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

• Published in: Nature communications Vol. 11; no. 1; pp. 2039 - 14
• Main Authors: Trembinski, D. Julia, Bink, Diewertje I., Theodorou, Kosta, Sommer, Janina, Fischer, Ariane, van Bergen, Anke, Kuo, Chao-Chung, Costa, Ivan G., Schürmann, Christoph, Leisegang, Matthias S., Brandes, Ralf P., Alekseeva, Tijna, Brill, Boris, Wietelmann, Astrid, Johnson, Christopher N., Spring-Connell, Alexander, Kaulich, Manuel, Werfel, Stanislas, Engelhardt, Stefan, Hirt, Marc N., Yorgan, Kaja, Eschenhagen, Thomas, Kirchhof, Luisa, Hofmann, Patrick, Jaé, Nicolas, Wittig, Ilka, Hamdani, Nazha, Bischof, Corinne, Krishnan, Jaya, Houtkooper, Riekelt H., Dimmeler, Stefanie, Boon, Reinier A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-04-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/2; 13/89; 38/61; 38/91; 45/15; 45/77; 45/88; 45/90; 59/57; 631/337/384/2568; 631/80/82/23; 64/60; 692/4019; Aging; Aging (artificial); Animals; Apoptosis; Cardiomyocytes; Cardiovascular disease; Cardiovascular diseases; Carrier Proteins - genetics; Cell Survival; Cell viability; Coenzyme A-Transferases - genetics; Deoxyribonucleic acid; Disease Models, Animal; DNA; Evolutionary conservation; Gene Silencing; Genes; Health risks; Humanities and Social Sciences; Humans; LIM Domain Proteins - genetics; Male; Mice; Mice, Inbred C57BL; multidisciplinary; Muscle contraction; Myocardial infarction; Myocardial Infarction - genetics; Myocytes, Cardiac - cytology; NF-E2-Related Factor 2 - genetics; Non-coding RNA; p300-CBP Transcription Factors - genetics; Recovery; Restoration; Ribonucleic acid; Risk analysis; Risk factors; RNA; RNA, Antisense - genetics; RNA, Long Noncoding - genetics; RNA, Small Interfering - genetics; RNA-mediated interference; Science; Science (multidisciplinary); Survival
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15995-2

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.
Aging induces cardiovascular disease, but which RNA molecules control cardiac aging is poorly understood. Here the authors identified the aging-regulated non-coding RNA
Sarrah
, which controls cardiomyocyte survival and cardiac function by inducing cardioprotective genes.