Title: AMP-activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension
Authors: Zhang, Jiao
Dong, Jianjie
Martin, Marcy
He, Ming
Gongol, Brendan
Marin, Traci L.
Chen, Lili
Shi, Xinxing
Yin, Yanjun
Shang, Fenqing
Wu, Yan
Huang, Hsi-Yuan
Zhang, Jin
Zhang, Yu
Kang, Jian
Moya, Esteban A.
Huang, Hsien-Da
Powell, Frank L.
Chen, Zhen
Thistlethwaite, Patricia A.
Yuan, Zu-Yi
Shyy, John Y. -J.
生物科技學系
生物資訊及系統生物研究所
Department of Biological Science and Technology
Institude of Bioinformatics and Systems Biology
Keywords: angiotensin;converting enzyme 2;AMP-activated protein kinase;pulmonary hypertension;vascular endothelium
Issue Date: 15-Aug-2018
Abstract: Rationale: Endothelial dysfunction plays an integral role in pulmonary hypertension (PH). AMPK (AMP-activated protein kinase) and ACE2 (angiotensin-converting enzyme 2) are crucial in endothelial homeostasis. The mechanism by which AMPK regulates ACE2 in the pulmonary endothelium and its protective role in PH remain elusive. Objectives: We investigated the role of AMPK phosphorylation of ACE2 Ser680 in ACE2 stability and deciphered the functional consequences of this post-translational modification of ACE2 in endothelial homeostasis and PH. Methods: Bioinformatics prediction, kinase assay, and antibody against phospho-ACE2 Ser680 (p-ACE2 S680) were used to investigate AMPK phosphorylation of ACE2 Ser680 in endothelial cells. Using CRISPR-Cas9 genomic editing, we created gain-of-function ACE2 S680D knock-in and loss-of-function ACE2 knockout (ACE22/2) mouse lines to address the involvement of p-ACE2 S680 and ACE2 in PH. The AMPK-p-ACE2 S680 axis was also validated in lung tissue from humans with idiopathic pulmonary arterial hypertension. Measurements and Main Results: Phosphorylation of ACE2 by AMPK enhanced the stability of ACE2, which increased Ang (angiotensin) 1-7 and endothelial nitric oxide synthase-derived NO bioavailability. ACE2 S680D knock-in mice were resistant to PH as compared with wild-type littermates. In contrast, ACE2-knockout mice exacerbated PH, a similar phenotype found in mice with endothelial cell-specific deletion of AMPK alpha 2. Consistently, the concentrations of phosphorylated AMPK, p-ACE2 S680, and ACE2 were decreased in human lungs with idiopathic pulmonary arterial hypertension. Conclusions: Impaired phosphorylation of ACE2 Ser680 by AMPK in pulmonary endothelium leads to a labile ACE2 and hence is associated with the pathogenesis of PH. Thus, AMPK regulation of the vasoprotective ACE2 is a potential target for PH treatment.
URI: http://dx.doi.org/10.1164/rccm.201712-2570OC
http://hdl.handle.net/11536/148016
ISSN: 1073-449X
DOI: 10.1164/rccm.201712-2570OC
Journal: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume: 198
Begin Page: 509
End Page: 520
Appears in Collections:Articles