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−1 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.
Abstract
The ACE2–Ang-(1–7)–Mas1 axis is probably involved in the pathophysiology of human pulmonary arterial hypertension http://ow.ly/pgS530jOxnd
Footnotes
This article has supplementary material available from erj.ersjournals.com
This study is registered at clinicaltrials.gov with identifier number NCT01884051.
Conflict of interest: A.R. Hemnes reports grants from the National Institutes of Health (NIH) and the Cardiovascular Medical Research and Education Fund, personal fees from Actelion, Bayer and United Therapeutics, and personal fees and nonfinancial support (drug supplies to perform experiments) from GlaxoSmithKline, during the conduct of the study. In addition, she has a patent Annamometer issued (noninvasive diagnosis of pulmonary vascular disease). E.A. Austin has received grants from the NIH. He has served as a consultant to Acceleron. E.L. Brittain has received grants from the NIH. He has served as a consultant to Hovine Pharmaceuticals. E.J. Carrier has received grants from the NIH. She has intellectual property pending with Cumberland Pharmaceuticals and has received a grant from this entity. J.P. Fessel has received grant support from the NIH, Gilead, Actelion, the LAM foundation and the Parker B. Francis Foundation. C.D. Fike is a co-inventor on patent applications filed on behalf of Vanderbilt University in the USA and abroad and licensed to Asklepion Pharmaceuticals for the use of intravenous citrulline in lung conditions, without current financial compensation. J.H. Newman has received grants from the NIH. M.E. Pugh has received grant funding from the NIH and has served as a consultant to Gilead. T.W. Rice has received grant funding from the NIH. He has served as a consultant to Avisa Pharma, ACI Clinical and Nestle. He is the Director of Medical Affairs at Cumberland Pharmaceuticals. I.M. Robbins has received funding from the NIH. J.E. Loyd has received grants from the NIH. J. West has received grants from the NIH and Cumberland Pharmaceuticals, and holds intellectual property without financial gain at Cumberland Pharmaceuticals.
Support statement: This work was supported by National Heart, Lung, and Blood Institute grant P01-HL-108800. The project was supported by CTSA award UL1TR000445 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. GlaxoSmithKline provided investigational compound and in-kind support in the form of RAS peptide assays. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received December 18, 2017.
- Accepted April 25, 2018.
- Copyright ©ERS 2018
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