Abstract 243: Structure and Sequence Analysis of AT1, AT2, and MAS: Insights into Differences and Similarities in Binding and Activation by Angiotensin Molecules

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Jeremy W Prokop ◽  
Robson A Santos ◽  
Amy Milsted
Keyword(s):  
Amino Acids ◽  
Molecular Mechanisms ◽  
Renin Angiotensin System ◽  
Site Directed Mutagenesis ◽  
Clear Understanding ◽  
Ang Ii ◽  
Sequence Alignments ◽  
New Model ◽  
Renin Inhibitors ◽  
Angiotensin Peptides

The renin-angiotensin system is involved in multiple conditions ranging from cardiovascular disorders to cancer. The components of the pathway are targets for disease treatments including ACE inhibitors, renin inhibitors and AT1 blockers. However, very little is understood about the molecular mechanisms by which G-protein coupled receptors (GPCRs) are activated by angiotensin peptides. This study addresses three known receptors of the pathway: AT1, AT2, and MAS. Combining biochemical and amino acid variation data with multiple species sequence alignments, structural models, and docking site predictions allows for visualization of how angiotensin peptides may bind and activate the three receptors. It also addresses conserved and variant mechanisms among receptors. Models of each receptor align with a root mean squared deviation of less than 2.1Å with sequence conservation of 14-30% when comparing to another GPCR (rhodopsin), revealing amino acids required to maintain the seven helixes of the structure. This study reveals that MAS possibly differs in binding to angiotensin peptides, favoring a binding to Ang-(1-7) and not Ang II. Consensus amino acids 512 (Lys) and 621 (His), believed to interact with Phe 8 of Ang II are not conserved in MAS but amino acids (118, 233, 231, 268, 419, 719, and 725) predicted to interact with amino acids 1-7 of either Ang II or Ang-(1-7) are conserved. Analysis of MAS related proteins shown to be activated by Ang peptides reveals possible amino acids (114, 120, 318, 342, 426, 526, 527, and 720) that may contribute to homo or heterodimer formations with other membrane bound proteins, a possible mechanism of activation by the MAS receptor family. Finally a new model of Ang II binding and activation of AT1 and AT2 is proposed that correlates data from site directed mutagenesis and photolabled binding. The initial binding occurs between amino acids 512 and 621of either AT1 or AT2 with Phe 8 of Ang II. Then the Phe of Ang II shifts position via conserved aromatic amino acids to the final photolabled position relative to either AT1 (725) or AT2 (336). Our new model of Ang II-receptor interactions can be verified in future experiments to allow for a clear understanding of angiotensin peptide receptors and their interactions with other molecules.

scholarly journals ACE2 Shedding and the Role in COVID-19

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.

scholarly journals Dysregulation of ACE (Angiotensin-Converting Enzyme)-2 and Renin-Angiotensin Peptides in SARS-CoV-2 Mediated Mortality and End-Organ Injuries

Hypertension ◽  
2021 ◽  
Author(s):  
Kaiming Wang ◽  
Mahmoud Gheblawi ◽  
Anish Nikhanj ◽  
Matt Munan ◽  
Erika MacIntyre ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Tumor Necrosis Factor Receptor ◽  
Renin Angiotensin System ◽  
Adverse Outcomes ◽  
Blood Collection ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Angiotensin Peptides

ACE (angiotensin-converting enzyme)-2 as the target for SARS-CoV-2 also negatively regulates the renin-angiotensin system. Pathological activation of ADAM17 (A disintegrin and metalloproteinase-17) may potentiate inflammation and diminish ACE2-mediated tissue protection through proteolytic shedding, contributing to SARS-CoV-2 pathogenesis. We aim to examine plasma soluble ACE2 and angiotensin profiles in relation to outcomes by enrolling consecutive patients admitted for COVID-19 with baseline blood collection at admission and repeated sampling at 7 days. The primary outcome was 90-day mortality, and secondary outcomes were the incidence of end-organ injuries. Overall, 242 patients were included, the median age was 63 (52–74) years, 155 (64.0%) were men, and 57 (23.6%) patients reached the primary end point. Baseline soluble ACE2 was elevated in COVID-19 but was not associated with disease severity or mortality. In contrast, an upward trajectory of soluble ACE2 at repeat sampling was independently associated with an elevated risk of mortality and incidence of acute myocardial injury and circulatory shock. Similarly, an increase in soluble tumor necrosis factor receptor levels was also associated with adverse outcomes. Plasma Ang I, Ang 1-7 (angiotensin 1–7) levels, and the Ang 1-7/Ang II (angiotensin II) ratio were elevated during SARS-CoV-2 infection related to downregulation of ACE activity at baseline. Moreover, patients having an upward trajectory of soluble ACE2 were characterized by an imbalance in the Ang 1-7/Ang II ratio. The observed dysregulation of ACE2 and angiotensin peptides with disease progression suggest a potential role of ADAM17 inhibition and enhancing the beneficial Ang 1-7/Mas axis to improve outcomes against SARS-CoV-2 infection.

scholarly journals The Biochemical Effects of Angiotensin-(1-7) on the Oxidative Stress Metabolism and Their Specific Parameters from the Temporal Lobe

2020 ◽  
Vol 71 (6) ◽  
pp. 307-311
Author(s):  
Sorin Ungurianu ◽  
Constantin Trus ◽  
Roxana-Rosmary Enciu
Keyword(s):  
Oxidative Stress ◽  
Temporal Lobe ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Angiotensin Peptides ◽  
Vascular Area ◽  
Ang Iv ◽  
The One

It is already known from a variety of previous reports that an independent brain renin�angiotensin system (RAS) exists, completely separated from the one in the periphery. This independent brain RAS has all the precursors and the enzymatic structures necessary for the generation of the angiotensin peptides. Thus, in the last few years various groups started focusing on the more central effects of less known angiotensins (e.g in comparison with Angiotensin (Ang) II), namely Ang III, Ang IV, Ang-(1�7) or Ang 5-8. One of these newly emerging angiotensins which has become an increased center of interest in many studies is Ang-(1-7), which is a heptapeptide previously described especially for its opposite effects to Ang II, in the peripheral vascular area, but also described for some opposite central functions vs. Ang II. These aspects are completed with the fact that it was recently suggested that the renin�angiotensin system could modulate the oxidative stress metabolism, and also it seems that the manifestations of Angiotensin-(1-7) on the basal oxidative stress status are contradictory, with a variety of reports describing controversial (e.g. both pro-oxidant and antioxidant actions) effects for this heptapeptide. Our results presented here are confirming a possible antioxidant effect of Ang-(1�7) administration on rat, as shown by the increased levels of antioxidant enzymes from the temporal lobe (superoxide dismutase and glutathione peroxidase) and decreased levels of malondialdehyde, as an important lipid peroxidation parameter.

scholarly journals Thromboplasminflammation in COVID-19 Coagulopathy: Three Viewpoints for Diagnostic and Therapeutic Strategies

2021 ◽  
Vol 12 ◽  
Author(s):  
Satoshi Gando ◽  
Takeshi Wada
Keyword(s):  
Angiotensin Ii ◽  
Plasminogen Activator ◽  
Thrombin Generation ◽  
Molecular Mechanisms ◽  
Endothelial Injury ◽  
Neutrophil Extracellular Trap ◽  
Tissue Type ◽  
Clear Understanding ◽  
Factor Xii ◽  
Ang Ii

Thromboplasminflammation in coronavirus disease 2019 (COVID-19) coagulopathy consists of angiotensin II (Ang II)-induced coagulopathy, activated factor XII (FXIIa)- and kallikrein, kinin system-enhanced fibrinolysis, and disseminated intravascular coagulation (DIC). All three conditions induce systemic inflammation via each pathomechanism-developed production of inflammatory cytokines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) downregulates angiotensin-converting enzyme 2, leading to an increase in Ang II levels. Ang II-induced coagulopathy comprising platelet activation, thrombin generation, plasminogen activator inhibitor-1 expression and endothelial injury causes thrombosis via the angiotensin II type 1 receptor. SARS-CoV-2 RNA and neutrophil extracellular trap (NET) DNA activate FXII, resulting in plasmin generation through FXIIa- and kallikrein-mediated plasminogen conversion to plasmin and bradykinin-induced tissue-type plasminogen activator release from the endothelium via the kinin B2 receptor. NETs induce immunothrombosis at the site of infection (lungs), through histone- and DNA-mediated thrombin generation, insufficient anticoagulation control, and inhibition of fibrinolysis. However, if the infection is sufficiently severe, immunothrombosis disseminates into the systemic circulation, and DIC, which is associated with the endothelial injury, occurs. Inflammation, and serine protease networks of coagulation and fibrinolysis, militate each other through complement pathways, which exacerbates three pathologies of COVID-19 coagulopathy. COVID-19 coagulopathy causes microvascular thrombosis and bleeding, resulting in multiple organ dysfunction and death in critically ill patients. Treatment targets for improving the prognosis of COVID-19 coagulopathy include thrombin, plasmin, and inflammation, and SARS-CoV-2 infection. Several drugs are candidates for controlling these conditions; however, further advances are required to establish robust treatments based on a clear understanding of molecular mechanisms of COVID-19 coagulopathy.

Abstract P104: Renin Angiotensin System (RAS) Modulation in Hypertension Program by Maternal Intrauterine Malnutrition

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Rafael S Banti ◽  
Rodrigo Yokota ◽  
Danielle S Aragão ◽  
Adriana Souza ◽  
Amanda Pedroso ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renin Angiotensin System ◽  
Control Group ◽  
Ang Ii ◽  
Alternative Pathways ◽  
Angiotensin Peptides ◽  
Increased Risk ◽  
Ace Activity ◽  
Intrauterine Malnutrition ◽  
Group D

Intrauterine malnutrition (IM) during the early stages of development can alter the function of organs and tissues and can predict a lifetime of increased risk for adverse health outcomes, such as diabetes and hypertension. The kidney plays a key role in the development of hypertension programmed by IM, with the participation of the RAS. Our objectives were to study ACE activity and angiotensin peptides levels in tissues. Pregnants Wistar rats were separated into two groups: control group (C), fed ad libitum, and malnourished group (D) submitted to food restriction (diet 50% of the amount of feed consumed by the group C). After birth the offspring were kept as experimental groups C and D, respectively. At 4 months of age, the animals were sacrificed, heart and kidney tissues were collected to quantify angiotensin peptides and ACE activity. The offspring born with low birth weight. Kidney ACE activity was higher in group D compared to group C (299 ±86.7 vs. 253.4 ±84.82 mU/mg, p<0.05), differing from Heart (D versus C: 0.15 ± 0.08 vs. 0.24 ±0.09 mU/mg). Group D presented high blood pressure values compared to group C (140.6 ±2.8 vs. 124,3±2.6 mmHg). Kidney and heart Ang II levels were increased in group D being significant when compared to group C (238.26 ±25.1 vs. 161.85 ±45.6 pmol/g and 397.89±74.9 vs. 223.33±48.7 pmol/g, p<0.05, respectively). The same was observed for Ang I. The vasodilator peptide Ang1-7 levels in group D from kidney and heart were lower in comparison with group C, thus emphasizing an enabling environment for hypertension (220.74 ± 48.74 vs. 288.09 ± 47 pmol/g and 152.1±41.2 pmol/g vs. 228.93±41.2 pmol/g, p<0.05, respectively). Our results indicate that perturbed maternal nutritional status alters tissue RAS resulting in higher blood pressure in the offspring, demonstrated by increased renal ACE activity and Ang II levels, with reduced Ang 1-7. The increase of Ang I and II in the heart, despite low ACE activity in this tissue suggests the activation of RAS alternative pathways. This study describes for the first time that low levels of Ang 1-7 contributed to the early development of hypertension.

scholarly journals The renin-angiotensin system: going beyond the classical paradigms

2019 ◽  
Vol 316 (5) ◽  
pp. H958-H970 ◽  
Author(s):  
Robson Augusto Souza Santos ◽  
Gavin Y. Oudit ◽  
Thiago Verano-Braga ◽  
Giovanni Canta ◽  
Ulrike Muscha Steckelings ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Protective Effects ◽  
Ang Ii ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Amino Terminal ◽  
Angiotensin Peptides ◽  
Protective Actions

Thirty years ago, a novel axis of the renin-angiotensin system (RAS) was unveiled by the discovery of angiotensin-(1−7) [ANG-(1−7)] generation in vivo. Later, angiotensin-converting enzyme 2 (ACE2) was shown to be the main mediator of this reaction, and Mas was found to be the receptor for the heptapeptide. The functional analysis of this novel axis of the RAS that followed its discovery revealed numerous protective actions in particular for cardiovascular diseases. In parallel, similar protective actions were also described for one of the two receptors of ANG II, the ANG II type 2 receptor (AT2R), in contrast to the other, the ANG II type 1 receptor (AT1R), which mediates deleterious actions of this peptide, e.g., in the setting of cardiovascular disease. Very recently, another branch of the RAS was discovered, based on angiotensin peptides in which the amino-terminal aspartate was replaced by alanine, the alatensins. Ala-ANG-(1−7) or alamandine was shown to interact with Mas-related G protein-coupled receptor D, and the first functional data indicated that this peptide also exerts protective effects in the cardiovascular system. This review summarizes the presentations given at the International Union of Physiological Sciences Congress in Rio de Janeiro, Brazil, in 2017, during the symposium entitled “The Renin-Angiotensin System: Going Beyond the Classical Paradigms,” in which the signaling and physiological actions of ANG-(1−7), ACE2, AT2R, and alatensins were reported (with a focus on noncentral nervous system-related tissues) and the therapeutic opportunities based on these findings were discussed.

scholarly journals Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

2016 ◽  
Vol 310 (2) ◽  
pp. H137-H152 ◽  
Author(s):  
Mark C. Chappell
Keyword(s):  
Renin Angiotensin System ◽  
Cellular Growth ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Angiotensin System ◽  
Physiological Regulation ◽  
Renin Angiotensin ◽  
Angiotensin Peptides ◽  
The Status ◽  
Biochemical Evaluation

The renin-angiotensin system (RAS) constitutes a key hormonal system in the physiological regulation of blood pressure through peripheral and central mechanisms. Indeed, dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies, and pharmacological blockade of this system by the inhibition of angiotensin-converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT1R) offers an effective therapeutic regimen. The RAS is now defined as a system composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS comprises the ACE-ANG II-AT1R axis that promotes vasoconstriction; water intake; sodium retention; and increased oxidative stress, fibrosis, cellular growth, and inflammation. In contrast, the nonclassical RAS composed primarily of the ANG II/ANG III-AT2R and the ACE2-ANG-(1–7)-AT7R pathways generally opposes the actions of a stimulated ANG II-AT1R axis. In lieu of the complex and multifunctional aspects of this system, as well as increased concerns on the reproducibility among laboratories, a critical assessment is provided on the current biochemical approaches to characterize and define the various components that ultimately reflect the status of the RAS.

scholarly journals Evidence for intraventricular secretion of angiotensinogen and angiotensin by the subfornical organ using transgenic mice

2017 ◽  
Vol 312 (6) ◽  
pp. R973-R981 ◽  
Author(s):  
Khristofor Agassandian ◽  
Justin L. Grobe ◽  
Xuebo Liu ◽  
Marianna Agassandian ◽  
Anthony P. Thompson ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Immunohistochemical Localization ◽  
Subfornical Organ ◽  
Ang Ii ◽  
Angiotensin System ◽  
Angiotensin Peptides ◽  
Human Renin ◽  
Brain Measurements ◽  
The Brain ◽  
Large Decline

Direct intracerebroventricular injection of angiotensin II (ANG II) causes increases in blood pressure and salt and water intake, presumably mimicking an effect mediated by an endogenous mechanism. The subfornical organ (SFO) is a potential source of cerebrospinal fluid (CSF), ANG I, and ANG II, and thus we hypothesized that the SFO has a secretory function. Endogenous levels of angiotensinogen (AGT) and renin are very low in the brain. We therefore examined the immunohistochemical localization of angiotensin peptides and AGT in the SFO, and AGT in the CSF in two transgenic models that overexpress either human AGT (A+ mice), or both human AGT (hAGT) and human renin (SRA mice) in the brain. Measurements were made at baseline and following volumetric depletion of CSF. Ultrastructural analysis with immunoelectron microscopy revealed that superficially located ANG I/ANG II and AGT immunoreactive cells in the SFO were vacuolated and opened directly into the ventricle. Withdrawal of CSF produced an increase in AGT in the CSF that was accompanied by a large decline in AGT immunoreactivity within SFO cells. Our data provide support for the hypothesis that the SFO is a secretory organ that releases AGT and possibly ANG I/ANG II into the ventricle at least under conditions when genes that control the renin-angiotensin system are overexpressed in mice.

scholarly journals The ins and outs of angiotensin processing within the kidney

2014 ◽  
Vol 307 (5) ◽  
pp. R487-R489 ◽  
Author(s):  
Bryan A. Wilson ◽  
Allyson C. Marshall ◽  
Ebaa M. Alzayadneh ◽  
Mark C. Chappell
Keyword(s):  
Renin Angiotensin System ◽  
Target Organ ◽  
Tubular Epithelium ◽  
Ang Ii ◽  
Renal Cells ◽  
Bioactive Components ◽  
Angiotensin System ◽  
Mas Receptor ◽  
Angiotensin Peptides ◽  
Current Review

The kidney is a key target organ for bioactive components of the renin-angiotensin system (RAS); however, various renal cells such as the tubular epithelium contain an intrinsic RAS. The renal RAS can be functionally divided into ANG II-AT1 receptor and ANG-(1–7)-AT7/Mas receptor arms that functionally oppose one another. The current review considers both extracellular and intracellular pathways that potentially govern the formation and metabolism of angiotensin peptides within the renal proximal tubules.

Role of angiotensin peptides in risk stratification and prognostication for heart failure: focus on plasma Ang 1–7/Ang II ratio

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K Wang ◽  
R Basu ◽  
M Poglitsch ◽  
J.A Bakal ◽  
G.Y Oudit
Keyword(s):  
Heart Failure ◽  
Survival Rates ◽  
Renin Angiotensin System ◽  
Adverse Outcomes ◽  
Funding Source ◽  
Ang Ii ◽  
Nested Models ◽  
Angiotensin Peptides ◽  
All Cause Mortality ◽  
Plasma Angiotensin

Abstract Background ACE2 and Ang 1–7 are endogenous negative regulators of the renin-angiotensin system (RAS) exerting cardioprotective effects in models of heart failure (HF). Recombinant ACE2 markedly increased plasma Ang 1–7 and lowered Ang II levels in clinical trials. Elevated plasma ACE2 activity is associated with adverse outcomes in HF patients. However, the direct effects of systemic and tissue ACE2 activation on angiotensin peptides in relation to long-term HF outcomes has yet to be examined. Purpose To generate insights into the ACE2 mediated cardioprotective arm through the relative levels of its substrates and products using the plasma Ang 1–7/Ang II ratio, and assess its prognostic utility in HF patients. Methods 110 HF patients were prospectively enrolled from outpatient clinics and the emergency department. Comprehensive circulating and equilibrium levels of plasma angiotensin peptides were assessed using novel liquid chromatography-mass spectrometry/mass spectroscopy techniques. Plasma aldosterone, BNP, active renin activity and clinical profiles were captured at baseline. Patients were stratified into above and below median cohorts based on equilibrium and circulating levels of Ang 1–7/Ang II ratio, as a surrogate for ACE2 functionality. During a median follow-up of 5.1±0.8 years, composite clinical outcomes were assessed through all-cause in-patient hospitalizations and mortality. Results Circulating and equilibrium angiotensin peptide levels strongly correlated in our patient cohort. All-cause mortality for HF patients with equilibrium Ang 1–7/Ang II ratios above the median showed higher survival rates compared to below median patients (76.4% vs. 50.9%; p=0.004); similar results were observed for circulating Ang 1–7/Ang II ratios (72.7% vs. 54.5%; p=0.041). Adjusting for covariates, elevated equilibrium (HR: 0.24; 95% CI: 0.09 to 0.69; p=0.008) and circulating (HR: 0.35; 95% CI: 0.13 to 0.94; p=0.036) Ang 1–7/Ang II ratios was associated with improved survival. Lower hospitalization duration was also associated with elevated equilibrium (p&lt;0.001) and circulating (p=0.023) Ang 1–7/Ang II ratios. In nested models, net reclassification analysis showed considerable improvement in risk prediction for all-cause mortality at 5 years provided by both the equilibrium (+45.0% [95% CI: 7.3% to 82.7%]) and circulating Ang 1–7/Ang II ratios (+24.3% [95% CI: 0.4% to 59.6%]) respectively. Conclusions We extensively profiled plasma angiotensin peptides in HF patients and identified elevated ACE2 signature, reflected through the Ang 1–7/Ang II ratio, as an independent and incremental predictor of beneficial outcomes, higher survival rate, and decreased hospitalization duration. These findings provide important clinical evidence supporting strategies aiming to promote the beneficial ACE2/Ang 1–7/Mas receptor axis concurrent with RAS blockade therapies inhibiting the detrimental ACE/Ang II/AT1 receptor axis. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Alberta Innovates, Canadian Institute of Health Research

Sign in / Sign up

Export Citation Format

Share Document