The aging-induced long non-coding RNAMIRIALcontrols endothelial cell and mitochondrial function

Abstract

AbstractAimsVascular aging is characterized by the progressive deterioration of endothelial function. Long non-coding RNAs (lncRNAs) are critical regulators of gene expression and protein function. However, their involvement in aging-related dysregulation of endothelial cell function remains largely unknown. Here, we aim to characterize the aging-regulated lncRNAMIRIALin endothelial cells.Methods + ResultsWe identifiedMirialas an aging-induced lncRNA in RNA-sequencing data of mouse cardiac endothelial cells. In human umbilical vein endothelial cells (HUVECs), gapmer-mediated knockdown ofMIRIALled to decreases in proliferation, migration and basal angiogenic sprouting. Additionally,MIRIALknockdown led to increased mitochondrial mass, spare respiratory capacity, and vascular endothelial growth factor (VEGF)-stimulated sprouting. Mechanistically, we demonstrate thatMIRIALforms anRNA·DNA:DNA triple helix (triplex) with a regulatory region of the quiescence-promoting Forkhead Box O1 (FOXO1) gene, thus inducing its expression. The formation of this triplex involves anAluelement within theMIRIALtranscript, representing a previously undescribed mechanism of action for a lncRNA. Further, we generated a globalMirialknockout mouse line of. Angiogenic sprouting of aortic rings fromMirialknockout mice was reduced under basal conditions, but increased after VEGF administration, validating thein vitroangiogenic phenotype. Importantly, cardiac contractile function after acute myocardial infarction is severely reduced inMirialknockout mice, as compared to wild-type littermates.ConclusionsThe lncRNAMIRIALis an aging-induced regulator of endothelial quiescence and metabolism.Translational PerspectiveLncRNAs often exhibit cell-type or tissue-specific expression and regulation, rendering them potentially druggable targets requiring lower doses and having fewer side effects compared to protein targets. Our current research highlights, that loss ofMirialcorrelates with adverse outcomes post-acute myocardial infarction in a murine model. Dysregulation ofMIRIALin various human pathological conditions, such as ischemic heart disease, abdominal aortic aneurysm, cancer, and aging, indicates its potential as a diagnostic marker. Mechanistically,MIRIALregulates endothelial quiescence by modulatingFOXO1expression, suggesting it as a promising therapeutic target to counteract the age-related decline in endothelial cell function.