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−1versus0.19, 0.10–0.37 pmol·mL−1; p<0.001) and of aldosterone (88.7, 58.7–132 ng·dL−1versus12.9, 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−1versus4.07, 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−1versus4.53, 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−1versus5.97, 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.