Angiotensin Converting Enzyme 2 and Angiotensin (1-7) axis in Pulmonary Arterial Hypertension

Sandoval J, Del Valle-Mondragón L, Masso F, Zayas N, Pulido T, Teijeiro R, Gonzalez-Pacheco H, Olmedo-Ocampo R, Sisniega C, Paez-Arenas A, Pastelin-Hernandez G, Gomez-Arroyo J, Voelkel NF.
Eur Respir J. 2020 Apr 2. pii: 1902416. doi: 10.1183/13993003.02416-2019. [Epub ahead of print] PMID: 32241831
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Background: In animal models of pulmonary arterial hypertension (PAH), angiotensin converting enzyme type 2 (ACE2) and Angiotensin 1-7 [Ang-(1-7)] have been shown to have vasodilatory, anti-proliferative, anti-fibrotic and anti-hypertrophic 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 etiologies. Fifty-five 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 angiotensin II (AngII) were measured by zone capillary electrophoresis. Aldosterone, Angiotensin-(1-9), Angiotensin A, (Ang-A) and ACE2 were measured by 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 [(1.03(IQR 0.72-1.88) versus 0.19(IQR 0.10-0.37)pmoles·mL-1;p<0.001)] and of aldosterone [(88.7(58.7-132) 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) versus 4.07(2.82-6.73)pmoles·mL-1;p<0.001)], and a lower concentration of Ang-(1-9), and Ang-A. Similarly, the ACE2 concentration was higher than in controls [(8.7(5.35-13.2) 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) versus 5.97(3.1-17.8)nmoles·mL-1;p<0.001)]. No significant differences were found among the three different etiologic 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.