Editors' ChoiceHeart Failure

The Key to Myheart

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Science Translational Medicine  27 Aug 2014:
Vol. 6, Issue 251, pp. 251ec146
DOI: 10.1126/scitranslmed.3010126

Heart failure (HF) is a leading cause of hospitalization and death in the United States. Five-year mortality rates exceed 40% despite the current standard of care, highlighting the urgent need for novel therapeutic approaches. Because broad abnormalities in gene expression are central to HF pathogenesis, modulation of cardiac gene control mechanisms has become an area of intense therapeutic interest. Although progress has been made in understanding the gene-regulatory function small noncoding RNAs, such as microRNAs, in HF, the role of long noncoding RNA (lncRNA) species in adult heart tissue is unknown. Now, Han et al. report the discovery of a cardioprotective lncRNA cluster named Myheart, establishing a role for lncRNAs in HF pathogenesis.

Myheart is a cluster of conserved cardiac-specific lncRNAs originating from antisense transcription within the MYH7 (cardiac muscle β myosin heavy chain) locus. Myheart expression is reduced in pressure-overloaded mouse hearts and in heart tissues from patients with cardiomyopathy. During pathological stress, repression of Myheart is mediated by a protein called BRG1. Heart cell–specific overexpression of Mhrt779 (the most abundant transcript from this cluster) protected against cardiac hypertrophy (enlargement of the heart), scar buildup, and contractile dysfunction in a mouse model of pressure overload. Mhrt779 was found to interact with BRG1, and this RNA–protein interaction inhibited BRG1 recruitment and transcriptional activity at the Myh7, Myh6, and Opn loci. Future studies using unbiased screens for Myheart-interacting proteins, and genome-wide analyses of chromatin state and transcriptional activity will provide insight into potentially broader aspects of this lncRNA cluster’s function.

This study is the first to implicate lncRNAs in HF pathogenesis and opens the door for a deeper understanding of how Myheart and other cardiac lncRNAs might function in this disease. Because RNAs can be chemically modified and delivered as drugs, the design of new therapeutics for human HF may be inspired by Mhrt779.

P. Han et al., A long noncoding RNA protects the heart from pathological hypertrophy. Nature 10.1038/nature13596 (2014). [Full Text]

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