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Decrease in Angiotensin-Converting Enzyme activity but not concentration in plasma/lungs in COVID-19 patients offers clues for diagnosis/treatment.

ABSTRACT: Although several therapeutics are used to treat coronavirus disease 2019 (COVID-19) patients, there is still no definitive metabolic marker to evaluate disease severity and recovery or a quantitative test to end quarantine. Because severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects human cells via the angiotensin-converting-enzyme 2 (ACE2) receptor and COVID-19 is associated with renin-angiotensin system dysregulation, we evaluated soluble ACE2 (sACE2) activity in the plasma/saliva of 80 hospitalized COVID-19 patients and 27 non-COVID-19 volunteers, and levels of ACE2/Ang (1-7) in plasma or membrane (mACE2) in lung autopsy samples. sACE2 activity was markedly reduced (p < 0.0001) in COVID-19 plasma (n = 59) compared with controls (n = 27). Nadir sACE2 activity in early hospitalization was restored during disease recovery, irrespective of patient age, demographic variations, or comorbidity; in convalescent plasma-administered patients (n = 45), restoration was statistically higher than matched controls (n = 22, p = 0.0021). ACE2 activity was also substantially reduced in the saliva of COVID-19 patients compared with controls (p = 0.0065). There is a strong inverse correlation between sACE2 concentration and sACE2 activity and Ang (1-7) levels in participant plasmas. However, there were no difference in membrane ACE2 levels in lungs of autopsy tissues of COVID-19 (n = 800) versus other conditions (n = 300). These clinical observations suggest sACE2 activity as a potential biomarker and therapeutic target for COVID-19.

SUBMITTER: Daniell H

PROVIDER: S-EPMC9258412 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Decrease in Angiotensin-Converting Enzyme activity but not concentration in plasma/lungs in COVID-19 patients offers clues for diagnosis/treatment.

Daniell Henry H Nair Smruti K SK Shi Yao Y Wang Ping P Montone Kathleen T KT Shaw Pamela A PA Choi Grace H GH Ghani Danyal D Weaver JoEllen J Rader Daniel J DJ Margulies Kenneth B KB Collman Ronald G RG Laudanski Krzysztof K Bar Katharine J KJ

Molecular therapy. Methods & clinical development 20220706

Although several therapeutics are used to treat coronavirus disease 2019 (COVID-19) patients, there is still no definitive metabolic marker to evaluate disease severity and recovery or a quantitative test to end quarantine. Because severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects human cells via the angiotensin-converting-enzyme 2 (ACE2) receptor and COVID-19 is associated with renin-angiotensin system dysregulation, we evaluated soluble ACE2 (sACE2) activity in the plasma/sa ...[more]

PMID: 35818571

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Project description:Angiotensin converting enzyme (ACE) is known for converting inactive angiotensin I into the potent vasoconstrictor angiotensin II, playing a critical role in blood pressure regulation. However, there is evidence that the dicarboxypeptidase activity of ACE is also essential for other physiological processes likely through processing of various peptide substrates. This study used mass spectrometry for the comprehensive detection and identification of natural substrates and products of ACE within the mouse plasma peptidome. The plasma peptidome of ACE KO mice was obtained through a multi-step purification process which included organic TCA precipitation as well as size exclusion and reversed phase chromatography. The obtained complex mixture of endogenous peptides was then subjected to in vitro cleavage by ACE. ACE-treated and untreated samples were then analyzed by LC/MS on an Orbitrap mass spectrometer, followed by alignment of MS1 data by Progenesis QI software. The MS1 signals that gained or lost intensity after treatment with ACE, were considered as possible products and substrates of ACE, respectively, and were selected for a targeted MS/MS analysis, and subsequently identified with PEAKS 8.5 and Proteome Discoverer software. Results. Close to 250 natural peptides were identified as possible substrates and products of ACE, demonstrating the high promiscuity of the enzyme. The use of internal standards as well as detection of some expected endogenous peptides, such as angiotensin II and bradykinin, supported the validity of the approach. Some of the newly identified substrates of ACE are known for their biological activities. For example, a fragment of complement C3, the 17-amino acid peptide C3f, exhibits spasminogenic activity and was processed by ACE. ACE cleavage of select peptides was further confirmed in vitro. Also, concentrations of ACE substrates in plasma from mice with variant genetic ACE domain backgrounds were determined by LC/MS using multiple reaction monitoring on a triple quadrupole mass spectrometer. The in vivo results were consistent with the in vitro results, in the sense that higher levels of the ACE substrates were observed when the respective processing domain was knocked out. The use of transgenic mice as well as ACE with single active domain allowed clarifying the ACE domain selectivity towards individual peptide substrates. This study resulted in creation of a library of substrates and products of ACE that can be further tested for their biological function and can help to elucidate the link between ACE and the numerous physiological effects attributed to its activity.

Project description:ImportanceIt has been hypothesized that angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) may make patients more susceptible to coronavirus disease 2019 (COVID-19) and to worse outcomes through upregulation of the functional receptor of the virus, angiotensin-converting enzyme 2.ObjectiveTo examine whether use of ACEI/ARBs was associated with COVID-19 diagnosis and worse outcomes in patients with COVID-19.Design, setting, and participantsTo examine outcomes among patients with COVID-19, a retrospective cohort study using data from Danish national administrative registries was conducted. Patients with COVID-19 from February 22 to May 4, 2020, were identified using ICD-10 codes and followed up from day of diagnosis to outcome or end of study period (May 4, 2020). To examine susceptibility to COVID-19, a Cox regression model with a nested case-control framework was used to examine the association between use of ACEI/ARBs vs other antihypertensive drugs and the incidence rate of a COVID-19 diagnosis in a cohort of patients with hypertension from February 1 to May 4, 2020.ExposuresACEI/ARB use was defined as prescription fillings 6 months prior to the index date.Main outcomes and measuresIn the retrospective cohort study, the primary outcome was death, and a secondary outcome was a composite outcome of death or severe COVID-19. In the nested case-control susceptibility analysis, the outcome was COVID-19 diagnosis.ResultsIn the retrospective cohort study, 4480 patients with COVID-19 were included (median age, 54.7 years [interquartile range, 40.9-72.0]; 47.9% men). There were 895 users (20.0%) of ACEI/ARBs and 3585 nonusers (80.0%). In the ACEI/ARB group, 18.1% died within 30 days vs 7.3% in the nonuser group, but this association was not significant after adjustment for age, sex, and medical history (adjusted hazard ratio [HR], 0.83 [95% CI, 0.67-1.03]). Death or severe COVID-19 occurred in 31.9% of ACEI/ARB users vs 14.2% of nonusers by 30 days (adjusted HR, 1.04 [95% CI, 0.89-1.23]). In the nested case-control analysis of COVID-19 susceptibility, 571 patients with COVID-19 and prior hypertension (median age, 73.9 years; 54.3% men) were compared with 5710 age- and sex-matched controls with prior hypertension but not COVID-19. Among those with COVID-19, 86.5% used ACEI/ARBs vs 85.4% of controls; ACEI/ARB use compared with other antihypertensive drugs was not significantly associated with higher incidence of COVID-19 (adjusted HR, 1.05 [95% CI, 0.80-1.36]).Conclusions and relevancePrior use of ACEI/ARBs was not significantly associated with COVID-19 diagnosis among patients with hypertension or with mortality or severe disease among patients diagnosed as having COVID-19. These findings do not support discontinuation of ACEI/ARB medications that are clinically indicated in the context of the COVID-19 pandemic.

Project description:Angiotensin-converting enzyme 2, as an internal anti regulator of the renin-angiotensin hormone cascade reaction, plays a protective role in vasodilation, inhibition of fibrosis, and initiation of anti-inflammatory and antioxidative stress by degrading angiotensin II and generating angiotensin (1-7). Multiple studies have shown that plasma angiotensin-converting enzyme 2 activity is low in healthy populations without significant cardiometabolic disease, and elevated plasma angiotensin-converting enzyme 2 levels can be used as a novel biomarker of abnormal myocardial structure and/or adverse events in cardiometabolic diseases. This article aims to elaborate the determinants of plasma angiotensin-converting enzyme 2 concentration, the relevance between angiotensin-converting enzyme 2 and cardiometabolic disease risk markers, and its relative importance compared with known cardiovascular disease risk factors. Confronted with the known cardiovascular risk factors, plasma angiotensin-converting enzyme 2 (ACE2) concentration uniformly emerged as a firm predictor of abnormal myocardial structure and/or adverse events in cardiometabolic diseases and may improve the risk prediction of cardiometabolic diseases when combined with other conventional risk factors. Cardiovascular disease is the leading cause of death worldwide, while the renin-angiotensin system is the main hormone cascade system involved in the pathophysiology of cardiovascular disease. A multi-ancestry global cohort study from the general population by Narula et al revealed that plasma ACE2 concentration was strongly associated with cardiometabolic disease and might be an easily measurable indicator of renin-angiotensin system disorder. The association between this atypical hormone disorder marker and cardiometabolic disease is isolated from conventional cardiac risk factors and brain natriuretic peptide, suggesting that a clearer comprehending of the changes in plasma ACE2 concentration and activity may help us to improve the risk prediction of cardiometabolic disease, guide early diagnosis and feasible therapies, and develop and test new therapeutic targets.

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Decrease in Angiotensin-Converting Enzyme activity but not concentration in plasma/lungs in COVID-19 patients offers clues for diagnosis/treatment.

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Decrease in Angiotensin-Converting Enzyme activity but not concentration in plasma/lungs in COVID-19 patients offers clues for diagnosis/treatment.

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