key: cord-0959960-vh65ihi9
authors: Perez-Vizcaino, Francisco
title: Lung ACE2 and ADAM17 in pulmonary arterial hypertension. Implications for COVID-19?
date: 2020-07-14
journal: J Heart Lung Transplant
DOI: 10.1016/j.healun.2020.07.003
sha: a2c2291be3873090d399a0fc6d65b1b8754e93b9
doc_id: 959960
cord_uid: vh65ihi9

nan

N-terminal pro brain natriuretic peptide (NT-proBNP) elevation is an independent risk factor for in-hospital death in Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its disease, COVID-19 1 . Pulmonary arterial hypertension (PAH) with right ventricular dysfunction, may be at risk from COVID-19. The angiotensin-converting enzyme 2 (ACE2) is the known cellular receptor and a necessary entry point for SARS-COV and SARS-COV-2 infection 2 .

Priming of the S glycoprotein present in the SARS-CoV-2 spikes by the host protease Transmembrane Protease Serine 2 (TMPRSS2), and possibly furin and cathepsin L, is essential for the interaction of the virus with ACE2.

The Gene Expression Omnibus (GEODataset, https://www.ncbi.nlm.nih.gov/gds/) was searched for transcriptomic datasets with key words "pulmonary", "hypertension", "homo" and "lung" and containing lung mRNA expression data from PAH patients. Four datasets GSE113439, GSE48149, GSE15197 and GSE53408 met the criteria and were selected for analysis. Details of the study cohorts, analytical procedures and ethical approval are given in the original reports.

Briefly, the datasets contained the gene expression profile of samples from explanted lungs of patients with PAH. Controls were lung samples without associated cardiovascular disease obtained from organ donors whose lungs were not used for lung transplantation or from healthy tissue flanking lung cancer resections. Only samples identified as PAH (class I pulmonary hypertension) were included for the analysis. Datasets contained samples from idiopathic PAH patients (IPAH), from connective tissue disease associated PAH patients (CTDPAH) or from congenital heart disease associated PAH patients (CHDPAH). The sample preparation, RNA extraction, cDNA synthesis, microarray analysis, gene annotation, preprocessing and data curation and normalization followed standard procedures. Microarrays were processed with either Affymetrix or Illumina platforms as described in the original reports. Random effects meta-analysis was performed using the Cochrane software RevMan Ver 5.4. The effect size as standardized mean difference was calculated and P<0.05 was considered statistically significant.

ACE2 gene expression in explanted lungs from PAH patients was strongly and consistently upregulated compared to controls in all the datasets analyzed and in the meta-analysis (~6 fold, P < 0.0001, figure 1 ). This was independent of the PAH subtype. Likewise, upregulated mRNA ACE2 (4-fold) has been reported in rat lungs with PAH induced by monocrotaline 3 . ACE2 exists in two forms, the most abundant membrane-bound ACE2 (mACE2) and the relatively scarce circulating soluble ACE2 (sACE2). sACE2 may serve as a competitive interceptor of the virus, decreasing the binding of the viral particles to mACE2 and, hence, preventing viral infection 4 . sACE2 results from proteolytic cleavage of mACE2 by the TNFα converting enzyme (TACE or ADAM17) in a process known as shedding which governs the mACE2/sACE2 ratio.

Thus, the lung expression of ADAM17 was meta-analyzed and resulted to be also significantly upregulated (figure 2), which favors a decreased mACE2/sACE2 and presumably a reduced infectivity. 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 (RAS), promoting vasodilation and antinflammatory effects. And second, ACE2 degrades des-Arg 9 -bradykinin and prevents the subsequent release of proinflammatory chemokines and exaggerated lung injury. Therefore, ACE2 activity is protective in acute lung injury induced by bacterial endotoxin or SARS-CoV-4 . During SARS-CoV infection, ACE2 is downregulated, resulting in a loss of its protective antinflammatory 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 PAH patients, its activity was reported to be diminished, possibly due to the increased presence of autoantibodies against ACE2 5 . This reduced ACE2 activity together with increased ACE activity is detrimental for both PAH 5 and COVID-19 4 . In addition, increased ADAM17 has negative effects on inflammation by promoting shedding of several membrane-bound proteins, including TNFα, releasing the active form of this proinflammatory cytokine.

In conclusion, ACE2 and ADAM17 are upregulated in PAH patients undergoing lung transplantation in a meta-analysis performed on lung transcriptomes. The changes are similar in IPAH, CTDPAH and CHDPAH. These two proteases seem to be double-edge swords in the context of SARS-CoV-2 infection. By itself, increased ACE2 may increase viral entry but together, ACE2 and ADAM17 upregulation account for increased sACE protein, potentially intercepting the coronavirus. These hypotheses require validation and further study. confidence interval. Square sizes are proportional to weight. CHDPAH = PAH associated to congenital heart disease with samples from GSE113439, CTD= PAH associated to connective tissue disease with samples from GSE113439 and GSE53408, IPAH=idiopathic PAH with samples from GSE113439, GSE15197 and GSE53408. The GSE53408 dataset did not identify the PAH subtypes. n indicates patients vs controls. Only samples with PAH (class I pulmonary hypertension) were included. 

Prognostic value of NT-proBNP in patients with severe COVID-19

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Angiotensin Converting Enzyme 2 and Angiotensin (1-7) axis in Pulmonary Arterial Hypertension