Abstract
In the previous study, we established a mouse model of cardiac hypertrophy using transverse aortic constriction (TAC) and found that the expression of long non-coding RNAs TINCR was downregulated in myocardial tissue. The present study was designed to determine the potential role of TINCR in the pathogenesis of cardiac hypertrophy. Our results showed that enforced expression of TINCR could attenuate cardiac hypertrophy in TAC mice. Angiotensin II (Ang-II) was found to be associated with reduced TINCR expression and increased hypertrophy in cultured neonatal cardiomyocytes. RNA-binding protein immunoprecipitation assay confirmed that TINCR could directly bind with EZH2 in cardiomyocytes. The results of chromatin immunoprecipitation assay revealed that EZH2 could directly bind to CaMKII promoter region and mediate H3K27me3 modification. Knockdown of TINCR was found to reduce EZH2 occupancy and H3K27me3 binding in the promoter of CaMKII in cardiomyocytes. In addition, enforced expression of TINCR was found to decrease CaMKII expression and attenuate Ang-II-induced cardiomyocyte hypertrophy. Furthermore, our results also showed that Ang-II could increase CaMKII expression in cardiomyocytes, which consequently contributed to cellular hypertrophy. In conclusion, our findings demonstrated that TINCR could attenuate myocardial hypertrophy by epigenetically silencing of CaMKII, which may provide a novel therapeutic strategy for cardiac hypertrophy.
Highlights
Myocardial hypertrophy is an adaptive reaction in response to increased afterload of the heart to maintain cardiac systolic function at an early stage
The results showed that heart/body ratio, left ventricular posterior wall thickness at end-diastole (LVPWd), left ventricular posterior wall thickness at endsystole (LVPWs), interventricular septum thickness at end-diastole (IVSd) and interventricular septum thickness at end-systole (IVSs) were significantly increased in the transverse aortic constriction (TAC) group compared to the control group, while terminal differentiationinduced ncRNA (TINCR) overexpression was found to attenuate cardiac hypertrophy in the TAC mice (Figure 1B–1F)
The results indicated that cross-sectional area (CSA) was markedly increased in the TAC mice and reduced following treatment with lentivirus pcDNA-TINCR (Figure 2A, 2B)
Summary
Myocardial hypertrophy is an adaptive reaction in response to increased afterload of the heart to maintain cardiac systolic function at an early stage. Sustained myocardial hypertrophy is associated with maladaptive ventricular remodelling and increased incidence of heart failure. Long non-coding RNAs (lncRNAs) are transcribed RNA molecules > 200 nucleotides in length without known protein-coding function. They can regulate the expression of target genes at epigenetic, transcriptional, and post-transcriptional levels [2]. Only a limited number of lncRNAs have been found to be associated with myocardial hypertrophy. Wang et al indicated that lncRNA CHRF was involved in the regulation of cardiac hypertrophy by targeting miR-489 [3]. Han et al found that lncRNA Mhrt could protect the heart against pathological hypertrophy [4]
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