Abstract 17177: Sarrah is an Aging-Regulated Anti-Apoptotic Long Non-Coding RNA in Cardiomyocytes that Augments Recovery From Acute Myocardial Infarction

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Abstract

Long non-coding RNAs (lncRNAs) contribute to (patho)physiological processes in the heart. Aging is the major risk factor for cardiovascular disease. Apoptosis of individual cardiomyocytes (CMs) is one of the underlying causes for age-related cardiac dysfunction. Here, we identified the lncRNA Sarrah that is regulated during aging in CMs and hypothesize that it has a protective effect on the myocardium. Comparing RNA deep sequencing profiles of CMs and other cell types from young and aged mouse hearts revealed 74 CM-enriched, aging-regulated lncRNAs. Silencing these 74 lncRNAs followed by a caspase assay identified Sarrah as an anti-apoptotic lncRNA. Sarrah is evolutionary conserved and we reproduced its anti-apoptotic effect in human cells. Flow cytometry using annexin V/7-AAD confirmed the anti-apoptotic function of Sarrah. Engineered heart tissue organoids consisting of human iPS-derived CMs and endothelial cells developed contractile force 7 days later upon Sarrah knockdown compared with controls, indicating that Sarrah is essential for proper human CM function. After acute myocardial infarction (AMI) in mice, Sarrah was profoundly downregulated in the infarct and border region. Hypoxia exposure and DFO treatment in vitro also downregulated Sarrah expression in mouse and human CMs. Using AAV9, we overexpressed Sarrah in mice to assess the therapeutic potential of Sarrah induction after AMI in vivo. Sarrah overexpressing mice showed a better recovery of cardiac contractile function after AMI as measured by echocardiography, consistent with a decrease in CM cell death as measured by TUNEL staining. We identified genes regulated after Sarrah knockdown in a microarray analysis. In the promoter regions of genes that are downregulated after Sarrah silencing, significant RNA-DNA triple helix formation between Sarrah and genomic DNA was computationally predicted, suggesting that Sarrah may function as a gene expression activator via triple helix formation. Consistently, Sarrah localizes to chromatin. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging and ischemia, as a pivotal regulator of CM apoptosis. Cardiac overexpression of Sarrah has beneficial effects on AMI recovery.

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