Abstract 234: Identification of a Novel Cardiomyocyte-enriched Long Noncoding Rna Counteracting Against Heart Failure Development

Abstract

Background: The number of patients with heart failure (HF) continues to increase as the elderly population grows, and mortality remains high, with about 50% of HF patients dying within 5 years of diagnosis. Therefore, defining molecular mechanisms underlying HF pathologies is urgently needed. Methods and Results: Using a gene trapping approach in mouse ES cells, we identified Caren (for car diomyocyte- en riched noncoding transcript), a novel cytoplasmic lncRNA abundantly expressed in cardiomyocytes. Caren expression in mice markedly decreased in heart failure (HF) induced by transverse aortic constriction (TAC), AngiotensinII loaded or aging. Caren ablation accelerated HF-related phenotypes, whereas Caren transgenic (Tg) mice in cardiomyocytes resisted TAC-induced HF. Furthermore, Caren overexpression in cardiomyocytes activated mitochondrial biogenesis and attenuated TAC-induced activation of Ataxia Telangiectasia Mutated (ATM) serine/threonine kinase, a regulator of the DNA damage response (DDR). Next, we generated Tg mice expressing Caren fragments (fragments A-E, from 5’ to 3’) respectively, by inserting that fragment into the corresponding endogenous Caren genomic locus. None of these Tg mice exhibited an anti-HF effect against TAC, suggesting that anti-HF effects of Caren may be more dependent on a structural motif displayed by the full-length lncRNA rather than on a specific Caren sequence. Consistently, restoration of expression of full-length Caren in TAC-induced failing cardiomyocytes slows HF progression in mice injected with AAV6- Caren . Mechanistically, Caren inhibited translation of mRNA encoding ‘ Caren Target Protein 1’ (CTP1), which activates the ATM-DDR pathway and reduces mitochondrial respiratory capacity in cardiomyocytes. CTP1 +/- mice resisted HF development, strongly suggesting that Caren protects against HF by suppressing CTP1 expression. Conclusion: This is the first study reporting that Caren , a novel cytoplasmic lncRNA , counteracts HF development and progression by inactivating the ATM-DDR pathway and activating mitochondrial bioenergetics, in part, by suppressing CTP1 translation in cardiomyocytes. Our findings could encourage development of RNA-based strategies to combat HF development.