AMPK/USP10 loop activation of ACE2: implications for pulmonary hypertension

BACKGROUND AND AIMS: The intricate balance between angiotensin-converting enzyme 1 (ACE1) and 2 (ACE2) in the pulmonary vasculature is pivotal for the pathogenesis of pulmonary arterial hypertension (PAH). Catalysing the K48-linked deubiquitination, ubiquitin carboxyl-terminal hydrolase 10 (USP10) is involved in tumour suppression, autophagy, and cell proliferation. This study aims to determine whether a positive feedback loop of USP10 and AMP-activated protein kinase (AMPK) in pulmonary endothelium is protective against PAH. METHODS: In silico data analyses and in vitro culture cell experiments were used to investigate the role of USP10 in human idiopathic PAH (IPAH) and rodent pulmonary hypertension (PH) as well as the underlying mechanism involving a positive feedback loop of AMPK and USP10 in lung endothelium. Endothelial cell (EC)-specific USP10 transgenic (Tg) mice and mice administered liraglutide were used to explore the efficacy of the AMPK/USP10 loop in mitigating PH in rodents. RESULTS: USP10 level was decreased in the lung endothelium of human IPAH and rodent PH. AMPK/USP10 loop activation increased ACE2 Ser-680 phosphorylation and Lys-788 deubiquitination, thus contributing to the homeostatic level of ACE2 and lung vascular patency. Mice with liraglutide administration phenocopied the mitigated PH in EC-specific USP10 Tg mice, in part because of the activated AMPK/USP10 loop in the pulmonary endothelium. CONCLUSIONS: Genetic or pharmacologic [via glucagon-like peptide-1 receptor agonists (GLP-1 RAs)] interventions in the AMPK/USP10 loop can augment ACE2 level in lung endothelium. This type of ACE2 enhancement garners protection against PAH in humans and PH in rodents, which provides a rationale for using GLP-1 RAs to alleviate PAH.