Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction

D. Julia Trembinski, Diewertje I. Bink, Kosta Theodorou, Janina Sommer, Ariane Fischer, Anke van Bergen, Chao Chung Kuo, Ivan G. Costa, Christoph Schürmann, Matthias S. Leisegang, Ralf P. Brandes, Tijna Alekseeva, Boris Brill, Astrid Wietelmann, Christopher N. Johnson, Alexander Spring-Connell, Manuel Kaulich, Stanislas Werfel, Stefan Engelhardt, Marc N. HirtKaja Yorgan, Thomas Eschenhagen, Luisa Kirchhof, Patrick Hofmann, Nicolas Jaé, Ilka Wittig, Nazha Hamdani, Corinne Bischof, Jaya Krishnan, Riekelt H. Houtkooper, Stefanie Dimmeler, Reinier A. Boon

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Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.

Original languageEnglish
Article number2039
JournalNature communications
Issue number1
Publication statusPublished - 1 Dec 2020

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