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

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.

Secretome Signature of Cardiopoietic Cells Echoed in Rescued infarcted Heart Proteome

“…24,25 Downregulation of miR-146a-5p or miR-146b-5p alters paracrine-mediated immunomodulatory outcomes in cardiac signaling and facilitates repair postinfarction. 26,27 The present study supports the notion that secretome proficiency contributes to rescue of organ failure. [28][29][30][31][32][33][34] Indeed, paracrine functionality was echoed in proteome restoration, underscoring connectivity between secretome signature and realized regenerative efficacy.…”

“…This is concordant with miRNA centrality in regulating regenerative and cardioprotective capacity 24,25 . Downregulation of miR‐146a‐5p or miR‐146b‐5p alters paracrine‐mediated immunomodulatory outcomes in cardiac signaling and facilitates repair postinfarction 26,27 . The present study supports the notion that secretome proficiency contributes to rescue of organ failure 28‐34 .…”

Identification of miRNA-target gene regulatory networks in liver fibrosis based on bioinformatics analysis

“…Among these miRNAs, only some have been studied in organ fibrosis. miR-146b-5p has been mainly focused on the heart, and it was found to activate fibroblast proliferation, migration and fibroblast-to-myofibroblast transition, and its silencing could improve cardiac remodeling ( Liao et al, 2021 ). miR-3135b was found to be elevated in hypertrophic scars ( Zhang et al, 2020 ).…”

Bioengineering the Cardiac Conduction System: Advances in Cellular, Gene, and Tissue Engineering for Heart Rhythm Regeneration

“…Non-viral strategies for gene delivery or reprogramming might be spare of some of these issues, but possible epigenetic modifications and genetic instabilities need to be investigated in depth, as they were observed also in hiPSCs reprogrammed with non-integrating methods (Schlaeger et al, 2015 ). Even if no data are available still regarding non-integrating gene delivery for in vivo biopacemaking, the strategies of microRNA-therapeutic silencing after myocardial infarction revealed to be immunotolerated in animal models (Liao et al, 2021 ). As far as concerning bioengineered conduction tissues, immunotolerance establishment depends both on scaffolds and cells, as well as on cell culture conditions (e.g., the use of xenogeneic reagents), employed to fabricate them; therefore, a careful selection of non-immunogenic components and/or manipulations for the antigenic moiety removal are required to prevent immune rejection, as in other cardiovascular tissue engineering applications (Iop et al, 2018 ).…”