The long noncoding RNA XIST regulates cardiac hypertrophy by targeting miR-101

Abstract

Cardiac hypertrophy and its resultant heart failure are among the most common causes of mortality, worldwide. Long noncoding RNAs (lncRNAs) are involved in diverse biological processes, and their vital role in the regulation of cardiac hypertrophy is increasingly being discovered. Nevertheless, the biological roles of lncRNA X-inactive specific transcript (XIST) in cardiac hypertrophy are scarcely reported, and the current study was designed to determine whether cardiac hypertrophy can be regulated by XIST and to elucidate the related mechanism. The animals were randomized to receive either an adeno-associated virus expressing XIST or control plasmid via a single bolus-tail vein injection. Two weeks later, hypertrophy was established by transverse aortic constriction (TAC) surgery. In vitro, H9c2 cells were used to explore the potential molecular mechanism of XIST in the regulation of phenylephrine (PE)-induced cardiomyocyte hypertrophy. A luciferase reporter assay and RNA immunoprecipitation were performed to explore the relationships among XIST, microRNA (miR)-101, and toll-like receptor 2 (TLR2). In this study, we demonstrated that the expression of XIST was significantly upregulated in hypertrophic mouse hearts and PE-treated cardiomyocytes. Then, we observed that knockdown of XIST attenuated PE-induced cardiomyocyte hypertrophy. Conversely, overexpression of XIST aggravated TAC-induced cardiac hypertrophy. Finally, we demonstrated that miR-101 was a direct target of XIST, whereas TLR2 was a target of miR-101. Rescue assays further confirmed that XIST promoted the progression of cardiac hypertrophy through competitively binding with miR-101 to enhance the expression of TLR2. Collectively, these in vivo and in vitro findings identify XIST as a necessary regulator of cardiac hypertrophy due to its regulation of the miR-101/TLR2 axis, suggesting that XIST might act as a therapeutic target for the treatment of cardiac hypertrophy and heart failure.

Keywords: TLR2; cardiac hypertrophy; lncRNA XIST; miR-101.