Dataset Information

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

ABSTRACT: 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 lead to minor alterations of signal transduction, ligand binding to AT₁R and AT₂R, but not to MasR, resulted in the 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.

SUBMITTER: Franco R

PROVIDER: S-EPMC7766085 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Franco Rafael R Lillo Alejandro A Rivas-Santisteban Rafael R Rodríguez-Pérez Ana I AI Reyes-Resina Irene I Labandeira-García José L JL Navarro Gemma G

International journal of molecular sciences 20201216 24

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 pept ...[more]

PMID: 33339432

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Project description:Rationale: Smoking is a major risk factor for the development of cardiovascular and pulmonary diseases. The importance of the renin–angiotensin system in the development of cardiovascular and pulmonary disease is well established. Angiotensin-II, by means of its type 1 receptor (angiotensin type 1 receptor, AT1R), promotes increased sympathetic activity, salt and water reabsorption, vasoconstriction, inflammation, and aldosterone and vasopressin release, contributing to tissue fibrosis, endothelium dysfunction, and hypertension. Angiotensin-converting enzyme 2 cleaves angiotensin-II into the vasodilator peptide, angiotensin-(1–7), hence playing a pivotal role in the angiotensin-converting enzyme 2/angiotensin-(1–7) compensatory axis of the renin–angiotensin system. Angiotensin type 2 receptor (AT2R), another receptor for angiotensin-II, opposes the deleterious effects of AT1R activation, and angiotensin-converting enzyme 2–formed angiotensin-(1–7) has been shown to activate AT2R. Objectives: The goal of the present study was to examine how nicotine, the addictive component of cigarette smoke, alters the homeostasis of the renin–angiotensin system. Methods: Quantitative real-time polymerase chain reaction was performed to examine the expression of the components of the renin–angiotensin system after cigarette smoke exposure or direct nicotine inhalation. Radio telemetry was used for continuous blood pressure recording in conscious, unrestrained mice. Results: Our study showed that cigarette smoke or direct nicotine inhalation inhibits the expression of angiotensin-converting enzyme 2/AT2R in multiple organs and cell types. In the lung, cigarette smoke (6 cigarettes/d, 12 wk) inhibited the expression of both angiotensin-converting enzyme 2 and AT2R. In cardiac fibroblasts, nicotine exposure resulted in near complete suppression of angiotensin-converting enzyme 2 and AT2R. In the brain, nicotine vapor inhalation inhibited angiotensin-converting enzyme 2 expression in the hypothalamus, a region involved in central regulation of cardiopulmonary function. In addition, cultured Neuro2A cells exposed to nicotine showed a dose-dependent reduction of enzymatic activity of angiotensin-converting enzyme 2. Functionally, mice exposed to nicotine vapor (12 h/d, 4 wk) exhibited significantly increased mean arterial blood pressure, which was more pronounced during the night active cycle (mean?±?SE, 124?±?0.6 mm Hg in nicotine vapor–exposed mice vs. 107?±?0.4 mm Hg in air control mice; P <?0.0001). Conclusions: Our findings suggest that, by downregulating the compensatory angiotensin-converting enzyme 2/AT2R elements, nicotine disrupts the homeostasis of the renin–angiotensin system in multiple organs, which is likely an important mechanism leading to the development of cardiovascular and pulmonary disease.

Project description:BackgroundRenin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown.ObjectivesTo evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension.Search methodsThe Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions.Selection criteriaWe included randomized, active-controlled, double-blinded studies (RCTs) with at least four weeks follow-up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension.Data collection and analysisTwo review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis.Main resultsWe include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow-up duration ranged from four weeks to 36.6 months. There was no difference between RIs and ACE inhibitors for the outcomes: all-cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low-certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low-certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants; moderate-certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low-certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low-certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end-stage renal disease or change in heart rate. Low-certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) -1.72, 95% CI -2.47 to -0.97; 9 RCTs, 5001 participants; and diastolic blood pressure: MD -1.18, 95% CI -1.65 to -0.72; 9 RCTs, 5001 participants, to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect. AUTHORS' CONCLUSIONS: For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all-cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty. More independent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.

Dataset Information

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

Publications

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

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