Long noncoding RNA Chast promotes cardiac remodeling

Janika Viereck, Regalla Kumarswamy, Ariana Foinquinos, Ke Xiao, Petros Avramopoulos, Meik Kunz, Marcus Dittrich, Tobias Maetzig, Karina Zimmer, Janet Remke, Annette Just, Jasmin Fendrich, Kristian Scherf, Emiliano Bolesani, Axel Schambach, Frank Weidemann, Robert Zweigerdt, Leon J. de Windt, Stefan Engelhardt, Thomas DandekarSandor Batkai, Thomas Thum*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.
Original languageEnglish
Article number326ra22
JournalScience Translational Medicine
Issue number326
Publication statusPublished - 17 Feb 2016

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