng Liao,Hao Li,Hao Cao, et al. Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype[J]. Protein Cell, 2021, 12(3): 194-212.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-020-00750-6
https://academic.hep.com.cn/pac/EN/Y2021/V12/I3/194

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