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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.
The advancement of medical technology has led not only to an increase in life expectancy but also to a rise in aging-related diseases. Aging promotes metabolic disorders, in turn affecting cardiovascular health. Derailment of biological processes in the pancreas, liver, adipose tissue, and skeletal muscle impairs glucose and lipid metabolism, and mitochondrial function, triggering the development of diabetes and lipid-related disorders that inflict damage on cardiac and vascular tissues. Long noncoding RNAs (lncRNAs) regulate a wide range of biological process and are one of the key factors controlling metabolism and mitochondria. Here, we discuss the versatile function of lncRNAs involved in the metabolic regulation of glucose and lipid, and mitochondrial function, and how the dysregulation of lncRNAs induces the development of various metabolic disorders and their cardiovascular consequences.