Angiotensin-converting enzyme 2 (ACE2) expression in COPD and IPF fibroblasts- the forgotten cell in COVID-19

The COVID-19 pandemic is associated with severe pneumonia and acute respiratory distress syndrome leading to death in susceptible individuals. For those who recover, post-COVID-19 complications may include development of pulmonary fibrosis. Factors contributing to disease severity or development of complications is not known. Using computational analysis with experimental data, we report that IPF and COPD-derived lung fibroblasts express higher levels of ACE2, the receptor for SARS-CoV-2 entry and part of the renin-angiotensin system that is anti-fibrotic and anti-inflammatory. In preclinical models, we found that chronic exposure to cigarette smoke, a risk factor for both COPD and IPF and potentially for SARS-CoV-2 infection, significantly increased pulmonary ACE2 protein expression. Further studies are needed to understand the functional implications of ACE2 on lung fibroblasts, a cell type that thus far as received relatively little attention in the context of COVID-19.

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Outcomes of COVID-19 Hospitalized Patients Previously Treated with Renin-Angiotensin System Inhibitors

Journal of Clinical Medicine ◽

10.3390/jcm9113472 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3472 ◽

Cited By ~ 1

Author(s):

Elena-Mihaela Cordeanu ◽

Lucas Jambert ◽

Francois Severac ◽

Hélène Lambach ◽

Jonathan Tousch ◽

...

Keyword(s):

Renin Angiotensin System ◽

Severe Pneumonia ◽

University Hospital ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Previously Treated ◽

The Impact ◽

Harmful Effects ◽

Observation Period

(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) penetrates respiratory epithelium through angiotensin-converting enzyme-2 binding, raising concerns about the potentially harmful effects of renin–angiotensin system inhibitors (RASi) on Human Coronavirus Disease 2019 (COVID-19) evolution. This study aimed to provide insight into the impact of RASi on SARS-CoV-2 outcomes in patients hospitalized for COVID-19. (2) Methods: This was a retrospective analysis of hospitalized adult patients with SARS-CoV-2 infection admitted to a university hospital in France. The observation period ended at hospital discharge. (3) Results: During the study period, 943 COVID-19 patients were admitted to our institution, of whom 772 were included in this analysis. Among them, 431 (55.8%) had previously known hypertension. The median age was 68 (56–79) years. Overall, 220 (28.5%) patients were placed under mechanical ventilation and 173 (22.4%) died. According to previous exposure to RASi, we defined two groups, namely, “RASi” (n = 282) and “RASi-free” (n = 490). Severe pneumonia (defined as leading to death and/or requiring intubation, high-flow nasal oxygen, noninvasive ventilation, and/or oxygen flow at a rate of ≥5 L/min) and death occurred more frequently in RASi-treated patients (64% versus 53% and 29% versus 19%, respectively). However, in a propensity score-matched cohort derived from the overall population, neither death (hazard ratio (HR) 0.93 (95% confidence interval (CI) 0.57–1.50), p = 0.76) nor severe pneumonia (HR 1.03 (95%CI 0.73–1.44), p = 0.85) were associated with RASi therapy. (4) Conclusion: Our study showed no correlation between previous RASi treatment and death or severe COVID-19 pneumonia after adjustment for confounders.

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COVID-19 and vascular disorders (literature review)

Regional blood circulation and microcirculation ◽

10.24884/1682-6655-2020-19-3-90-98 ◽

2020 ◽

Vol 19 (3) ◽

pp. 90-98

Author(s):

N. N. Petrishchev ◽

O. V. Khalepo ◽

Y. A. Vavilenkova ◽

T. D. Vlasov

Keyword(s):

Cell Surface ◽

Prognostic Value ◽

Distress Syndrome ◽

Alveolar Epithelium ◽

Renin Angiotensin System ◽

Pulmonary Vessel ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Inflammatory Agent ◽

Time Correction

The review describes pathogenesis of the disease caused by the new SARS-CoV-2 virus. It infects the human cells by linking angiotensin-converting enzyme-2 (ACE2) and a number of other receptors. The virus imbalances the renin-angiotensin system, results to vasoconstriction and acts like pro-inflammatory agent. ACE2 is exposed on the alveolar epithelium cell surface. It is the main gates for virus entering and damaging of the respiratory system resulted in an acute respiratory distress syndrome. The injuring of the pulmonary vessel endothelium is the most important part of the COVID-19 pathogenesis. ACE2 of the endothelial and smooth muscle cell surface upon the SARS-CoV-2 infection facilitates the injury of cardiovascular system. The development of endotheliitis induced by «cytokine storm» leads to the main signs of the disease and the multiple disorder of the microcirculation. The investigation of that condition has a prognostic value and determines the treatment especially in critically ill patients. Systemic endothelial dysfunction upon the COVID-19 largely triggers the hemostasis disorders. High activity of platelets adhesion and aggregation, blood coagulation in died COVID-19 patients, disorder of fibrinolysis system functional activity could be induced by the endothelium activation. The unchanged anticoagulation blood activity in the COVID-19 patients distinguishes them from the patients with disseminated intravascular coagulation. Monitoring of the hemostasis system in COVID-19 is important for the disease severity assess and its prognosis, for justin-time correction of detected deviations.

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Pathological Role of Angiotensin II in Severe COVID-19

TH Open ◽

10.1055/s-0040-1713678 ◽

2020 ◽

Vol 04 (02) ◽

pp. e138-e144 ◽

Cited By ~ 5

Author(s):

Wolfgang Miesbach

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Treatment Options ◽

Renin Angiotensin System ◽

Target Cells ◽

Converting Enzyme ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Novel Coronavirus

AbstractThe activated renin–angiotensin system induces a prothrombotic state resulting from the imbalance between coagulation and fibrinolysis. Angiotensin II is the central effector molecule of the activated renin–angiotensin system and is degraded by the angiotensin-converting enzyme 2 to angiotensin (1–7). The novel coronavirus infection (classified as COVID-19) is caused by the new coronavirus SARS-CoV-2 and is characterized by an exaggerated inflammatory response that can lead to severe manifestations such as acute respiratory distress syndrome, sepsis, and death in a proportion of patients, mostly elderly patients with preexisting comorbidities. SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor to enter the target cells, resulting in activation of the renin–angiotensin system. After downregulating the angiotensin-converting enzyme 2, the vasoconstrictor angiotensin II is increasingly produced and its counterregulating molecules angiotensin (1–7) reduced. Angiotensin II increases thrombin formation and impairs fibrinolysis. Elevated levels were strongly associated with viral load and lung injury in patients with severe COVID-19. Therefore, the complex clinical picture of patients with severe complications of COVID-19 is triggered by the various effects of highly expressed angiotensin II on vasculopathy, coagulopathy, and inflammation. Future treatment options should focus on blocking the thrombogenic and inflammatory properties of angiotensin II in COVID-19 patients.

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Effects of Yinchenhao decoction on self-regulation of renin-angiotensin system by targeting angiotensin converting enzyme 2 in bile duct-ligated rat liver

Journal of Huazhong University of Science and Technology [Medical Sciences] ◽

10.1007/s11596-015-1463-9 ◽

2015 ◽

Vol 35 (4) ◽

pp. 519-524 ◽

Cited By ~ 4

Author(s):

Lin Wu ◽

Pi-qi Zhou ◽

Ji-wen Xie ◽

Rui Zhu ◽

Sun-chang Zhou ◽

...

Keyword(s):

Bile Duct ◽

Angiotensin Converting Enzyme ◽

Rat Liver ◽

Self Regulation ◽

Renin Angiotensin System ◽

Converting Enzyme ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin

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ACE2: the molecular doorway to SARS-CoV-2

Cell & Bioscience ◽

10.1186/s13578-020-00519-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Miriam Marlene Medina-Enríquez ◽

Sandra Lopez-León ◽

José Alberto Carlos-Escalante ◽

Zuleika Aponte-Torres ◽

Angelica Cuapio ◽

...

Keyword(s):

Renin Angiotensin System ◽

Cell Types ◽

Negative Regulator ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Functional Activities ◽

Pathological Conditions ◽

Organ Systems ◽

Different Cell Types ◽

Functional Receptor

AbstractThe angiotensin-converting enzyme 2 (ACE2) is the host functional receptor for the new virus SARS-CoV-2 causing Coronavirus Disease 2019. ACE2 is expressed in 72 different cell types. Some factors that can affect the expression of the ACE2 are: sex, environment, comorbidities, medications (e.g. anti-hypertensives) and its interaction with other genes of the renin-angiotensin system and other pathways. Different factors can affect the risk of infection of SARS-CoV-2 and determine the severity of the symptoms. The ACE2 enzyme is a negative regulator of RAS expressed in various organ systems. It is with immunity, inflammation, increased coagulopathy, and cardiovascular disease. In this review, we describe the genetic and molecular functions of the ACE2 receptor and its relation with the physiological and pathological conditions to better understand how this receptor is involved in the pathogenesis of COVID-19. In addition, it reviews the different comorbidities that interact with SARS-CoV-2 in which also ACE2 plays an important role. It also describes the different factors that interact with the virus that have an influence in the expression and functional activities of the receptor. The goal is to provide the reader with an understanding of the complexity and importance of this receptor.

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ACE2 Shedding and the Role in COVID-19

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.789180 ◽

2022 ◽

Vol 11 ◽

Author(s):

Jieqiong Wang ◽

Huiying Zhao ◽

Youzhong An

Keyword(s):

Amino Acids ◽

Viral Entry ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Underlying Mechanism ◽

Ang Ii ◽

Converting Enzyme ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Transmembrane Glycoprotein

Angiotensin converting enzyme 2 (ACE2), a transmembrane glycoprotein, is an important part of the renin-angiotensin system (RAS). In the COVID-19 epidemic, it was found to be the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). ACE2 maintains homeostasis by inhibiting the Ang II-AT1R axis and activating the Ang I (1-7)-MasR axis, protecting against lung, heart and kidney injury. In addition, ACE2 helps transport amino acids across the membrane. ACE2 sheds from the membrane, producing soluble ACE2 (sACE2). Previous studies have pointed out that sACE2 plays a role in the pathology of the disease, but the underlying mechanism is not yet clear. Recent studies have confirmed that sACE2 can also act as the receptor of SARS-COV-2, mediating viral entry into the cell and then spreading to the infective area. Elevated concentrations of sACE2 are more related to disease. Recombinant human ACE2, an exogenous soluble ACE2, can be used to supplement endogenous ACE2. It may represent a potent COVID-19 treatment in the future. However, the specific administration concentration needs to be further investigated.

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Mechanism of ligand recognition by human ACE2 receptor

10.1101/2020.10.30.362749 ◽

2020 ◽

Author(s):

Apurba Bhattarai ◽

Shristi Pawnikar ◽

Yinglong Miao

Keyword(s):

Ligand Binding ◽

Renin Angiotensin System ◽

Rational Drug Design ◽

Renal Diseases ◽

Ligand Recognition ◽

Conformational Ensemble ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Accelerated Molecular Dynamics ◽

Rational Drug

AbstractAngiotensin converting enzyme 2 (ACE2) plays a key role in renin-angiotensin system regulation and amino acid homeostasis. Human ACE2 acts as the receptor for severe acute respiratory syndrome coronaviruses SARS-CoV and SARS-CoV-2. ACE2 is also widely expressed in epithelial cells of lungs, heart, kidney and pancreas. It is considered an important drug target for treating SARS-CoV-2, as well as pulmonary diseases, heart failure, hypertension, renal diseases and diabetes. Despite the critical importance, the mechanism of ligand binding to the human ACE2 receptor remains unknown. Here, we address this challenge through all-atom simulations using a novel ligand Gaussian accelerated molecular dynamics (LiGaMD) method. Microsecond LiGaMD simulations have successfully captured both binding and unbinding of the MLN-4760 inhibitor in the ACE2 receptor. In the ligand unbound state, the ACE2 receptor samples distinct Open, Partially Open and Closed conformations. Ligand binding biases the receptor conformational ensemble towards the Closed state. The LiGaMD simulations thus suggest a conformational selection mechanism for ligand recognition by the ACE2 receptor. Our simulation findings are expected to facilitate rational drug design of ACE2 against coronaviruses and other related human diseases.

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