Angiotensin converting enzyme 2 and angiotensin (1-7) axis in pulmonary arterial hypertension.

Background: In animal models of pulmonary arterial hypertension (PAH), angiotensin-converting enzyme (ACE)2 and angiotensin (Ang)-(1-7) have been shown to have vasodilatory, antiproliferative, antifibrotic and antihypertrophic properties. However, the status and role of the ACE2-Ang(1-7) axis in human PAH is incompletely understood.
Methods: We studied 85 patients with a diagnosis of PAH of distinct aetiologies. 55 healthy blood donors paired for age and sex served as controls. Blood samples were obtained from the pulmonary artery in patients with PAH during right heart catheterisation. Peripheral blood was obtained for both groups. Ang(1-7) and -II were measured using zone capillary electrophoresis. Aldosterone, Ang(1-9), AngA and ACE2 were measured using ELISA, and ACE2 activity was determined enzymatically.
Results: Of the 85 patients, 47 had idiopathic PAH, 25 had PAH associated with congenital heart disease and 13 had PAH associated with collagen vascular disease. Compared to controls, patients with PAH had a higher concentration of AngII (median 1.03, interquartile range 0.72-1.88 pmol·mL ^-1 versus 0.19, 0.10-0.37 pmol·mL ^-1 ; p<0.001) and of aldosterone (88.7, 58.7-132 ng·dL ^-1 versus 12.9, 9.55-19.9 ng·dL ^-1 ; p<0.001). Conversely, PAH patients had a lower concentration of Ang(1-7) than controls (0.69, 0.474-0.91 pmol·mL ^-1 versus 4.07, 2.82-6.73 pmol·mL ^-1 ; p<0.001), and a lower concentration of Ang(1-9) and AngA. Similarly, the ACE2 concentration was higher than in controls (8.7, 5.35-13.2 ng·mL ^-1 versus 4.53, 1.47-14.3 ng·mL ^-1 ; p=0.011), whereas the ACE2 activity was significantly reduced (1.88, 1.08-2.81 nmol·mL ^-1 versus 5.97, 3.1-17.8 nmol·mL ^-1 ; p<0.001). No significant differences were found among the three different aetiological forms of PAH.
Conclusions: The AngII-ACE2-Ang(1-7) axis appears to be altered in human PAH and we propose that this imbalance, in favour of AngII, plays a role in the pathogenesis of the severe PAH. Further mechanistic studies are warranted.
Competing Interests: Conflict of interest: J. Sandoval has nothing to disclose. Conflict of interest: L. Del Valle-Mondragón has nothing to disclose. Conflict of interest: F. Masso has nothing to disclose. Conflict of interest: N. Zayas has nothing to disclose. Conflict of interest: T. Pulido reports grants from and personal fees for advisory board work and lectures from Actelion and Bayer, grants from Lilly, Reata Pharmaceuticals and United Therapeutics, personal fees for advisory board work from Pfizer and Akros Pharma, outside the submitted work. Conflict of interest: R. Teijeiro reports grants from CONACYT (FOSISS project 2015-1-262511), during the conduct of the study. Conflict of interest: H. González-Pacheco has nothing to disclose. Conflict of interest: R. Olmedo-Ocampo has nothing to disclose. Conflict of interest: C. Sisniega has nothing to disclose. Conflict of interest: A. Paez-Arenas has nothing to disclose. Conflict of interest: G. Pastelin-Hernandez has nothing to disclose. Conflict of interest: J. Gómez-Arroyo has nothing to disclose. Conflict of interest: N.F. Voelkel has nothing to disclose.
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