AMPK/USP10 loop activation of ACE2: implications for pulmonary hypertension.
Summary
USP10 was reduced in pulmonary endothelium from human idiopathic pulmonary arterial hypertension and rodent pulmonary hypertension. Activation of an AMPK/USP10 positive-feedback loop increased ACE2 Ser-680 phosphorylation and Lys-788 deubiquitination, preserved endothelial ACE2 and pulmonary vascular patency, and attenuated pulmonary hypertension in endothelial USP10-transgenic mice and liraglutide-treated mice.
Key Findings
- USP10 levels were decreased in pulmonary endothelium from human idiopathic pulmonary arterial hypertension and rodent pulmonary hypertension.
- AMPK/USP10 loop activation enhanced ACE2 phosphorylation and deubiquitination, supporting endothelial ACE2 homeostasis and pulmonary vascular patency.
- Endothelial USP10 overexpression and liraglutide treatment both mitigated pulmonary hypertension in mice.
Clinical Implications
The results provide a rationale for investigating GLP-1 receptor agonists, such as liraglutide, as adjunctive or disease-modifying treatments for pulmonary hypertension. Clinical trials are required to determine efficacy, appropriate patient subsets, dose, interactions with approved pulmonary hypertension therapies, and cardiovascular safety.
Why It Matters
This study identifies a previously underappreciated endothelial AMPK/USP10–ACE2 regulatory mechanism and connects it to pulmonary hypertension biology. The use of human disease data, cellular experiments, genetic mouse models, and pharmacological activation provides a strong translational rationale for repurposing or testing glucagon-like peptide-1 receptor agonists, while clinical efficacy remains unproven.
Limitations
- The evidence is predominantly preclinical, and the abstract does not report a randomized clinical trial in patients with pulmonary hypertension.
- The protective effects of GLP-1 receptor agonism may involve mechanisms beyond AMPK/USP10 activation, and the clinically relevant dose and patient phenotype remain uncertain.
Future Directions
Prospective translational studies should confirm the AMPK/USP10–ACE2 pathway in pulmonary hypertension patients, identify biomarkers of pathway activity, and test GLP-1 receptor agonists in controlled trials alongside standard pulmonary hypertension therapy.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- II - Translational mechanistic study integrating human disease observations with in vitro experiments, genetic animal models, and pharmacological intervention.
- Study Design
- OTHER