miR-590-3p Is a Novel MicroRNA in Myocarditis by Targeting Nuclear Factor Kappa-B in vivo

Abstract

Objective: Nuclear factor kappa-B (NF-κB)-induced inflammation leads to myocarditis and heart dysfunction. How microRNAs (miRNAs) contribute to this process is poorly defined. The aim of this study was to investigate whether miRNAs regulate NF-κB-induced inflammation in experimental autoimmune myocarditis (EAM) in vivo. Methods and Results: NF-κB and its related proinflammatory genes, including interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a), were activated in EAM. Profiling of NF-κB-related miRNAs revealed that miR-590-3p was strikingly reduced in EAM. We found IL-6-induced proinflammatory signaling via miR-590-3p reduction, p50 induction, NF-κB activation and IL-6/TNF-a expression. Moreover, a luciferase reporter assay demonstrated that miR-590-3p directly interacted with the 3' UTR (untranslated region) of the p50 subunit, and that miR-590-3p overexpression inhibited p50 expression. Finally, miR-590-3p transfection through adeno-associated virus significantly inhibited p50 expression, suppressed NF-κB activity and blocked IL-6/TNF-a expression in vivo, reducing the lesion area and improving cardiac function in EAM. Conclusion: miR-590-3p is a novel NF-κB-related miRNA that directly targets the p50 subunit. This may provide a novel strategy for the treatment of myocarditis.

MiR‐590 Promotes Transdifferentiation of Porcine and Human Fibroblasts Toward a Cardiomyocyte‐Like Fate by Directly Repressing Specificity Protein 1

“…The miR‐590 family, more specifically, which is comprised of 2 miRNAs—miR‐590‐5p and miR‐590‐3p—is thought to play a key role in cardiovascular disease through its protection of blood vessels, regulation of lipid metabolism, and prevention of myocarditis and atherosclerosis through its target genes . miR‐590 is expressed in human induced pluripotent stem‐cell‐derived cardiomyocytes and in the human heart .…”

“…26 The miR-590 family, more specifically, which is comprised of 2 miRNAs-miR-590-5p and miR-590-3p-is thought to play a key role in cardiovascular disease through its protection of blood vessels, regulation of lipid metabolism, and prevention of myocarditis and atherosclerosis through its target genes. [27][28][29] miR-590 is expressed in human induced pluripotent stem-cell-derived cardiomyocytes and in the human heart. 30,31 miR-590 regulates signaling pathways (TGF-b, protein kinase B) involved in cardiac fibrosis/remodeling, embryonic stem cell proliferation/cardiac differentiation, and metabolism by suppressing TGF-b receptor II.…”

Dysregulated CD4+ T Cells and microRNAs in Myocarditis

“…Suppressing secreted phosphoprotein 1 (SPP1) and p50 can inhibit NF-κB pathways, while suppressing ITCH, an NF-κB signaling suppressor, can enhance NF-κB pathways. Consist with this, overexpression of miR-93 in mice with VMC or miR-590-3p in rats with EAM reduced cardiac inflammation by targeting SPP1 or p50, respectively (145,146), while overexpression of miR-214 in neonatal murine cardiac myocytes infected with VMC enhanced myocardial inflammation by targeting ITCH (147).…”

Emodin Attenuates Lipopolysaccharide-Induced Injury via Down-Regulation of miR-223 in H9c2 Cells

“…miRNAs have emerged as key regulators of the immune system, which protect myocarditis against various stimulations by inhibiting apoptosis or targeting nuclear factor kappa-B. [26][27][28] miR-223 was initially described as a modulator of hematopoietic lineage differentiation. 29) Many studies have illustrated that miR-223 can be used as a new potential target for the diagnosis and treatment of inflammatory diseases, such as atopic dermatitis, 30) immune-mediated neuroinflammatory diseases, 31) and acute lung injury.…”