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Sci Transl Med. 2016 Feb 17;8(326):326ra22. doi: 10.1126/scitranslmed.aaf1475.

Long noncoding RNA Chast promotes cardiac remodeling.

Author information

1
Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Integriertes Forschungs- und Behandlungszentrum Transplantation (IFB-Tx), Hannover Medical School, D-30625 Hannover, Germany. Excellence Cluster REBIRTH, Hannover Medical School, D-30625 Hannover, Germany.
2
Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Integriertes Forschungs- und Behandlungszentrum Transplantation (IFB-Tx), Hannover Medical School, D-30625 Hannover, Germany.
3
Institute of Pharmacology and Toxicology, Technical University of Munich, D-80802 Munich, Germany. German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, D-80802 Munich, Germany.
4
Department of Bioinformatics, University of Würzburg, D-97074 Würzburg, Germany.
5
Department of Bioinformatics, University of Würzburg, D-97074 Würzburg, Germany. Institute of Human Genetics, University of Würzburg, D-97074 Würzburg, Germany.
6
Institute of Experimental Hematology, Hannover Medical School, D-30625 Hannover, Germany.
7
Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, D-30625 Hannover, Germany.
8
Department of Cardiology, Julius-Maximilians University, D-97080 Würzburg, Germany. Comprehensive Heart Failure Center, University of Würzburg, D-97078 Würzburg, Germany.
9
Department of Cardiology, Maastricht University, 6202 AZ Maastricht, Netherlands.
10
Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Integriertes Forschungs- und Behandlungszentrum Transplantation (IFB-Tx), Hannover Medical School, D-30625 Hannover, Germany. Excellence Cluster REBIRTH, Hannover Medical School, D-30625 Hannover, Germany. National Heart and Lung Institute, Imperial College London, SW3 6NP London, UK. thum.thomas@mh-hannover.de.

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.

PMID:
26888430
DOI:
10.1126/scitranslmed.aaf1475
[Indexed for MEDLINE]

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