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

Abstract

BackgroundIn 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.MethodsWe 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.ResultsOf 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.ConclusionsThe 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.

Essential genes and miRNA-mRNA network contributing to the pathogenesis of idiopathic pulmonary arterial hypertension

“…2). Among these genes, the roles of some ones had been well explored in PAH, such as interleukin 13 receptor alpha 2 (IL13RA2), angiotensin I converting enzyme 2 (ACE2) [15] and vascular cell adhesion molecule 1 (VCAM1) [16]. Notably, some genes were novel, and their functions in PAH had not been researched in published literature, such as hemoglobin alpha 2 (HBA2), frizzled-related protein 2 (SFRP2), and ribonucleases 2 (RNASE2).…”

Pulmonary artery hypertension patients and the coronavirus disease of 2019 (COVID-19): are they protected from severe disease?

“…The PAH patients have declined circulating ACE2, ACE2 activity and angiotensin 1-7. 14,22 The reduced circulating ACE2 associates with reduced neutralizing effect of soluble ACE2 because of elimination ofits binding into the SARS-CoV2. 22 The disruption of angiotensinII/ACE2/angiotensin 1-7 axis in PAH conveys greater risk to have severe COVID-19 because it leads to exacerbation of viral activity and enhancement of angiotensin deleterious effects.…”

“…22 The disruption of angiotensinII/ACE2/angiotensin 1-7 axis in PAH conveys greater risk to have severe COVID-19 because it leads to exacerbation of viral activity and enhancement of angiotensin deleterious effects. 22…”

Lung ACE2 and ADAM17 in pulmonary arterial hypertension: Implications for COVID-19?

“…Likewise, a recent report has also found an increase in circulating plasma protein ACE2 concentration in patients with PAH. 5 Besides the receptor function of ACE2 for SARS-CoV-2, its catalytic activity has important pathophysiological consequences for both PAH 5 and COVID-19. 4 First, ACE2 converts angiotensin I into Ang1−9 and angiotensin II into Ang1−7 and thereby negatively regulates the renin angiotensin system, promoting vasodilation and anti-inflammatory effects.…”

“…During SARS-CoV infection, ACE2 is downregulated, resulting in a loss of its protective anti-inflammatory effects, enhanced lung vascular permeability, and exacerbated pneumonia progression. 4 Altogether, upregulated ACE2 activity should be interpreted as a beneficial effect for PAH 5 and in part for COVID-19. 4 However, despite the increased ACE2 protein in plasma of patients with PAH, its activity was reported to be diminished, possibly because of the increased presence of autoantibodies against ACE2.…”