AMP-activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension

Jiao Zhang, Jianjie Dong, Marcy Martin, Ming He, Brendan Gongol, Traci L. Marin, Lili Chen, Xinxing Shi, Yanjun Yin, Fenqing Shang, Yan Wu, Hsi-Yuan Huang, Jin Zhang, Yu Zhang, Jian Kang, Esteban A. Moya, Hsien-Da Huang, Frank L. Powell, Zhen Chen, Patricia A. ThistlethwaiteZu-Yi Yuan, John Y. -J. Shyy

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


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.
Original languageEnglish
Pages (from-to)509-520
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number4
StatePublished - 15 Aug 2015


  • angiotensin; converting enzyme 2; AMP-activated protein kinase; pulmonary hypertension; vascular endothelium

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