Abstract 461: Enhanced Glycolysis in Endothelial Cells Protects Against Atherosclerosis

Abstract

Background: Increased aerobic glycolysis in endothelial cells (ECs) of atheroprone areas of blood vessels is hypothesized to drive increased inflammation and lesion burden but the direct links are not yet established. The goal of this study was to determine how metabolic adaptation in ECs impacts atherosclerosis. Methods: The immunostaining, Real-time PCR, Western blots, Seahorse assayes are used to analyze the expression and activity of PRKA/AMPKs and metabolic glycolysis in the arterial endothelium of mice and cultured endothelial cells under disturbed flows. Staining of Edu, TUNNEL and Evans blue were utilized to evaluate endothelial turnover and endothelium integrity. Oil Red O staining and histological cellular characterization were performed to evaluate atherosclerosis. Results: ECs exposed to disturbed flow in vivo and in vitro exhibit increased levels of PRKA/AMPKs (protein kinase AMP-activated; AMP-activated protein kinases) and glycolysis. Selective deletion of endothelial Prkaa1 (protein kinase AMP-activated catalytic subunit alpha1) reduced glycolysis, compromised EC proliferation and EC monolayer integrity, and accelerated the formation of atherosclerotic lesions in hyperlipidemic mice. Rescue of impaired glycolysis in Prkaa1-deficient ECs through Slc2a1 transfection enhanced EC viability and integrity of the EC barrier and reversed susceptibility to atherosclerosis. These results suggest that increased glycolysis in the endothelium of atheroprone arteries is a protective mechanism. Conclusions: Endothelial glycolysis plays a vital role in EC proliferation, repair of the EC monolayer, and protects mice from atherosclerosis. Thus, approaches such as activating AMPK activity or increasing endothelial glycolysis are preventive and therapeutic for arterial diseases.