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.
Highlights
Myocardial infarction is the leading cause of mortality and morbidity worldwide (Nagpal et al, 2016), indicating an Modulating miR-146b-5p improves porcine cardiac remodeling urgent need for studies investigating the underlying mechanisms of myocardial infarction (MI) to identify innovative therapeutic strategies.Pathological cardiac remodeling is characterized by complex multicellular alterations, such as cardiomyocyte death, immune cell activation, and excessive deposition of the extracellular matrix, that exacerbate cardiac dysfunction, and often progresses to heart failure (Sutton and Sharpe, 2000; Prabhu and Frangogiannis, 2016a, b; Shiraishi et al, 2016)
Using quantitative real-time polymerase chain reaction, we found that miR-146b-5p expression was significantly increased in the plasma of chronic total occlusion (CTO) patients compared to noischemia volunteers (n = 8 per group, P = 0.02; Fig. 1A)
We found that miR-146b-5p expression increased continuously in the infarct zone, but not in the remote myocardium, over 14 days following the induction of MI (Fig. 1E)
Summary
Myocardial infarction is the leading cause of mortality and morbidity worldwide (Nagpal et al, 2016), indicating an Modulating miR-146b-5p improves porcine cardiac remodeling urgent need for studies investigating the underlying mechanisms of MI to identify innovative therapeutic strategies.Pathological cardiac remodeling is characterized by complex multicellular alterations, such as cardiomyocyte death, immune cell activation, and excessive deposition of the extracellular matrix, that exacerbate cardiac dysfunction, and often progresses to heart failure (Sutton and Sharpe, 2000; Prabhu and Frangogiannis, 2016a, b; Shiraishi et al, 2016). Myocardial infarction is the leading cause of mortality and morbidity worldwide (Nagpal et al, 2016), indicating an Modulating miR-146b-5p improves porcine cardiac remodeling urgent need for studies investigating the underlying mechanisms of MI to identify innovative therapeutic strategies. Pioneering studies have demonstrated that adverse remodeling following MI is caused by the phenotypic modulation of cardiac cells, with the inappropriate and untimely activation and resolution of inflammation being a crucial driving factor (Epelman et al, 2015; Westman et al, 2016; Meyer et al, 2017; Huang and Frangogiannis, 2018). Therapeutic modulation of immunoregulatory factors and reparative phenotypes of resident cells may be a promising approach for preventing post-infarction remodeling (Prabhu and Frangogiannis, 2016a, b). The functions of these microRNAs in the cardiac inflammatory cascade and adverse remodeling remain unclear
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