The Roles And Mechanisms Of MiR-21-3p Regulating Cardiac Hypertrophic Response By Targeting Histone Deacetylase-8

Background and Aim Cardiac hypertrophy refers to increased heart size with no change in the number of myocardial cells. Initially, cardiac hypertrophy is an adaptive response to altered stress and injury. Sustained external stress often leads to maladaptive pathological hypertrophy. Pathological hypertrophy is accompanied by adverse events, such as increased expression of foetal gene, downregulated cardiac contractile proteins, perivascular and interstitial fibrosis and impaired heart function. Cardiac hypertrophy often results in severely pathological cardiac disease, including reduced heart function, cardiomyopathy and so on. Sustained pathological hypertrophy is a key risk factor for the development of heart failure and associated with an increased risk of mortality and morbidity.miRNAs are endogenous small non-coding RNAs and the length of it is18-25nt. miRNAs exerts its biological effect by post-transcriptional regulation of gene expression. Binding of miRNAs to target mRNAs3’ UTR usually results in the inhibition of target gene expression by either inhibiting the translation or degrading the target mRNA. More and more evidences suggest that miRNAs play an important role in pathogenesis of cardiac hypertrophy. Increasing evidence has revealed that miRNAs play an important role in cardiac hypertrophy. Multiple miRNAs have been identified as biomarkers for the diagnosis and prognosis of cardiac hypertrophy. This study was designed to investigate the effect and mechanism of miR-21-3p in cardiac hypertrophy.Methods and ResultsOur study found that the expression of miR-21-3p decreased in TAC-induced and Angll-induced hypertrophic mice. To further explore the effect of miR-21-3p on cardiac hypertrophy, rAAV-miR-21-3p was administered in mice via tail vein. As determined by cardiac function measurement and cardiac hypertrophy biomarkers detection, overexpression of miR-21-3p significantly suppressed both TAC-induced and Angll-induced cardiac hypertrophy. In addition, Western blots showed that miR-21-3p inhibited the protein expression of histone deacetylase8(HDAC8), and luciferase reporter assays showed that miR-21-3p directly binds to the3’UTR of HDAC8. Furthermore, restored HDAC8expression attenuated the effect of miR-21-3p on Akt/Gsk3p Pathway by modulating phos-Akt and phos-Gsk3β.ConclusionsOur results showed that miR-21-3p markedly suppressed cardiac hypertrophy response in TAC-induced and AngⅡ-induced hypertrophic mice. miR-21-3p attenuated cardiac hypertrophy response by inhibiting HDAC8expression to affect Akt/Gsk3β pathway. Akt/Gsk3β pathway is the mediator of miR-21-3p/HDAC8pathway mediated hypertrophic response. The modulation of miR-21-3p may provide a novel therapeutic methods for cardiac hypertrophy.