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

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

Nature communications (2020-04-29)

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 Hirt, Kaja 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

PMID32341350

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.

MATERIALS

Product Number

Brand

Product Description

X100

Sigma-Aldrich

Triton^™ X-100, laboratory grade

12-370

Sigma-Aldrich

Normal Rabbit IgG, Normal Rabbit IgG Polyclonal Antibody control validated for use in Immunoprecipitation & Western Blotting.

6570

Millipore

L-Tyrosine, Free Base, Non-essential amino acid for human development. Precursor for the synthesis of thyroid hormones and select neurotransmitters, such as dopamine and norepinephrine.