A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

Clinical Implications of SARS-CoV-2 Interaction With Renin Angiotensin System

“…Treatment with rhACE2 showed improved cardiac output which coincided with maximum suppression of plasma cytokines and reduction in nitrotyrosine levels, improved peripheral vascular resistance as well as improved renal perfusion [59].…”

“…An additional pilot study (NCT101884051) investigated the effects of rhACE2 in human pulmonary arterial hypertension which is characterized by reduced ACE2 activity [59].…”

“…There is some evidence to suggest soluble ACE2 is able to regulate systemic Ang II. Clinical trials have shown rhACE2 could convert systemic Ang II to Ang 1-7 [58,59], and play some pathological, compensatory, or counter regulatory roles.…”

Counter-regulatory renin–angiotensin system in cardiovascular disease

“…A pilot study evaluated the effects of increasing the enzy matic activity of ACE2 through intravenous infusion of 0.2 mg/kg or 0.4 mg/kg of rhACE2 in patients with PAH 33 . The drug was well tolerated and had beneficial effects on pulmonary vascular resistance and cardiac output, in addition to reducing inflammatory markers and increasing superoxide dismutase 2 levels in plasma.…”

“…Despite the substantial amount of evidence suggesting a counter regulatory role for the non canonical RAS in protecting against the deleterious actions of a dysregu lated classical RAS, the complexity of the relationship between the two systems remains to be fully elucidated. For example, ACE2 is elevated in patients with HF 86 or pre hypertension 60 , but depressed in patients with PAH 33 . These discrepancies suggest that the components of the counter regulatory RAS are upregulated or down regulated depending on the stage, severity or type of CVD.…”