Abstract 4141937: Long Noncoding RNA SNRKAS as a SNRK Inhibitor Triggers Endothelium Senescence

Background: Although sucrose non-fermenting 1-related kinase (SNRK) in endothelial cells (EC) has a critical role in anti-inflammation and anti-fibrosis in the kidney, whether SNRK controls EC senescence and vascular aging, and how SNRK is regulated have never been studied. Long noncoding RNAs (lncRNAs) are involved in endothelial function and are altered during aging and in response to various senescence stimuli. However, whether lncRNA controls SNRK protein levels, which regulate EC senescence and cardiovascular diseases (CVD), is still poorly understood. Methods: Immunohistochemistry was performed on mouse aortic samples. RNA fluorescence in situ hybridization (RNA-FISH) staining was taken with young and aged arteries. Young and senescent primary human ECs were used for molecular signaling analysis, and SNRK expression was manipulated using plasmid overexpression and depletion. Senescence-associated β-galactosidase (SA-β-gal) staining was performed in vitr o and in vivo . Results: Analyzing the expression of senescence-associated lncRNAs by qRT-PCR in human endothelial cells, we identified a long noncoding antisense (AS) transcript of SNRK, SNRKAS, which was upregulated by forkhead box A2 (FOXA2) activation in senescent human EC in vitro and EC from aged human vessels in vivo . SNRKAS, acting in a cis-regulatory manner, downregulated SNRK expression via RNA-mRNA interaction in EC. The passaging of primary EC and X-ray irradiation (XRI) substantially decreased SNRK protein levels, while elevating SNRKAS levels; SNRK overexpression reversed XRI-induced protein and mRNA upregulation of p16, a cellular senescence marker. Furthermore, SNRK was required for the expression of lamin B1, while negatively regulating the stimulator of interferon genes (STING) signaling in EC. Finally, endothelial SNRK deficiency in mice promoted endothelial senescence, aortic stiffness, and atherogenesis in vivo . Conclusions: We conclude that lncRNA SNRKAS acts as a negative regulator of endothelial senescence via downregulation of SNRK.