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

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.

Impact of supervised beego, a traditional Chinese water-only fasting, on thrombosis and haemostasis

“…For context, oxidative stress and mitochondrial membrane potential are both hallmarks of ageing, 30 and loss of cells through apoptosis is also representative of ageing; such cell loss can be regulated by caloric restriction. 83 The effect of the deceleration of platelet ageing is consistent with better controlled activation of platelets with reduced P-selectin level (figure 4F). Functional analysis of hearts and vessels also shows that some of the cardiovascular function were improved and rejuvenated.…”

Age-Related Pathways in Cardiac Regeneration: A Role for lncRNAs?

“…Inhibition of Sarrah induces caspase activity in mouse and human cardiomyocytes, promoting apoptosis. Gene set enrichment analysis after SARRAH silencing showed enrichment of apoptosis-related pathways, corroborating previous observations ( Trembinski et al, 2020 ). SARRAH was also found to directly bind to the promoters through RNA-DNA triplex helix structures, suggesting that its binding may activate gene expression.…”

“…More recently, Trembinski et al (2020) identified lncRNA SCOT1-antisense RNA regulated during aging in the heart ( SARRAH ), whose expression declines during aging. Inhibition of Sarrah induces caspase activity in mouse and human cardiomyocytes, promoting apoptosis.…”

“…SARRAH was also found to directly bind to the promoters through RNA-DNA triplex helix structures, suggesting that its binding may activate gene expression. Indeed, it was reported that SARRAH interacted with cardiac transcription factor cysteine-rich protein 2 (CRIP2) and p300, which acetylates histone H3 lysine 27 to activate transcription ( Trembinski et al, 2020 ). On the other hand, overexpression of SARRAH led to a decrease in caspase activity.…”

“…In adult mice a decline in apoptosis was observed after overexpressing SARRAH, suggesting that reduced expression levels of this lncRNA in aged mice might contribute to cardiomyocyte cell death in vivo . Furthermore, reduced levels of Sarrah were observed in the infarcted and border regions after acute MI ( Trembinski et al, 2020 ).…”