scholarly journals Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1–7) in regulation of cardiovascular function

2005 ◽  
Vol 289 (6) ◽  
pp. H2281-H2290 ◽  
Author(s):  
Carlos M. Ferrario ◽  
Aaron J. Trask ◽  
Jewell A. Jessup
Keyword(s):  
Angiotensin Ii ◽  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Integral Membrane Protein ◽  
Type I ◽  
Converting Enzyme ◽  
Basic Residue ◽  
Angiotensin Converting Enzyme 2 ◽  
Functional Roles ◽  
Potent Vasoconstrictor

Angiotensin-converting enzyme 2 (ACE2) is the first human homologue of ACE to be described. ACE2 is a type I integral membrane protein that functions as a carboxypeptidase, cleaving a single hydrophobic/basic residue from the COOH-terminus of its substrates. Because ACE2 efficiently hydrolyzes the potent vasoconstrictor angiotensin II to angiotensin (1–7), this has changed our overall perspective about the classical view of the renin angiotensin system in the regulation of hypertension and heart and renal function, because it represents the first example of a feedforward mechanism directed toward mitigation of the actions of angiotensin II. This paper reviews the new data regarding the biochemistry of angiotensin-(1–7)-forming enzymes and discusses key findings such as the elucidation of the regulatory mechanisms participating in the expression of ACE2 and angiotensin-(1–7) in the control of the circulation.

scholarly journals Pathological Role of Angiotensin II in Severe COVID-19

TH Open ◽  
2020 ◽  
Vol 04 (02) ◽  
pp. e138-e144 ◽  
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.

scholarly journals Functional Complexes of Angiotensin-Converting Enzyme 2 and Renin-Angiotensin System Receptors: Expression in Adult but Not Fetal Lung Tissue

2020 ◽  
Vol 21 (24) ◽  
pp. 9602
Author(s):  
Rafael Franco ◽  
Alejandro Lillo ◽  
Rafael Rivas-Santisteban ◽  
Ana I. Rodríguez-Pérez ◽  
Irene Reyes-Resina ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cell Surface ◽  
Angiotensin Converting Enzyme ◽  
Ligand Binding ◽  
Renin Angiotensin System ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2

Angiotensin-converting enzyme 2 (ACE2) is a membrane peptidase and a component of the renin-angiotensin system (RAS) that has been found in cells of all organs, including the lungs. While ACE2 has been identified as the receptor for severe acute respiratory syndrome (SARS) coronaviruses, the mechanism underlying cell entry remains unknown. Human immunodeficiency virus infects target cells via CXC chemokine receptor 4 (CXCR4)-mediated endocytosis. Furthermore, CXCR4 interacts with dipeptidyl peptidase-4 (CD26/DPPIV), an enzyme that cleaves CXCL12/SDF-1, which is the chemokine that activates this receptor. By analogy, we hypothesized that ACE2 might also be capable of interactions with RAS-associated G-protein coupled receptors. Using resonance energy transfer and cAMP and mitogen-activated protein kinase signaling assays, we found that human ACE2 interacts with RAS-related receptors, namely the angiotensin II type 1 receptor (AT1R), the angiotensin II type 2 receptor (AT2R), and the MAS1 oncogene receptor (MasR). Although these interactions led to various alterations of signal transduction, but, more importantly, ligand binding to AT1R resulted in the downregulation of ACE2 cell surface expression, while ligand binding to AT2R, but not to MasR, resulted in upregulation of ACE2 cell surface expression. Proximity ligation assays performed in situ revealed macromolecular complexes containing ACE2 and AT1R, AT2R or MasR in adult but not fetal mouse lung tissue. These findings highlight the relevance of RAS in SARS-CoV-2 infection and the role of ACE2-containing complexes as potential therapeutic targets.

scholarly journals Angiotensin-converting enzyme 2. Approaches to pathogenetic therapy of COVID-19

2020 ◽  
Vol 97 (4) ◽  
pp. 339-345
Author(s):  
Polina O. Shatunova ◽  
Anatoly S. Bykov ◽  
Oksana A. Svitich ◽  
Vitaly V. Zverev
Keyword(s):  
Angiotensin Ii ◽  
Angiotensin Converting Enzyme ◽  
Binding Free Energy ◽  
Renin Angiotensin System ◽  
Converting Enzyme ◽  
Angiotensin Ii Receptor ◽  
Angiotensin Converting Enzyme 2 ◽  
Pathogenetic Therapy ◽  
Receptor Blockers ◽  
Coronavirus Infection

The SARS-CoV-2 virus is a pathogen causing the coronavirus infection that culminated in a worldwide pandemic in 2020. It belongs to β-coronaviruses and has high genetic similarity to the SARS-CoV virus that is responsible for an outbreak of severe acute respiratory syndrome in 2002–2003. The analysis of molecular interactions shows that SARS-CoV-2 has higher virulence due to lower binding free energy in interaction with the angiotensin-converting enzyme 2 (ACE2), which is used by the virus to enter the host cell. At the time of the global coronavirus pandemic, the thorough study of ACE2 as a key component of the disease pathogenesis comes to the fore. The detailed study of the enzyme, which is a receptor located on the surface of different tissues and which normally catalyzes the conversion of angiotensin II to angiotensin (1–7), led to diverging conclusions. Being non-tissue specific, the receptor is abundantly present in the heart, kidneys, small intestine, testes, thyroid, and adipose tissue. Besides regulating blood pressure, it suppresses inflammation, mainly in the lung tissue, participates in amino acid transport and maintains the activity of the gut microbiome. With all its essential positive functions, the role of ACE2 is highly ambiguous, specifically in coronavirus infection. The influence on the renin-angiotensin system can be seen as a promising therapeutic route in treatment of coronavirus infection. The preliminary data on using of ACE2 inhibitors, soluble forms of ACE2, and angiotensin II receptor blockers demonstrate their effectiveness and, consequently, improvement in symptoms and prognoses for patients with coronavirus infection. The review presents information about ACE2 distribution in human tissues, explores its interaction with SARS-CoV-2, provides a theoretical basis for medications involving ACE2 metabolic pathways and for using them in treatment of coronavirus infection and its prevention.

Abstract 169: Angiotensin-Converting Enzyme 2: Species-Specific Features and Pharmacologic Characterization by RAS Fingerprinting

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Marko Poglitsch ◽  
Oliver Domenig ◽  
Cornelia Schwager ◽  
Hans Loibner ◽  
Manfred Schuster
Keyword(s):  
Angiotensin Ii ◽  
Angiotensin Converting Enzyme ◽  
Whole Blood ◽  
Renin Angiotensin System ◽  
Converting Enzyme ◽  
Angiotensin I ◽  
Peptide Substrates ◽  
Angiotensin Converting Enzyme 2 ◽  
Species Specific ◽  
The Impact

The carboxypeptidase Angiotensin Converting Enzyme 2 (ACE2) is a crucial player of the Renin-Angiotensin-System (RAS) as it balances the ratio between vasoconstrictive and fibrotic Angiotensin II and vasodilative and anti-fibrotic Angiotensin 1-7. This balance is affected by ACE2 either by direct conversion of Angiotensin II to Angiotensin 1-7, or by cleavage of Angiotensin I to Angiotensin 1-9, which is further converted to Ang 1-7 by Angiotensin Converting Enzyme (ACE) or Neutral Endopeptidase (NEP). An increased activity of ACE2 leads to a shift of the RAS towards an Angiotensin 1-7 dominated pattern, which was shown to be protective in various models of cardiovascular and fibrotic diseases. We performed a comparative pharmacologic characterization of recombinant murine and human ACE2 using natural peptide substrates for the evaluation of the substrate specific ACE2 activity in whole blood. Furthermore, we investigated the impact of ACE2 activators and inhibitors on murine and human ACE2 in whole blood using an LC-MS/MS based approach allowing the simultaneous quantification of 10 different angiotensin peptides (RAS-Fingerprinting). The investigation of inhibitors and activators of ACE2 using our experimental setting revealed the presence of species-specific enzymatic features, which was indicated by differences between the human and murine enzyme regarding the susceptibility to pharmacologic manipulation and the specificity for different endogenous peptide substrates. Our studies demonstrate that sequence diversity observed between recombinant human and murine ACE2 significantly affects substrate specificity and pharmacologic enzyme properties. The utilization of Angiotensin I by ACE2 generates Angiotensin 1-7 via Angiotensin 1-9 and represents a pathway of alternative RAS activation, which might have been systematically underestimated in previous studies. The strongly reduced affinity of murine ACE2 for Angiotensin I results in a lack of production of Angiotensin 1-7 via this pathway, which might be of particular importance during anti-hypertensive treatments with ACE inhibitors, where the formation of Angiotensin II is prevented while increased levels of Angiotensin I are observed in circulation.

Resveratrol ameliorates the cyclosporine-induced vascular and renal impairments: possible impact of the modulation of renin–angiotensin system

2019 ◽  
Vol 97 (12) ◽  
pp. 1115-1123 ◽  
Author(s):  
Seldag Bekpinar ◽  
Ece Karaca ◽  
Selin Yamakoğlu ◽  
F. İlkay Alp-Yıldırım ◽  
Vakur Olgac ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Immunosuppressive Drug ◽  
Oxidative Stress Marker ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
System Components ◽  
Renal Tubular

Cyclosporine, an immunosuppressive drug, exhibits a toxic effect on renal and vascular systems. The present study investigated whether resveratrol treatment alleviates renal and vascular injury induced by cyclosporine. Cyclosporine (25 mg/kg per day, s.c.) was given for 7 days to rats either alone or in combination with resveratrol (10 mg/kg per day, i.p.). Relaxation and contraction responses of aorta were examined. Serum levels of blood urea nitrogen, creatinine, angiotensin II, and angiotensin 1-7 were measured. Histopathological examinations as well as immunostaining for 4-hydroxynonenal and nitrotyrosine were performed in the kidney. RNA expressions of renin–angiotensin system components were also measured in renal and aortic tissues. Cyclosporine decreased the endothelium-dependent relaxation and increased vascular contraction in the aorta. It caused renal tubular degeneration and increased immunostaining for 4-hydroxynonenal, an oxidative stress marker. Cyclosporine also caused upregulations of the vasoconstrictive renin–angiotensin system components in renal (angiotensin-converting enzyme) and aortic (angiotensin II type 1 receptor) tissues. Resveratrol co-treatment prevented the cyclosporine-related deteriorations. Moreover, it induced the expressions of vasodilatory effective angiotensin-converting enzyme 2 and angiotensin II type 2 receptor in aorta and kidney, respectively. We conclude that resveratrol may be effective in preventing cyclosporine-induced renal tubular degeneration and vascular dysfunction at least in part by modulating the renin–angiotensin system.

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