Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction.
D Julia TrembinskiDiewertje I BinkKosta TheodorouJanina SommerAriane FischerAnke S van BergenChao-Chung KuoIvan G CostaChristoph SchürmannMatthias S LeisegangRalf P BrandesTijna AlekseevaBoris BrillAstrid WietelmannChristopher N JohnsonAlexander Spring-ConnellManuel KaulichStanislas WerfelStefan EngelhardtMarc N HirtKaja YorganThomas EschenhagenLuisa KirchhofPatrick HofmannNicolas JaéIlka WittigNazha HamdaniCorinne BischofJaya KrishnanRiekelt H HoutkooperStefanie DimmelerReinier Abraham BoonPublished in: Nature communications (2020)
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.
Keyphrases
- long non coding rna
- cell death
- poor prognosis
- acute myocardial infarction
- oxidative stress
- transcription factor
- cardiovascular disease
- left ventricular
- skeletal muscle
- cell cycle arrest
- endoplasmic reticulum stress
- endothelial cells
- type diabetes
- cell proliferation
- heart failure
- percutaneous coronary intervention
- genome wide
- high glucose
- anti inflammatory
- angiotensin ii
- high fat diet induced
- dna methylation
- insulin resistance
- cardiovascular risk factors
- free survival