TY - JOUR
T1 - PRKAA1/AMPKα1-driven glycolysis in endothelial cells exposed to disturbed flow protects against atherosclerosis
AU - Yang, Qiuhua
AU - Xu, Jiean
AU - Ma, Qian
AU - Liu, Zhiping
AU - Varadarajan, Sudhahar
AU - Cao, Yapeng
AU - Wang, Lina
AU - Zeng, Xianqiu
AU - Zhou, Yaqi
AU - Zhang, Min
AU - Xu, Yiming
AU - Wang, Yong
AU - Weintraub, Neal Lee
AU - Zhang, Chunxiang
AU - Fukai, Tohru
AU - Wu, Chaodong
AU - Huang, Lei
AU - Han, Zhen
AU - Wang, Tao
AU - Fulton, David J
AU - Hong, Mei
AU - Huo, Yuqing
N1 - Funding Information:
This work was supported by grants from the Shenzhen Science and Technology Innovation Committee (JCYJ20170412150405310, JCYJ20160525154531263, JCYJ20160506170316776, and JCYJ20170810163238384), Guangdong Natural Science Foundation (2014A030312004), American Heart Association (16GRNT30510010), and the National Institutes of Health (R01HL134934, R01DK095862, and R01 HL142097).
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-07132-x
DO - 10.1038/s41467-018-07132-x
M3 - Article
C2 - 30405100
AN - SCOPUS:85056098496
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4667
ER -