General Information:

Id: 11,821
Diseases: COVID-19
Mammalia
review
Reference: Kai H and Kai MInteractions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19 [PMID: 32341442]

Interaction Information:

Comment A novel coronavirus, named severe acute respiratory syn-drome coronavirus 2 (SARS-CoV-2), was discovered in December 2019 in Wuhan, China, and an ongoing pandemic of coronavirus disease 2019 (COVID-19) has been spreading around the world as of early April 2020. The clinical spectrum of COVID-19 ranges from asymptomatic upper respiratory infection to critically ill pneumonia associated with acute respiratory distress syndrome (ARDS).
Formal Description
Interaction-ID: 116755

environment

SARS-CoV-2

increases_activity of

disease

COVID-19

Comment it has been shown that angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS-CoV-2 infection.
Formal Description
Interaction-ID: 116756

environment

SARS-CoV-2

interacts (colocalizes) with

gene/protein

ACE2

Drugbank entries Show/Hide entries for ACE2
Comment ACE2 degrades angiotensin II to generate angiotensin 1-7, which activates the mas oncogene receptor that negatively regulates a variety of angiotensin II actions mediated by angiotensin II type 1 receptor (AT1R).
Formal Description
Interaction-ID: 116757

gene/protein

ACE2

decreases_quantity of

gene/protein

Angiotensin II

Drugbank entries Show/Hide entries for ACE2
Comment ACE2 degrades angiotensin II to generate angiotensin 1-7, which activates the mas oncogene receptor that negatively regulates a variety of angiotensin II actions mediated by angiotensin II type 1 receptor (AT1R).
Formal Description
Interaction-ID: 116758

gene/protein

ACE2

increases_quantity of

gene/protein

Angiotensin (1-7)

Drugbank entries Show/Hide entries for ACE2
Comment ACE2 degrades angiotensin II to generate angiotensin 1-7, which activates the mas oncogene receptor that negatively regulates a variety of angiotensin II actions mediated by angiotensin II type 1 receptor (AT1R).
Formal Description
Interaction-ID: 116759

gene/protein

Angiotensin (1-7)

increases_activity of

gene/protein

MAS1

Comment ACE2 degrades angiotensin II to generate angiotensin 1-7, which activates the mas oncogene receptor that negatively regulates a variety of angiotensin II actions mediated by angiotensin II type 1 receptor (AT1R).
Formal Description
Interaction-ID: 116760

gene/protein

MAS1

decreases_activity of

gene/protein

AGTR1

Drugbank entries Show/Hide entries for AGTR1
Comment Human ACE2 is an established functional receptor by which SARS-CoV enters host target cells. The transmembrane spike glycoprotein (S protein) of SARS-CoV binds to the cellular membrane ACE2; SARS-CoV then attaches to the target cells, followed by SARS-CoV-S protein priming by cellular surface proteases, such as transmembrane protease serine 2 (TMPRSS2), allowing the fusion of viral and cellular membranes and resulting in SARS-CoV entry and replication in the target cell.
Formal Description
Interaction-ID: 116761

environment

SARS-CoV S protein

interacts (colocalizes) with

gene/protein

ACE2

Drugbank entries Show/Hide entries for ACE2
Comment Human ACE2 is an established functional receptor by which SARS-CoV enters host target cells. The transmembrane spike glycoprotein (S protein) of SARS-CoV binds to the cellular membrane ACE2; SARS-CoV then attaches to the target cells, followed by SARS-CoV-S protein priming by cellular surface proteases, such as transmembrane protease serine 2 (TMPRSS2), allowing the fusion of viral and cellular membranes and resulting in SARS-CoV entry and replication in the target cell.
Formal Description
Interaction-ID: 116762

gene/protein

TMPRSS2

increases_activity of

environment

SARS-CoV S protein

Comment ACE2 knockout greatly reduces viral infection and replication in mice after experimental SARS-CoV infection.
Formal Description
Interaction-ID: 116763

gene/protein

ACE2

affects_activity of

disease

SARS-CoV infection

Drugbank entries Show/Hide entries for ACE2
Comment Experimental SARS-CoV infection induces acute respiratory failure and lung parenchymal injury characterized by alveolar wall thickening, pulmonary vascular hyperpermeability, and inflammatory cell infiltration in mice. After SARS-CoV infection in mice, lung ACE2 protein levels are greatly reduced, while ACE levels are not changed. These findings are consistent with the previous observation that coronaviruses specifically downregulate ACE2 expression in host cells, depending on virus replication. SARS-CoV-induced acute lung injury is remarkably attenuated in ACE2 knockout mice compared with wild-type mice.
Formal Description
Interaction-ID: 116764

disease

SARS-CoV infection

decreases_quantity of

gene/protein

ACE2

in lung
Drugbank entries Show/Hide entries for ACE2
Comment Lung angiotensin II levels increase in wild-type mice after SARS-CoV infection.
Formal Description
Interaction-ID: 116766

disease

SARS-CoV infection

increases_quantity of

gene/protein

Angiotensin II

in lung
Comment A similar mechanism is proposed for the severe lung injury caused by the avian influenza A virus H5N1, which has spread worldwide in humans with a high mortality rate. After H5N1 virus infection in mice, lung ACE2 expression is downregulated, and serum angiotensin II levels increase. Acute lung injury is augmented by ACE2 knockout in H5N1-infected mice, while the administration of recombinant human ACE2 ameliorates H5N1-induced lung injury in mice.
Formal Description
Interaction-ID: 116768

disease

Influenza A H5N1 infection

decreases_expression of

gene/protein

ACE2

in lung
Drugbank entries Show/Hide entries for ACE2
Comment A similar mechanism is proposed for the severe lung injury caused by the avian influenza A virus H5N1, which has spread worldwide in humans with a high mortality rate. After H5N1 virus infection in mice, lung ACE2 expression is downregulated, and serum angiotensin II levels increase. Acute lung injury is augmented by ACE2 knockout in H5N1-infected mice, while the administration of recombinant human ACE2 ameliorates H5N1-induced lung injury in mice.
Formal Description
Interaction-ID: 116769

disease

Influenza A H5N1 infection

increases_quantity of

gene/protein

Angiotensin II

in blood serum
Comment Several kinds of ARBs (e.g., olmesartan, telmisartan,losartan, and azilsartan) have been shown to increase the mRNA or protein levels of ACE2 in animal models of heart diseases (hypertensive hypertrophy, autoimmune myocarditis, dilated cardiomyopathy, myocardial infarction, and diabetic cardiomyopathy) and chronic kidney disease (hypertensive nephropathy and diabetic nephropathy), as well as normal rat heart and renal vasculature and hypertensive rat aorta (but not the carotid artery). It should be noted that the doses of ARBs and ACEIs used in these animal studies were much greater than those in clinical practice so that the observed effects of these drugs on ACE2 expression and activity could not be extrapolated to clinical situations in humans. Importantly, no clinical data exist regarding the effects of ARBs and ACEIs on human tissue ACE2 expression or activity in vivo.
Formal Description
Interaction-ID: 116771

drug/chemical compound

Angiotensin II type 1 receptor blocker

increases_quantity of

gene/protein

ACE2

Drugbank entries Show/Hide entries for ACE2
Comment ACEI does not inhibit ACE2 as a pharmacological property.
Formal Description
Interaction-ID: 116774

drug/chemical compound

ACE inhibitor

NOT decreases_activity of

gene/protein

ACE2

Drugbank entries Show/Hide entries for ACE2
Comment It has been shown that pretreatment with losartan, an ARB, ameliorates acute pulmonary edema and lung injury in SARS-CoV-S protein-treated mice after acid aspiration. Taken together with the lung angiotensin II level elevation, this evidence suggested that even after considering the speculation that viral load would be enhanced by ACE2 upregulation, the net effects of ARBs would be favorable to prevent SARS-CoV-induced acute lung injury in this model. In addition, there is another possibility that the ARB pretreatment-induced baseline ACE2 increase prior to SARS-CoV infection would result in higher ACE2 levels that remained after SARS-CoV-induced downregulation and consequently conferred protection against lung injury in this model. However, in interpreting the results of this study, it should be noted that the effects of losartan have been observed merely in mice treated with SARS-CoV-S protein in addition to acid aspiration but not in mice treated with SARS-CoV-S protein alone. Data on lung ACE2 levels before and after treatment with SARS-CoV-Sprotein and acid aspiration are lacking in mice pretreated with or without losartan.
Formal Description
Interaction-ID: 116778

drug/chemical compound

Angiotensin II type 1 receptor blocker

decreases_activity of

phenotype

pulmonary edema

in SARS-CoV-S protein-treated mice after acid aspiration
Comment Earlier studies reported that the case fatality rate was high in COVID-19 patients with comorbidities such as older age, hypertension, diabetes mellitus, CVD, chronic pulmonary disease, and malignancy.
Formal Description
Interaction-ID: 116779

phenotype

hypertension

increases_activity of

phenotype

increased mortality induced by COVID-19

Comment Earlier studies reported that the case fatality rate was high in COVID-19 patients with comorbidities such as older age, hypertension, diabetes mellitus, CVD, chronic pulmonary disease, and malignancy.
Formal Description
Interaction-ID: 116783

disease

Diabetes mellitus

increases_activity of

phenotype

increased mortality induced by COVID-19

Comment Earlier studies reported that the case fatality rate was high in COVID-19 patients with comorbidities such as older age, hypertension, diabetes mellitus, CVD, chronic pulmonary disease, and malignancy.
Formal Description
Interaction-ID: 116785

disease

Cardiovascular disease

increases_activity of

phenotype

increased mortality induced by COVID-19

Comment Earlier studies reported that the case fatality rate was high in COVID-19 patients with comorbidities such as older age, hypertension, diabetes mellitus, CVD, chronic pulmonary disease, and malignancy.
Formal Description
Interaction-ID: 116786

disease

Pulmonary disease, chronic

increases_activity of

phenotype

increased mortality induced by COVID-19

Comment Earlier studies reported that the case fatality rate was high in COVID-19 patients with comorbidities such as older age, hypertension, diabetes mellitus, CVD, chronic pulmonary disease, and malignancy.
Formal Description
Interaction-ID: 116787

disease

Cancer

increases_activity of

phenotype

increased mortality induced by COVID-19

Comment A small case study reported that plasma angiotensin II levels were markedly elevated and linearly associated with viral load and lung injury severity in COVID-19 pneumonia patients. Given that a remarkable elevation of circulating levels was also documented in various kinds of cytokines (IL-6, IL-10, TNF-alpha, etc.), it is unknown whether these findings of angiotensin II are the cause or result of a systemic cytokine storm in COVID-19 patients.
Formal Description
Interaction-ID: 116788

disease

COVID-19

increases_quantity of

gene/protein

Angiotensin II

in blood plasma
Comment In the context of the effects of ARBs and AECIs, a retrospective, single-center analysis enrolling 112 COVID-19 patients showed that the use of ARBs and ACEIs had no effects on the morbidity and mortality of COVID-19 patients with CVD.
Formal Description
Interaction-ID: 116789

drug/chemical compound

Angiotensin II type 1 receptor blocker

NOT affects_activity of

phenotype

increased mortality induced by COVID-19

Comment In the context of the effects of ARBs and AECIs, a retrospective, single-center analysis enrolling 112 COVID-19 patients showed that the use of ARBs and ACEIs had no effects on the morbidity and mortality of COVID-19 patients with CVD.
Formal Description
Interaction-ID: 116808

drug/chemical compound

ACE inhibitor

NOT affects_activity of

phenotype

increased mortality induced by COVID-19