PRKAA1/AMPK\u03b11-driven glycolysis in endothelial cells exposed to disturbed flow protects against atherosclerosis

Qiuhua Yang,Zhiping Liu,Yong Wang,David Fulton ,Lina Wang,Neal L Weintraub,Chunxiang Zhang,Tao Wang,Jiean Xu,Xiangwu Zeng ,Tohru Fukai,Chaodong Wu,Varadarajan Sudhahar,Yapeng Cao,Yuwen Zhou ,Lei Huang,Zhen Han,Qian Ma,Min Zhang,Yiming Xu,Mei Hong,Yuqing Huo

doi:10.1038/s41467-018-07132-x

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 endothelial Prkaa1, 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 in Prkaa1-deficient endothelial cells through Slc2a1 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 silencing PRKAA1 reduces glycolysis and endothelial viability. Collectively, these results suggest that increased glycolysis in the endothelium of atheroprone arteries is a protective mechanism.

Highlights

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
En face staining of the endothelium revealed increased levels of pPrka and Prkaa[1] on the inner curvature of the aortic arch, an area that is prone to the development of atherosclerotic plaques, as compared to the levels observed in atheroprotective areas of the descending aorta (Supplementary Fig. 1a; Fig. 1a)
To examine which molecule is able to transmit mechanical tension to the intracellular signaling pathways that are associated with AMPK upregulation and activation, HUVECs were treated with siRNA of CDH5, PTK2, or PECAM-1

Summary

Introduction

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. 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). PRKAA1 is upregulated by disturbed flow, and silencing PRKAA1 reduces glycolysis and endothelial viability These results suggest that increased glycolysis in the endothelium of atheroprone arteries is a protective mechanism. The combination of low wall shear stress and other atherosclerotic risk factors promotes increased EC death and compromises the integrity of the endothelial barrier[6] This is accompanied by the infiltration of lipids and leukocytes into the arterial vessel wall and, eventually, the formation of atherosclerotic plaques.

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Results

Conclusion