Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells.
Angiotensin-converting enzyme 2 (ACE2) is a newly discovered homolog of ACE whose actions oppose those of angiotensin II (AngII). However, the underlying mechanisms by which ACE2 effectively suppresses early atherosclerotic lesions remain poorly understood. Here, we show, both in vitro and in vivo, that ACE2 inhibited the development of early atherosclerotic lesions by suppressing the growth of vascular smooth muscle cells (VSMCs) and improving endothelial function. In a relatively large cohort animal study (66 rabbits), aortic segments transfected by Ad-ACE2 showed significantly attenuated fatty streak formation, neointimal macrophage infiltration, and alleviation of impaired endothelial function. Segments also showed decreased expression of monocyte chemoattractant protein 1, lectin-like oxidized low-density lipoprotein receptor 1, and proliferating cell nuclear antigen, which led to the delayed onset of atherosclerotic lesions. At the cellular level, ACE2 significantly modulated AngII-induced growth and migration in human umbilical vein endothelial cells and VSMCs. The antiatherosclerotic effect of ACE2 involved down-regulation of the ERK-p38, JAK-STAT, and AngII-ROS-NF-kappaB signaling pathways and up-regulation of the PI3K-Akt pathway. These findings revealed the molecular mechanisms of the antiatherosclerotic activity of ACE2 and suggested that modulation of ACE2 could offer a therapeutic option for treating atherosclerosis.
Zhang
Cheng
C
Shandong University Qilu Hospital, Jinan, China.
Zhao
Yu Xia
YX
Zhang
Yue Hui
YH
Zhu
Li
L
Deng
Bi Ping
BP
Zhou
Zhao Li
ZL
Li
Shu Ying
SY
Lu
Xiao Ting
XT
Song
Li Li
LL
Lei
Xue Ming
XM
Tang
Wen Bo
WB
Wang
Nan
N
Pan
Chun Ming
CM
Song
Huai Dong
HD
Liu
Chun Xi
CX
Dong
Bo
B
Zhang
Yun
Y
Cao
Yihai
Y
D000085962:Angiotensin-Converting Enzyme 2; D050197:Atherosclerosis / Q000201:enzymology / Q000503:physiopathology*; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D008084:Lipoxygenase / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*
D018932:Chemokine CCL2; D008084:Lipoxygenase; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2
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