MiRNA‐339‐5p promotes isoproterenol‐induced cardiomyocyte hypertrophy by targeting VCP to activate the mTOR signaling

Abstract

MicroRNAs (miRNAs) regulate multiple biological processes and participate in various cardiovascular diseases. This study aims to investigate the role of miR-339-5p in cardiomyocyte hypertrophy and the involved mechanism. Neonatal rat cardiomyocytes (NRCMs) were cultured and stimulated with isoproterenol (ISO). The hypertrophic responses were monitored by measuring the cell surface area and expression of hypertrophic markers including β-myosin heavy chain (β-MHC) and atrial natriuretic factor (ANF). Bioinformatic prediction tools and dual-luciferase reporter assay were performed to identify the target gene of miR-339-5p. Quantitative realtime polymerase chain reaction and western blot analysis were used to determine the levels of miR-339-5p and its downstream effectors. Our data showed that miR-339-5p was upregulated during cardiomyocyte hypertrophy triggered by ISO. MiR-339-5p overexpression resulted in enlargement of cell size and increased the levels of hypertrophic markers. In contrast, inhibition of miR-339-5p significantly attenuated ISO-induced hypertrophic responses of NRCMs. Valosin-containing protein (VCP), a suppressor of cardiac hypertrophy via inhibiting mechanistic target of rapamycin (mTOR) signaling, was validated as a target of miR-339-5p. MiR-339-5p suppressed VCP protein expression, leading to elevated phosphorylation of mTOR and ribosomal protein S6 kinase (S6K). VCP depletion activated the mTOR/S6K cascade and could compromise the anti-hypertrophic effects of miR-339-5p inhibitor. Additionally, the hypertrophic responses caused by miR-339-5p was alleviated in the presence of mTOR inhibitor rapamycin. In conclusion, our research revealed that miR-339-5p promoted ISO-induced cardiomyocyte hypertrophy by targeting VCP to activate the mTOR signaling, suggesting a promising therapeutic intervention by interfering miR-339-5p.

mTORC1 hyperactivation and resultant suppression of macroautophagy contribute to the induction of cardiomyocyte necroptosis by catecholamine surges

“…Previous studies addressed the importance of mTORC1 and mTORC1‐regulated macroautophagy in cardiac hypertrophy, myocardial ischemic injury, and heart failure although the role of mTORC1 in the induction of cardiomyocyte necrosis has been controversial. Most studies have acknowledged that mTORC1 signaling is activated in the induction of cardiac hypertrophy by chronic infusion of ISO, probably due to the important regulatory role of mTORC1‐P70S6K in protein synthesis required for cardiac hypertrophy (Bi et al., 2022; Gao et al., 2020a, 2020b; Lin et al., 2022; Mao et al., 2020; Sun et al., 2021). Mao et al.…”

Puerarin attenuates isoproterenol‑induced myocardial hypertrophy via inhibition of the Wnt/β‑catenin signaling pathway

“…A previous study used surface area of cells stained with gentian violet to assess MH (68). Studies have also aimed to use cell surface area to assess the role of miR-339-5p in cardiomyocyte hypertrophy (69) and determine the therapeutic potential of pyrroloquinoline quinone for ISO-induced cardiac hypertrophy (59). In the present study, pretreatment with PU was demonstrated to exert protective effects against ISO-induced MH, demonstrated by decreased area of cardiomyocytes and expression of markers of cardiac hypertrophy.…”

Progress and Challenges of Understanding Cardiorenal Syndrome Type 3

“…Other miRNAs may be called pro-hypertrophic miR-NAs because of regulating key cardiac components during hypertrophy. miR-339-5p contributes to cardiomyocyte hypertrophy by depleting valosin-containing protein (VCP), in turn promoting activation of the mTOR/S6K pathway, an important sarcomeric protein synthesis pathway [73,74]. miR-208a and miR-208b are only expressed in the heart together with MCH and β-myosin heavy chain (β-MHC).…”