PRKAA1/AMPKα1-driven glycolysis in endothelial cells exposed to disturbed flow protects against atherosclerosis. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Yang, Qiuhua; Xu, Jiean; Ma, Qian; Liu, Zhiping; Sudhahar, Varadarajan; Cao, Yapeng; Wang, Lina; Zeng, Xianqiu; Zhou, Yaqi; Zhang, Min; Xu, Yiming; Wang, Yong; Weintraub, Neal; Zhang, Chunxiang; Fukai, Tohru; Wu, Chaodong; Huang, Lei; Han, Zhen; Wang, Tao; Fulton, David; Hong, Mei; Huo, Yuqing
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 17
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-07132-x
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract Increased aerobic glycolysis in endothelial cells of atheroprone areas of blood vessels has been hypothesized to drive increased inflammation and lesion burden but direct links remain to be established. Here we show that endothelial cells exposed to disturbed flow in vivo and in vitro exhibit increased levels of protein kinase AMP-activated (PRKA)/AMP-activated protein kinases (AMPKs). Selective deletion of endothelialPrkaa1, coding for protein kinase AMP-activated catalytic subunit alpha1, reduces glycolysis, compromises endothelial cell proliferation, and accelerates the formation of atherosclerotic lesions in hyperlipidemic mice. Rescue of the impaired glycolysis inPrkaa1 -deficient endothelial cells throughSlc2a1 overexpression enhances endothelial cell viability and integrity of the endothelial cell barrier, and reverses susceptibility to atherosclerosis. In human endothelial cells, PRKAA1 is upregulated by disturbed flow, and silencingPRKAA1 reduces glycolysis and endothelial viability. Collectively, these results suggest that increased glycolysis in the endothelium of atheroprone arteries is a protective mechanism. Increased glycolysis and inflammatory responses have been observed in endothelial cells exposed to disturbed flow. However, the role of endothelial glycolysis in atherosclerosis is unclear. Here the authors unveil a protective role for glycolysis by showing that endothelial deletion of Prkaa1 accelerates atherosclerosis in hyperlipidemic mice through a reduction of glycolytic metabolism.