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 |