scholarly journals Research Progress on Pulmonary Arterial Hypertension and the Role of the Angiotensin Converting Enzyme 2-Angiotensin-(1–7)-Mas Axis in Pulmonary Arterial Hypertension

2021 ◽  
Author(s):  
Feng Zhang ◽  
Aidong Chen ◽  
Yan Pan ◽  
Xingxing Wang ◽  
Yu Xu ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Angiotensin Converting Enzyme ◽  
Arterial Hypertension ◽  
Research Progress ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Pulmonary Arterial

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

2020 ◽  
Vol 56 (1) ◽  
pp. 1902416 ◽  
Author(s):  
Julio Sandoval ◽  
Leonardo Del Valle-Mondragón ◽  
Felipe Masso ◽  
Nayeli Zayas ◽  
Tomás Pulido ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Angiotensin Converting Enzyme ◽  
Arterial Hypertension ◽  
Blood Donors ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Right Heart Catheterisation ◽  
The Status ◽  
Pulmonary Arterial

BackgroundIn animal models of pulmonary arterial hypertension (PAH), angiotensin-converting enzyme (ACE)2 and angiotensin (Ang)-(1–7) have been shown to have vasodilatory, antiproliferative, antifibrotic and antihypertrophic 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 aetiologies. 55 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 -II were measured using zone capillary electrophoresis. Aldosterone, Ang(1–9), AngA and ACE2 were measured using 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 (median 1.03, interquartile range 0.72–1.88 pmol·mL−1versus 0.19, 0.10–0.37 pmol·mL−1; p<0.001) and of aldosterone (88.7, 58.7–132 ng·dL−1versus 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 pmol·mL−1versus 4.07, 2.82–6.73 pmol·mL−1; p<0.001), and a lower concentration of Ang(1–9) and AngA. Similarly, the ACE2 concentration was higher than in controls (8.7, 5.35–13.2 ng·mL−1versus 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 nmol·mL−1versus 5.97, 3.1–17.8 nmol·mL−1; p<0.001). No significant differences were found among the three different aetiological 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.

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

2018 ◽  
Vol 51 (6) ◽  
pp. 1702638 ◽  
Author(s):  
Anna R. Hemnes ◽  
Anandharajan Rathinasabapathy ◽  
Eric A. Austin ◽  
Evan L. Brittain ◽  
Erica J. Carrier ◽  
...  
Keyword(s):  
Pilot Study ◽  
Pulmonary Arterial Hypertension ◽  
Angiotensin Converting Enzyme ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
Converting Enzyme ◽  
Open Label ◽  
Angiotensin Converting Enzyme 2 ◽  
Markers Of Inflammation ◽  
Pulmonary Arterial

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.

scholarly journals MDM2-Mediated Ubiquitination of Angiotensin-Converting Enzyme 2 Contributes to the Development of Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (12) ◽  
pp. 1190-1204 ◽  
Author(s):  
Hui Shen ◽  
Jiao Zhang ◽  
Chen Wang ◽  
Pritesh P. Jain ◽  
Mingmei Xiong ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Angiotensin Converting Enzyme ◽  
Arterial Hypertension ◽  
Posttranslational Modification ◽  
E3 Ligase ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Pulmonary Arterial

Background: Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II, a potent vasoconstrictor, to angiotensin-(1–7) and is also a membrane protein that enables coronavirus disease 2019 (COVID-19) infectivity. AMP-activated protein kinase (AMPK) phosphorylation of ACE2 enhances ACE2 stability. This mode of posttranslational modification of ACE2 in vascular endothelial cells is causative of a pulmonary hypertension (PH)–protective phenotype. The oncoprotein MDM2 (murine double minute 2) is an E3 ligase that ubiquitinates its substrates to cause their degradation. In this study, we investigated whether MDM2 is involved in the posttranslational modification of ACE2 through its ubiquitination of ACE2, and whether an AMPK and MDM2 crosstalk regulates the pathogenesis of PH. Methods: Bioinformatic analyses were used to explore E3 ligase that ubiquitinates ACE2. Cultured endothelial cells, mouse models, and specimens from patients with idiopathic pulmonary arterial hypertension were used to investigate the crosstalk between AMPK and MDM2 in regulating ACE2 phosphorylation and ubiquitination in the context of PH. Results: Levels of MDM2 were increased and those of ACE2 decreased in lung tissues or pulmonary arterial endothelial cells from patients with idiopathic pulmonary arterial hypertension and rodent models of experimental PH. MDM2 inhibition by JNJ-165 reversed the SU5416/hypoxia-induced PH in C57BL/6 mice. ACE2-S680L mice (dephosphorylation at S680) showed PH susceptibility, and ectopic expression of ACE2-S680L/K788R (deubiquitination at K788) reduced experimental PH. Moreover, ACE2-K788R overexpression in mice with endothelial cell–specific AMPKα2 knockout mitigated PH. Conclusions: Maladapted posttranslational modification (phosphorylation and ubiquitination) of ACE2 at Ser-680 and Lys-788 is involved in the pathogenesis of pulmonary arterial hypertension and experimental PH. Thus, a combined intervention of AMPK and MDM2 in the pulmonary endothelium might be therapeutically effective in PH treatment.

Navigating the Road to Transplant in Pulmonary Arterial Hypertension: A Road Less Taken

2016 ◽  
Vol 15 (1) ◽  
pp. 12-13
Author(s):  
Adaani E. Frost ◽  
Harrison W. Farber
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Lung Transplantation ◽  
Small Cell ◽  
Small Cell Lung ◽  
Donor Organ ◽  
The Road ◽  
Lung Allocation Score ◽  
Pulmonary Arterial

Dramatic advances in therapy for pulmonary arterial hypertension (PAH) in the last 20 years have improved survival from a median of 2.5 years in the pretreatment era to 7.5 years currently. However, impressive as that may seem, it is important to note that a median survival of 7.5 years is equivalent to that of surgically resected non-small cell lung cancer, thus underscoring the importance of lung transplantation as a treatment option in patients with PAH. In this edition of Advances, Edelman has reviewed the pathway to transplantation for patients with PAH, detailing the recommendations for timing of referral, listing for lung transplantation, the role of the lung allocation score in allocating a donor organ, and the outcome of lung transplantation.

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