Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs (miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34c-5p on cardiac hypertrophy and the mechanism involved. The expression of miR-34c-5p was proved to be elevated in heart tissues from isoprenaline (ISO)-infused mice. ISO also promoted miR-34c-5p level in primary cultures of neonatal rat cardiomyocytes (NRCMs). Transfection with miR-34c-5p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor (Anf) and β-myosin heavy chain (β-Mhc) in NRCMs. In contrast, treatment with miR-34c-5p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34c-5p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34c-5p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34c-5p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4B (ATG4B) was identified as a direct target of miR-34c-5p, and miR-34c-5p was certified to interact with 3' untranslated region of Atg4b mRNA by dual-luciferase reporter assay. miR-34c-5p reduced the expression of ATG4B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34c-5p abolished the detrimental effects of ISO by restoring ATG4B and increasing autophagy. In conclusion, our findings illuminate that miR-34c-5p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4B and autophagy. It suggests that regulation of miR-34c-5p may offer a new way for handling hypertrophy-related cardiac dysfunction.
Keywords: 3-MA, 3-methyladenine; 3′ UTR, 3′ untranslated region; ANF, atrial natriuretic factor; ATG4B; ATG4B, autophagy related gene 4B; Autophagic flux; Autophagy; BNP, brain natriuretic polypeptide; Baf A1, bafilomycin A1; CQ, Chloroquine; EF, ejection fraction; FS, fractional shortening; GFP, green fluorescent protein; HE, hematoxylin–eosin; ISO, isoprenaline; IVS,d: interventricular septal wall dimension at end-diastole, IVS,s: interventricular septal well dimension at end-systole; Isoprenaline; LC3; LC3, microtubule-associated protein 1 light chain 3; LV Vol,d, left ventricular end-diastolic volume; LV Vol,s, left ventricular end-systolic volume; LVID,d, left ventricular end-diastolic internal diameter; LVID,s, left ventricular end-systolic internal diameter; LVPW,d, left ventricular end-diastolic posterior wall thickness; LVPW,s, left ventricular end-systolic posterior wall thickness; Mice; NS, normal saline; Neonatal rat cardiomyocytes; PSR, Picric–Sirius red; Pathological cardiac hypertrophy; mTOR, mammalian target of rapamycin; miR-34c-5p; miRNA, microRNA; qRT-PCR, quantitative real-time polymerase chain reaction; β-AR, β-adrenergic receptor; β-MHC, beta-myosin heavy chain.
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