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

Area of Science:

• Pulmonary vascular research
• Endothelial cell biology
• Hypertension mechanisms

Background:

• Pulmonary arterial hypertension (PAH) pathogenesis involves an imbalance between angiotensin-converting enzyme 1 (ACE1) and ACE2.
• Ubiquitin carboxyl-terminal hydrolase 10 (USP10) regulates deubiquitination and is implicated in cell proliferation and tumor suppression.
• AMP-activated protein kinase (AMPK) is a key cellular energy sensor.

Purpose of the Study:

• To investigate the role of USP10 in pulmonary hypertension (PH) and idiopathic PAH (IPAH).
• To determine if a positive feedback loop between USP10 and AMPK in pulmonary endothelium is protective against PAH.
• To explore the therapeutic potential of modulating the AMPK/USP10 loop.

Main Methods:

• In silico data analysis and in vitro cell culture experiments.
• Investigation of USP10 levels in human IPAH and rodent PH models.
• Utilizing endothelial cell-specific USP10 transgenic mice and liraglutide administration in rodents.

Main Results:

• USP10 levels were reduced in the lung endothelium of IPAH and PH patients/rodents.
• Activation of the AMPK/USP10 loop increased ACE2 phosphorylation and deubiquitination, maintaining ACE2 homeostasis and lung vascular patency.
• Liraglutide treatment mimicked the protective effects seen in USP10 transgenic mice by activating the AMPK/USP10 loop.

Conclusions:

• Augmenting the AMPK/USP10 loop, through genetic or pharmacologic means (GLP-1 RAs), increases ACE2 levels in lung endothelium.
• This ACE2 enhancement provides protection against PAH in humans and PH in rodents.
• Modulating the AMPK/USP10 loop represents a potential therapeutic strategy for alleviating PAH.