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 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. Hirt, Kaja Yorgan, Thomas Eschenhagen, Luisa Kirchhof, Patrick Hofmann, Nicolas Jaé, Ilka Wittig, Nazha Hamdani, Corinne Bischof, Jaya Krishnan, Riekelt H. Houtkooper, Stefanie Dimmeler and Reinier A. Boon ()
Additional contact information
D. Julia Trembinski: Goethe University Frankfurt am Main
Diewertje I. Bink: VU University Medical Center
Kosta Theodorou: Goethe University Frankfurt am Main
Janina Sommer: Goethe University Frankfurt am Main
Ariane Fischer: Goethe University Frankfurt am Main
Anke Bergen: VU University Medical Center
Chao-Chung Kuo: RWTH Aachen University
Ivan G. Costa: RWTH Aachen University
Christoph Schürmann: Goethe University Frankfurt am Main
Matthias S. Leisegang: German Center for Cardiovascular Research (DZHK)
Ralf P. Brandes: German Center for Cardiovascular Research (DZHK)
Tijna Alekseeva: Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy
Boris Brill: Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy
Astrid Wietelmann: Max-Planck-Institute for Heart and Lung Research
Christopher N. Johnson: Vanderbilt University Medical Center
Alexander Spring-Connell: Georgia State University
Manuel Kaulich: Goethe University
Stanislas Werfel: German Center for Cardiovascular Research (DZHK)
Stefan Engelhardt: German Center for Cardiovascular Research (DZHK)
Marc N. Hirt: German Center for Cardiovascular Research (DZHK)
Kaja Yorgan: German Center for Cardiovascular Research (DZHK)
Thomas Eschenhagen: German Center for Cardiovascular Research (DZHK)
Luisa Kirchhof: Goethe University Frankfurt am Main
Patrick Hofmann: Goethe University Frankfurt am Main
Nicolas Jaé: Goethe University Frankfurt am Main
Ilka Wittig: German Center for Cardiovascular Research (DZHK)
Nazha Hamdani: VU University Medical Center
Corinne Bischof: Goethe University Frankfurt am Main
Jaya Krishnan: Goethe University Frankfurt am Main
Riekelt H. Houtkooper: Academic Medical Center
Stefanie Dimmeler: Goethe University Frankfurt am Main
Reinier A. Boon: Goethe University Frankfurt am Main

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15995-2

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