Role of the cGAS-STING Pathway in Aging-related Endothelial Dysfunction

Abstract

Endothelial dysfunction develops gradually with age, and is the foundation of many age-related diseases in the elderly. The purpose of this study was to investigate the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in aging-related endothelial dysfunction. Endothelial functional parameters and biochemical indices of vascular function were examined in 2-, 6-, 12- and 24-month-old mice. Then, 6-month-old mice were administered RU.521, a specific inhibitor of cGAS, for 6 months, and endothelial functional parameters and biochemical indices of vascular function were re-examined. An in vitro model of cell senescence was established by treating human aortic endothelial cells (HAECs) with D-Galactose (D-GAL). Using inhibitors or siRNA interference, cGAS and STING were suppressed or silenced in senescent HAECs, and changes in the expression of eNOS, the senescence markers, p53, p21 and p16, components of the cGAS-STING pathway and Senescence-Associated β-galactosidase (SA-β-gal) staining were examined. Finally, cGAS, STING and p-IRF3 levels were measured in aorta tissue sections from eight patients. A decline in endothelial function, up-regulation of p53, p21 and p16 expression, and activation of the cGAS-STING pathway were observed in aging mice. Inhibition of cGAS was found to improve endothelial function and reverse the increased expression of aging markers. Our in vitro data demonstrated that D-GAL induced a decrease in eNOS expression and cell senescence, which could be partly reversed by cGAS inhibitor, STING inhibitor, siRNA-cGAS and siRNA-STING treatment. Higher expression levels of cGAS, STING and p-IRF3 were observed in aged human aortic intima tissue compared to young aortic intima tissue. Our study demonstrated that activation of the cGAS-STING pathway played a vital role in aging-related endothelial dysfunction. Thus, the cGAS-STING pathway may be a potential target for the prevention of cardiovascular diseases in the elderly.