Aging-regulated Anti-apoptotic Long Non-coding RNA Sarrah Augments Recovery from Acute Myocardial Infarction

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Apr 29

PMID 32341350

Citations 45

Authors

D Julia Trembinski

Diewertje I Bink

Kosta Theodorou

Janina Sommer

Ariane Fischer

Anke van Bergen

Chao-Chung Kuo

Ivan G Costa

Christoph Schurmann

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 Hirt

Kaja Yorgan

Thomas Eschenhagen

Luisa Kirchhof

Patrick Hofmann

Nicolas Jae

Ilka Wittig

Nazha Hamdani

Corinne Bischof

Jaya Krishnan

Riekelt H Houtkooper

Stefanie Dimmeler

Reinier A Boon

Affiliations

Soon will be listed here.

Abstract

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.

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