LncRNA TINCR attenuates cardiac hypertrophy by epigenetically silencing CaMKII

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.

The lncRNA Hand2os1/Uph locus orchestrates heart development through regulation of precise expression of Hand2

“…Several lncRNAs have been reported to have roles in regulating heart development and function. For example, depletion of Chast/Wisper and overexpression of Mhrt, Tincr or Carel protected the heart from hypertrophy in response to pressure overload following transverse aortic constriction surgery (Cai et al, 2018;Han et al, 2014b;Micheletti et al, 2017;Shao et al, 2017;Viereck et al, 2016). Inhibition of Fendrr led to embryonic lethality around E13.5 with cardiac hypoplasia (Grote et al, 2013).…”

LncRNAs in cardiac hypertrophy: From basic science to clinical application

“…Arrhythmia is always combined with HCM, which may be as- (Figure 2). 46 Lnc-H19 as the precursor of miR-675, which inhibit the expression of CaMKIIδ, is a negative regulator of cardiomyocyte hypertrophy (Figure 2). 47 Calcineurin is serine/threonine protein phosphatase regulated by CaMKII, which plays an important role in the regulation of pathological hypertrophy.…”

Long non-coding RNAs in the failing heart and vasculature

“…Another lncRNA that seems to play an important role in cardiac hypertrophy is terminal differentiation-induced ncRNA ( TINCR ). Forced expression of this lncRNA attenuated cardiac hypertrophy in mice, and decreased calmodulin-dependent protein kinase IIδ (CAMKIIδ) expression by directly targeting enhancer of zeste 2 (EZH2) [ 71 ]. EZH2 is a methyltransferase that plays a fundamental role in H3K27me3 modification and can bind to the CAMKIIδ promoter region to regulate its expression [ 72 ].…”