Research ArticleCARDIAC HYPERTROPHY

Long noncoding RNA Chast promotes cardiac remodeling

Science Translational Medicine  17 Feb 2016:
Vol. 8, Issue 326, pp. 326ra22
DOI: 10.1126/scitranslmed.aaf1475

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The missing lnc in cardiac hypertrophy

RNA that does not code for a protein comprises a large portion of the human genome. These so-called noncoding RNAs are emerging as important players in disease pathogenesis, yet their functional roles are not always well known. Viereck et al. have discovered a new long noncoding RNA (lncRNA) that promotes cardiac remodeling and hypertrophy in mice, which could one day be targeted with therapeutics to treat human cardiovascular diseases. The identified lncRNA, which the authors named Chast (for “cardiac hypertrophy–associated transcript”), was discovered to be up-regulated in hypertrophic mouse hearts. When mouse and human heart cells expressed Chast, they tended to be larger than their normal counterparts. By silencing Chast with antisense oligonucleotides, mice either did not develop hypertrophy or were rescued from established disease. In a step toward translation, the authors discovered a human homolog, CHAST, that similarly caused cells in a dish to enlarge. Additional investigation in patients will confirm the relevance of this lncRNA in human disease and whether it is indeed a promising target for treating cardiac hypertrophy and heart failure.

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.

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