James West, Megha Talati, Erica Carrier, Anandharajan Rathinasabapathy, Ibragim Gaidarov, Benjamin Vigl, Ying Cai, Hongpeng Jia, Tom Blackwell, Santhi Gladson, Christie Moore, Sheila Shay, Ethan Sevier, Anna Hemnes
Vanderbilt University Medical Center. Eurofins Beacon Discovery. Alterras Therapeutics. Johns Hopkins University School of Medicine.
United States and Austria
Pulmonary Circulation
Pulm Circ 2025; 15:
DOI: 10.1002/pul2.70083
Abstract
ACE2 has shown effectiveness in treating pulmonary hypertension in multiple animal models and has some promise in early human trials. The key barrier to translation is that enzymatically active ACE2 is difficult to manufacture and exhibits a short half-life in humans, making chronic administration challenging. Understanding the mechanism of effect is thus key to finding ways to bypass ACE2 while still reproducing therapeutic effects. In this study, we test the hypotheses that ACE2 produces its therapeutic effect through increased Mas1 signaling and that Ang(1-7) is sufficient as the Mas1 ligand. We found that the ACE2 effect is blocked in Mas1 knockout mice and that the Mas1 agonist AR234960 reproduces the ACE2 effect, indicating that Mas1 activation is necessary and sufficient for the ACE2 therapeutic effect. However, neither AlbudAb-stabilized Ang(1-7) nor Ang(1-7) stabilized through the use of protease inhibitors were capable of reproducing ACE2 effectiveness, indicating that Ang(1-7) alone does not activate Mas1 in this context. RNA-seq suggests that the key mechanisms downstream of Mas1 responsible for the therapeutic effect of ACE2 and AR234960 are the rescue of cytoskeletal and microtubule defects. Together, these findings indicate that direct activation of Mas1 will likely be effective in treating pulmonary arterial hypertension, but raise the question of the identity of the endogenous ligand(s).
Category
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Medical Therapy. Efficacy or Lack of Efficacy
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes