miR-421-mediated suppression of FGF13 as a novel mechanism ameliorates cardiac hypertrophy by inhibiting endoplasmic reticulum stress.

Pathological cardiac hypertrophy is an independent risk factor for heart failure. Currently, clinical treatments offer limited effectiveness, and both mortality and morbidity from cardiac hypertrophy and heart failure continue to be significant. Therefore, it is extremely urgent to find new intervention targets to prevent and alleviate pathological cardiac hypertrophy. In this study, we explored FGF13 expression and its upstream regulators in hypertrophic hearts. Firstly, we observed an increase in FGF13 expression levels in human hypertrophic myocardium tissues, as well as in mouse models of TAC-induced hypertrophy and in neonatal rat cardiomyocyte (NRCM) models induced by isoproterenol (ISO). Moreover, these elevated levels of FGF13 were shown to positively correlate with hypertrophic markers, including ANP and BNP. By using both gain-of-function and loss-of-function approaches in an in vitro hypertrophy model, we demonstrated that FGF13 knockdown could inhibit endoplasmic reticulum stress (ERS), thereby ameliorating cardiomyocyte hypertrophy. Meanwhile, we investigated the upstream regulators of FGF13 in hypertrophic hearts, and a dual-luciferase reporter assay confirmed that FGF13 is a direct target of miR-421. Overexpression of miR-421 decreased the protein level of FGF13 and ameliorated ISO-induced cardiomyocyte hypertrophy via modulating ER stress. In contrast, overexpression of FGF13 attenuated the ameliorative effect of miR-421 on ISO-induced cardiomyocyte hypertrophy. Taken together, the present results suggested that miR-421 ameliorated ISO-induced cardiomyocyte hypertrophy by negatively regulating FGF13 expression. This finding may offer a novel approach for the treatment of cardiac hypertrophy.