Abstract
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.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. SANDOVAL has nothing to disclose.
Conflict of interest: Dr. Del Valle-Mondragon has nothing to disclose.
Conflict of interest: Dr. Masso has nothing to disclose.
Conflict of interest: Dr. Zayas has nothing to disclose.
Conflict of interest: Dr. Pulido reports grants from Actelion, personal fees from Actelion, personal fees from Actelion, grants from Bayer, personal fees from Bayer, personal fees from Bayer, grants from Lilly, personal fees from Pfizer, grants from Reata Pharmaceuticals, personal fees from Akros Pharma, grants from United Therapeutics, outside the submitted work; .
Conflict of interest: Dr. Teijeiro Paradis reports grants from CONACYT , during the conduct of the study; .
Conflict of interest: Dr. González-Pacheco has nothing to disclose.
Conflict of interest: Dr. Olmedo- Ocampo has nothing to disclose.
Conflict of interest: Dr. Sisniega has nothing to disclose.
Conflict of interest: Dr. Paez-Arenas has nothing to disclose.
Conflict of interest: Dr. Pastelin has nothing to disclose.
Conflict of interest: Dr. Gómez-Arroyo has nothing to disclose.
Conflict of interest: Dr. Voelkel has nothing to disclose.
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- Received December 17, 2019.
- Accepted March 21, 2020.
- Copyright ©ERS 2020