Long noncoding RNA Chast promotes cardiac remodeling

Abstract

Recent studies highlighted long noncoding RNAs (lncRNAs) to play an important role in cardiac development. However, understanding of lncRNAs in cardiac diseases is still limited. Global lncRNA expression profiling indicated that several lncRNA transcripts are deregulated during pressure overload-induced cardiac hypertrophy in mice. Using stringent selection criteria, we identified Chast (cardiac hypertrophy-associated transcript) as a potential lncRNA candidate that influences cardiomyocyte hypertrophy. Cell fractionation experiments indicated that Chast is specifically up-regulated in cardiomyocytes in vivo in transverse aortic constriction (TAC)-operated mice. In accordance, CHAST homolog in humans was significantly up-regulated in hypertrophic heart tissue from aortic stenosis patients and in human embryonic stem cell-derived cardiomyocytes upon hypertrophic stimuli. Viral-based overexpression of Chast was sufficient to induce cardiomyocyte hypertrophy in vitro and in vivo. GapmeR-mediated silencing of Chast both prevented and attenuated TAC-induced pathological cardiac remodeling with no early signs on toxicological side effects. Mechanistically, Chast negatively regulated Pleckstrin homology domain-containing protein family M member 1 (opposite strand of Chast), impeding cardiomyocyte autophagy and driving hypertrophy. These results indicate that Chast can be a potential target to prevent cardiac remodeling and highlight a general role of lncRNAs in heart diseases.

Therapeutic targeting of autophagy in myocardial infarction and heart failure

“…GapmeR-mediated Chast-silencing both prevented and attenuated experimentally induced hypertrophic cardiac remodeling [123].…”

Identification and Functional Characterization of Hypoxia-Induced Endoplasmic Reticulum Stress Regulating lncRNA (HypERlnc) in Pericytes

“…For example, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) has been shown to regulate endothelial cell function, 9 whereas lncRNA SENCR (smooth muscle and endothelial cell-enriched migration/ differentiation-associated long noncoding RNA) has been demonstrated to stabilize the smooth muscle cell contractile phenotype. 10 Recent experimental studies have outlined the importance of lncRNAs in modulating clinically relevant processes such as cholesterol synthesis 11 and cardiac hypertrophy, 12 making them promising molecular targets in cardiovascular disease. However, the contribution of lncRNAs to hPC function is yet unclear.…”

Long noncoding RNAs in cardiovascular disease, diagnosis, and therapy

“…In a whole-genome lncRNA profiling study of TAC-operated mice, Viereck et al [3] identified a RNA transcript named cardiac hypertrophy-associated ( Chast ) being highly expressed in cardiomyocytes from hypertrophic hearts. Similarly, human Chast homolog expression was induced in hypertrophic heart tissue from aortic stenosis patients.…”

“…Mechanistically, Chast overlaps with Plekhml , which is a regulatory factor for autophagy [4]. Plekhml expression inversely correlated with Chast and silencing of Plekhml mimicked the Chast overexpression phenotype, thereby blocking autophagy of cardiomyocytes and promoting cardiac hypertrophy [3]. …”