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Jing H, Wu X, Xiang M, Liu L, Novakovic VA, Shi J. Pathophysiological mechanisms of thrombosis in acute and long COVID-19. Front Immunol 2022; 13:992384. [PMID: 36466841 PMCID: PMC9709252 DOI: 10.3389/fimmu.2022.992384] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 10/27/2022] [Indexed: 08/02/2023] Open
Abstract
COVID-19 patients have a high incidence of thrombosis, and thromboembolic complications are associated with severe COVID-19 and high mortality. COVID-19 disease is associated with a hyper-inflammatory response (cytokine storm) mediated by the immune system. However, the role of the inflammatory response in thrombosis remains incompletely understood. In this review, we investigate the crosstalk between inflammation and thrombosis in the context of COVID-19, focusing on the contributions of inflammation to the pathogenesis of thrombosis, and propose combined use of anti-inflammatory and anticoagulant therapeutics. Under inflammatory conditions, the interactions between neutrophils and platelets, platelet activation, monocyte tissue factor expression, microparticle release, and phosphatidylserine (PS) externalization as well as complement activation are collectively involved in immune-thrombosis. Inflammation results in the activation and apoptosis of blood cells, leading to microparticle release and PS externalization on blood cells and microparticles, which significantly enhances the catalytic efficiency of the tenase and prothrombinase complexes, and promotes thrombin-mediated fibrin generation and local blood clot formation. Given the risk of thrombosis in the COVID-19, the importance of antithrombotic therapies has been generally recognized, but certain deficiencies and treatment gaps in remain. Antiplatelet drugs are not in combination with anticoagulant treatments, thus fail to dampen platelet procoagulant activity. Current treatments also do not propose an optimal time for anticoagulation. The efficacy of anticoagulant treatments depends on the time of therapy initiation. The best time for antithrombotic therapy is as early as possible after diagnosis, ideally in the early stage of the disease. We also elaborate on the possible mechanisms of long COVID thromboembolic complications, including persistent inflammation, endothelial injury and dysfunction, and coagulation abnormalities. The above-mentioned contents provide therapeutic strategies for COVID-19 patients and further improve patient outcomes.
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Affiliation(s)
- Haijiao Jing
- Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Xiaoming Wu
- Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Mengqi Xiang
- Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Langjiao Liu
- Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China
| | - Valerie A. Novakovic
- Department of Research, VA Boston Healthcare System, Harvard Medical School, Boston, MA, United States
| | - Jialan Shi
- Department of Hematology, The First Hospital, Harbin Medical University, Harbin, China
- Department of Research, VA Boston Healthcare System, Harvard Medical School, Boston, MA, United States
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
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2
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Abstract
COVID-19 is a primary respiratory illness that is frequently complicated by systemic involvement of the vasculature. Vascular involvement leads to an array of complications ranging from thrombosis to pulmonary edema secondary to loss of barrier function. This review will address the vasculopathy of COVID-19 with a focus on the role of the endothelium in orchestrating the systemic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The endothelial receptor systems and molecular pathways activated in the setting of COVID-19 and the consequences of these inflammatory and prothrombotic changes on endothelial cell function will be discussed. The sequelae of COVID-19 vascular involvement at the level of organ systems will also be addressed, with an emphasis on the pulmonary vasculature but with consideration of effects on other vascular beds. The dramatic changes in endothelial phenotypes associated with COVID-19 has enabled the identification of biomarkers that could help guide therapy and predict outcomes. Knowledge of vascular pathogenesis in COVID-19 has also informed therapeutic approaches that may control its systemic sequelae. Because our understanding of vascular response in COVID-19 continues to evolve, we will consider areas of controversy, such as the extent to which SARS-CoV-2 directly infects endothelium and the degree to which vascular responses to SARS-CoV-2 are unique or common to those of other viruses capable of causing severe respiratory disease. This conceptual framework describing how SARS-CoV-2 infection affects endothelial inflammation, prothrombotic transformation, and barrier dysfunction will provide a context for interpreting new information as it arises addressing the vascular complications of COVID-19.
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Affiliation(s)
| | | | - Alec A Schmaier
- Division of Hemostasis and Thrombosis and
- Division of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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Cook JR, Ausiello J. Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19. Rev Endocr Metab Disord 2022; 23:151-170. [PMID: 34195965 PMCID: PMC8245275 DOI: 10.1007/s11154-021-09663-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/04/2021] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2, the virus responsible for COVID-19, uses angiotensin converting enzyme 2 (ACE2) as its primary cell-surface receptor. ACE2 is a key enzyme in the counter-regulatory pathway of the broader renin-angiotensin system (RAS) that has been implicated in a broad array of human pathology. The RAS is composed of two competing pathways that work in opposition to each other: the "conventional" arm involving angiotensin converting enzyme (ACE) generating angiotensin-2 and the more recently identified ACE2 pathway that generates angiotensin (1-7). Following the original SARS pandemic, additional studies suggested that coronaviral binding to ACE2 resulted in downregulation of the membrane-bound enzyme. Given the similarities between the two viruses, many have posited a similar process with SARS-CoV-2. Proponents of this ACE2 deficiency model argue that downregulation of ACE2 limits its enzymatic function, thereby skewing the delicate balance between the two competing arms of the RAS. In this review we critically examine this model. The available data remain incomplete but are consistent with the possibility that the broad multisystem dysfunction of COVID-19 is due in large part to functional ACE2 deficiency leading to angiotensin imbalance with consequent immune dysregulation and endothelial cell dysfunction.
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Affiliation(s)
- Joshua R Cook
- New York-Presbyterian Hospital and the Columbia University Irving Medical Center, New York, NY, USA
| | - John Ausiello
- New York-Presbyterian Hospital and the Columbia University Irving Medical Center, New York, NY, USA.
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Luo W, Liu X, Bao K, Huang C. Ischemic stroke associated with COVID-19: a systematic review and meta-analysis. J Neurol 2022; 269:1731-1740. [PMID: 34652503 PMCID: PMC8517946 DOI: 10.1007/s00415-021-10837-7] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19), a contagious infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread across the world. Apart from respiratory complications, an increasing number of patients with ischemic stroke have been reporting. OBJECTIVE This systematic review and meta-analysis aims to explore the characteristics of ischemic stroke after SARS-CoV-2 infection, and provides valuable reference materials for subsequent clinical treatment. MATERIALS AND METHODS PubMed, Web of Science, and Ovid-Embase databases were searched up to 24th March 2021. We utilized the search strategy of medical subject headings combined with entry terms to search all related literatures. All studies identified with the electronic and manual searches were listed by citation, title, authors, and abstract. Only studies involving patients with COVID-19-related stroke were eligible. The references of included studies were also manually screened. RESULTS The meta-analysis was conducted following the PRISMA and MOOSE reporting guidelines. Bias risk was assessed using the Newcastle-Ottawa Scale (NOS). Ten articles, including 26,691 participants and 280 patients with ischemic stroke and COVID-19, were selected. The pooled prevalence of ischemic stroke in COVID-19 was 2% (95% CI 1-2%; p < 0.01). The pooled proportions of hypertension, hyperlipidemia and diabetes in COVID-19-related ischemic stroke was 66% (95% CI 51-81%; p < 0.01), 48% (95% CI 19-76%; p < 0.01) and 40% (95% CI 29-51%; p < 0.01), respectively. Notably, the pooled proportions of female was 36% (95% CI 21-50%; p < 0.01) in patients with COVID-19 and stroke. In addition, in TOAST classification, cryptogenic stroke subtype was associated with a high trend, and its pooled proportion was 35% (95% CI 12-59%; p < 0.01). CONCLUSION Ischemic stroke caused by COVID-19 has its own unique clinical features. Although common high-risk factors can also be observed, its importance may have changed. The major inflammatory storm of COVID-19 is more likely to occur in male patients. The increase in the proportion of cryptogenic stroke has also made stroke related to COVID-19 complicated.
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Affiliation(s)
- Wenzhang Luo
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No.25 of Taiping Street, Luzhou, 646000, Sichuan, China
| | - Xiang Liu
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No.25 of Taiping Street, Luzhou, 646000, Sichuan, China
| | - Kunyang Bao
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No.25 of Taiping Street, Luzhou, 646000, Sichuan, China
| | - Changren Huang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No.25 of Taiping Street, Luzhou, 646000, Sichuan, China.
- Neurosurgical Clinical Research Center of Sichuan Province, Luzhou, China.
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
- Laboratory of Neurological Diseases and Brain Functions, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
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Zhang Q, Ling S, Hu K, Liu J, Xu JW. Role of the renin-angiotensin system in NETosis in the coronavirus disease 2019 (COVID-19). Pharmacotherapy 2022; 148:112718. [PMID: 35176710 PMCID: PMC8841219 DOI: 10.1016/j.biopha.2022.112718] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 12/20/2022]
Abstract
Myocardial infarction and stroke are the leading causes of death in the world. Numerous evidence has confirmed that hypertension promotes thrombosis and induces myocardial infarction and stroke. Recent findings reveal that neutrophil extracellular traps (NETs) are involved in the induction of myocardial infarction and stroke. Meanwhile, patients with severe COVID-19 suffer from complications such as myocardial infarction and stroke with pathological signs of NETs. Due to the extremely low amount of virus detected in the blood and remote organs (e.g., heart, brain and kidney) in a few cases, it is difficult to explain the mechanism by which the virus triggers NETosis, and there may be a different mechanism than in the lung. A large number of studies have found that the renin-angiotensin system regulates the NETosis at multiple levels in patients with COVID-19, such as endocytosis of SARS-COV-2, abnormal angiotensin II levels, neutrophil activation and procoagulant function at multiple levels, which may contribute to the formation of reticular structure and thrombosis. The treatment of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II type 1 receptor blockers (ARBs) and neutrophil recruitment and active antagonists helps to regulate blood pressure and reduce the risk of net and thrombosis. The review will explore the possible role of the angiotensin system in the formation of NETs in severe COVID-19.
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Grau-Expósito J, Perea D, Suppi M, Massana N, Vergara A, Soler MJ, Trinite B, Blanco J, García-Pérez J, Alcamí J, Serrano-Mollar A, Rosado J, Falcó V, Genescà M, Buzon MJ. Evaluation of SARS-CoV-2 entry, inflammation and new therapeutics in human lung tissue cells. PLoS Pathog 2022; 18:e1010171. [PMID: 35025963 PMCID: PMC8791477 DOI: 10.1371/journal.ppat.1010171] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/26/2022] [Accepted: 12/06/2021] [Indexed: 12/15/2022] Open
Abstract
The development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions directly from primary human lung tissues (HLT), we have developed a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. The direct use of HLT cells, without long-term cell culture and in vitro differentiation approaches, preserves main immune and structural cell populations, including the most susceptible cell targets for SARS-CoV-2; alveolar type II (AT-II) cells, while maintaining the expression of proteins involved in viral infection, such as ACE2, TMPRSS2, CD147 and AXL. Further, antiviral testing of 39 drug candidates reveals a highly reproducible method, suitable for different SARS-CoV-2 variants, and provides the identification of new compounds missed by conventional systems, such as VeroE6. Using this method, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a relevant and rapid method for the study of SARS-CoV-2.
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Affiliation(s)
- Judith Grau-Expósito
- Infectious Diseases Department, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, VHIR Task Force COVID-19, Barcelona, Spain
| | - David Perea
- Infectious Diseases Department, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, VHIR Task Force COVID-19, Barcelona, Spain
| | - Marina Suppi
- Infectious Diseases Department, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, VHIR Task Force COVID-19, Barcelona, Spain
| | - Núria Massana
- Infectious Diseases Department, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, VHIR Task Force COVID-19, Barcelona, Spain
| | - Ander Vergara
- Nephrology Research Department, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, VHIR Task Force COVID-19, Barcelona, Spain
| | - Maria José Soler
- Nephrology Research Department, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, VHIR Task Force COVID-19, Barcelona, Spain
| | - Benjamin Trinite
- IrsiCaixa AIDS Research Institute, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Autonomous University of Barcelona (UAB), Badalona, Spain
| | - Julià Blanco
- IrsiCaixa AIDS Research Institute, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Autonomous University of Barcelona (UAB), Badalona, Spain
- University of Vic–Central University of Catalonia (UVic-UCC), Vic, Spain
| | - Javier García-Pérez
- AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - José Alcamí
- AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Clinic HIV Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain
| | - Anna Serrano-Mollar
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Joel Rosado
- Thoracic Surgery and Lung Transplantation Department, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron, VHIR Task Force COVID-19, Barcelona, Spain
| | - Vicenç Falcó
- Infectious Diseases Department, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, VHIR Task Force COVID-19, Barcelona, Spain
| | - Meritxell Genescà
- Infectious Diseases Department, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, VHIR Task Force COVID-19, Barcelona, Spain
| | - Maria J. Buzon
- Infectious Diseases Department, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, VHIR Task Force COVID-19, Barcelona, Spain
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Research Progress on Pulmonary Arterial Hypertension and the Role of the Angiotensin Converting Enzyme 2-Angiotensin-(1-7)-Mas Axis in Pulmonary Arterial Hypertension. Cardiovasc Drugs Ther 2022; 36:363-370. [PMID: 33394361 PMCID: PMC7779643 DOI: 10.1007/s10557-020-07114-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/13/2020] [Indexed: 01/31/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease with a complex aetiology and high mortality. Functional and structural changes in the small pulmonary arteries lead to elevated pulmonary arterial pressure, resulting in right heart failure. The pathobiology of PAH is not fully understood, and novel treatment targets in PAH are desperately needed. The renin-angiotensin system is critical for maintaining homeostasis of the cardiovascular system. The system consists of the angiotensin converting enzyme (ACE)-angiotensin (Ang) II-angiotensin type 1 receptor (AT1R) axis and the ACE2-Ang-(1-7)-Mas receptor axis. The former, the ACE-Ang II-AT1R axis, is involved in vasoconstrictive and hypertensive actions along with cardiac and vascular remodelling. The latter, the ACE2-Ang-(1-7)-Mas axis, generally mediates counterbalancing effects against those mediated by the ACE-Ang II-AT1R axis. Based on established functions, the ACE2-Ang-(1-7)-Mas axis may represent a novel target for the treatment of PAH. This review focuses on recent advances in pulmonary circulation science and the role of the ACE2-Ang-(1-7)-Mas axis in PAH.
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Wu C, Qu G, Wang L, Cao S, Xia D, Wang B, Fan X, Wang C. Clinical Characteristics and Inflammatory Immune Responses in COVID-19 Patients With Hypertension: A Retrospective Study. Front Pharmacol 2021; 12:721769. [PMID: 34759820 PMCID: PMC8573086 DOI: 10.3389/fphar.2021.721769] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/18/2021] [Indexed: 11/21/2022] Open
Abstract
Coronavirus disease (COVID-19) patients with cardiovascular and metabolic disorders have been found to have a high risk of developing severe conditions with high mortality, further affecting the prognosis of COVID-19. However, the effect of hypertension and angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB) agents on the clinical characteristics and inflammatory immune responses in COVID-19 patients is still undefined. In this study, 90 COVID-19 patients were divided into hypertension and nonhypertension groups. The hypertension group was divided into well-controlled and poorly controlled subgroups based on blood pressure levels; moreover, hypertensive patients were also divided into ACEI/ARB and non-ACEI/ARB subgroups according to the administration of ACEI/ARB antihypertensive agents. The clinical characteristics of and inflammatory immune biomarker levels in the different groups of COVID-19 patients were compared, and the association between the combined effect of hypertension with ACEI/ARB antihypertensive agents and the severity of COVID-19 was examined. The results showed that the levels of aminotransferase (AST) and hs-cTnI were higher in the hypertension group compared with the nonhypertension group. The long-term use of ACEI/ARB agents in patients had statistically significantly lower AST, low-density lipoprotein cholesterol (LDL-C), and oxygen uptake and lower white cell count, neutrophil count, and levels of CD4, CD8, CRP, and PCT but without statistical significance. In addition, compared with COVID-19 patients without hypertension, hypertensive patients without the use of ACEI/ARB had a higher risk of developing severity of COVID-19 (for poorly controlled patients: OR = 3.97, 95% CI = 1.03–15.30; for well-controlled patients: OR = 6.48, 95% CI = 1.77–23.81). Hypertension could cause organ damage in COVID-19 patients, but the long-term use of ACEI/ARB agents may be beneficial to alleviate this injury.
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Affiliation(s)
- Chaoran Wu
- Department of Cardiology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guangbo Qu
- Department of Epidemiology and Health Statistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Lei Wang
- Department of Cardiology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shiyu Cao
- Department of Cardiology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Dandan Xia
- Department of Cardiology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Baolong Wang
- Department of Cardiology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaoyun Fan
- Department of Geriatric Respiratory and Critical Care, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Changhui Wang
- Department of Cardiology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
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Alavi P, Rathod AM, Jahroudi N. Age-Associated Increase in Thrombogenicity and Its Correlation with von Willebrand Factor. J Clin Med 2021; 10:4190. [PMID: 34575297 PMCID: PMC8472522 DOI: 10.3390/jcm10184190] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/08/2021] [Accepted: 09/10/2021] [Indexed: 02/07/2023] Open
Abstract
Endothelial cells that cover the lumen of all blood vessels have the inherent capacity to express both pro and anticoagulant molecules. However, under normal physiological condition, they generally function to maintain a non-thrombogenic surface for unobstructed blood flow. In response to injury, certain stimuli, or as a result of dysfunction, endothelial cells release a highly adhesive procoagulant protein, von Willebrand factor (VWF), which plays a central role in formation of platelet aggregates and thrombus generation. Since VWF expression is highly restricted to endothelial cells, regulation of its levels is among the most important functions of endothelial cells for maintaining hemostasis. However, with aging, there is a significant increase in VWF levels, which is concomitant with a significant rise in thrombotic events. It is not yet clear why and how aging results in increased VWF levels. In this review, we have aimed to discuss the age-related increase in VWF, its potential mechanisms, and associated coagulopathies as probable consequences.
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Affiliation(s)
| | | | - Nadia Jahroudi
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2S2, Canada; (P.A.); (A.M.R.)
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Liu LP, Zhang XL, Li J. New perspectives on angiotensin-converting enzyme 2 and its related diseases. World J Diabetes 2021; 12:839-854. [PMID: 34168732 PMCID: PMC8192247 DOI: 10.4239/wjd.v12.i6.839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/30/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Since the worldwide outbreak of coronavirus disease 2019, angiotensin-converting enzyme 2 (ACE2) has received widespread attention as the cell receptor of the severe acute respiratory syndrome coronavirus 2 virus. At the same time, as a key enzyme in the renin-angiotensin-system, ACE2 is considered to be an endogenous negative regulator of vasoconstriction, proliferation, fibrosis, and proinflammation caused by the ACE-angiotensin II-angiotensin type 1 receptor axis. ACE2 is now implicated as being closely connected to diabetes, cardiovascular, kidney, and lung diseases, and so on. This review covers the available information on the host factors regulating ACE2 and discusses its role in a variety of pathophysiological conditions in animal models and humans.
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Affiliation(s)
- Li-Ping Liu
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Xiao-Li Zhang
- TheFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg 68135, Baden-Württemberg, Germany
| | - Jian Li
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Changsha 410013, Hunan Province, China
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De Cristofaro R, Liuzzo G, Sacco M, Lancellotti S, Pedicino D, Andreotti F. Marked von Willebrand factor and factor VIII elevations in severe acute respiratory syndrome coronavirus-2-positive, but not severe acute respiratory syndrome coronavirus-2-negative, pneumonia: a case-control study. Blood Coagul Fibrinolysis 2021; 32:285-289. [PMID: 33443926 DOI: 10.1097/mbc.0000000000000998] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Patients with novel coronavirus pneumonia show increased thrombotic risk. Although hemostatic alterations have been described in novel coronavirus pneumonia patients, case-control studies of von Willebrand factor (VWF), factor VIII (FVIII), and a disintegrin-like and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) are lacking. VWF, ADAMTS13, FVIII, d-dimer, C-reactive protein, and routine blood cells and chemistry were measured in 10 novel coronavirus pneumonia patients and 10 non-novel coronavirus pneumonia controls. Hemostatic factors were measured less than 48 h of hospital admission in patients without invasive ventilation. d-Dimer, C-reactive protein, and fibrinogen concentrations, high in both groups, did not differ significantly in novel coronavirus pneumonia vs. non-novel coronavirus pneumonia patients. Median VWF-antigen (324 vs. 153 IU/dl, P < 0.0001), VWF-Rco (342 vs. 133 IU/dl, P < 0.001), and FVIII-activity levels (203 vs. 123 IU/dl, P < 0.0001) were significantly higher in novel coronavirus pneumonia cases vs. controls ADAMTS13-activity was normal in both groups. Coronavirus pneumonia cases vs. non-novel coronavirus pneumonia controls showed marked VWF/FVIII elevation, suggesting specific virus-induced endothelial activation causing VWF/FVIII hypersecretion, which may represent a therapeutic target in novel coronavirus pneumonia.
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Affiliation(s)
- Raimondo De Cristofaro
- Servizio Malattie Emorragiche e Trombotiche, Fondazione Policlinico Universitario A. Gemelli IRCCS
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica S. Cuore, Facoltà di Medicina e Chirurgia 'Agostino Gemelli'
| | - Giovanna Liuzzo
- Dipartimento di Scienze Cardiovascolari, Fondazione Policlinico Universitario A. Gemelli IRCCS
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Monica Sacco
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica S. Cuore, Facoltà di Medicina e Chirurgia 'Agostino Gemelli'
| | - Stefano Lancellotti
- Servizio Malattie Emorragiche e Trombotiche, Fondazione Policlinico Universitario A. Gemelli IRCCS
| | - Daniela Pedicino
- Dipartimento di Scienze Cardiovascolari, Fondazione Policlinico Universitario A. Gemelli IRCCS
| | - Felicita Andreotti
- Dipartimento di Scienze Cardiovascolari, Fondazione Policlinico Universitario A. Gemelli IRCCS
- Università Cattolica del Sacro Cuore, Rome, Italy
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Ghosh R, Roy D, Mandal A, Pal SK, Chandra Swaika B, Naga D, Pandit A, Ray BK, Benito-León J. Cerebral venous thrombosis in COVID-19. Diabetes Metab Syndr 2021; 15:1039-1045. [PMID: 34015627 PMCID: PMC8128714 DOI: 10.1016/j.dsx.2021.04.026] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Initially, novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was considered primarily a respiratory pathogen. However, with time it has behaved as a virus with the potential to cause multi-system involvement, including neurological manifestations. Cerebral venous sinus thrombosis (CVT) has increasingly been reported in association with coronavirus infectious disease of 2019 (COVID-19). Here, we have shed light upon CVT and its possible mechanisms in the backdrop of the ongoing COVID-19 pandemic. METHODS In this review, data were collected from PubMed, EMBASE and Web of Science, until March 30, 2021, using pre-specified searching strategies. The search strategy consisted of a variation of keywords of relevant medical subject headings and keywords, including "COVID-19", "SARS-CoV-2", "coronavirus", and "cerebral venous sinus thrombosis". RESULTS COVID-19 has a causal association with a plethora of neurological, neuropsychiatric and psychological effects. CVT has gained particular importance in this regard. The known hypercoagulable state in SARS-CoV-2 infection is thought to be the main mechanism in COVID-19 related CVT. Other plausible mechanisms may include vascular endothelial dysfunction and altered flow dynamics. CONCLUSIONS Although there are no specific clinical characteristics, insidious or acute onset headache, seizures, stroke-like, or encephalopathy symptoms in a patient with, or who has suffered COVID-19, should prompt the attending physician to investigate for CVT. The treatment of COVID-19 associated CVT does not differ radically from the therapy of CVT without the infection, i.e. urgent initiation of parenteral unfractionated heparin or low molecular weight heparin followed by conventional or mostly newer oral anticoagulants.
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Affiliation(s)
- Ritwik Ghosh
- Department of General Medicine, Burdwan Medical College and Hospital, Burdwan, West Bengal, India
| | - Dipayan Roy
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Jodhpur, Rajasthan, India
| | - Arpan Mandal
- Department of General Medicine, Burdwan Medical College and Hospital, Burdwan, West Bengal, India
| | - Shyamal Kanti Pal
- Department of General Medicine, Burdwan Medical College and Hospital, Burdwan, West Bengal, India
| | - Bikash Chandra Swaika
- Department of General Medicine, Burdwan Medical College and Hospital, Burdwan, West Bengal, India
| | - Dinabandhu Naga
- Department of General Medicine, Burdwan Medical College and Hospital, Burdwan, West Bengal, India
| | - Alak Pandit
- Bangur Institute of Neurosciences, Kolkata, West Bengal, India
| | - Biman Kanti Ray
- Bangur Institute of Neurosciences, Kolkata, West Bengal, India
| | - Julián Benito-León
- Department of Neurology, University Hospital "12 de Octubre", Madrid, Spain; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Department of Medicine, Universidad Complutense, Madrid, Spain.
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13
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Oz M, Lorke DE, Kabbani N. A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor. Pharmacol Ther 2021; 221:107750. [PMID: 33275999 PMCID: PMC7854082 DOI: 10.1016/j.pharmthera.2020.107750] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 02/06/2023]
Abstract
The recent emergence of coronavirus disease-2019 (COVID-19) as a global pandemic has prompted scientists to address an urgent need for defining mechanisms of disease pathology and treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, employs angiotensin converting enzyme 2 (ACE2) as its primary target for cell surface attachment and likely entry into the host cell. Thus, understanding factors that may regulate the expression and function of ACE2 in the healthy and diseased body is critical for clinical intervention. Over 66% of all adults in the United States are currently using a prescription drug and while earlier findings have focused on possible upregulation of ACE2 expression through the use of renin angiotensin system (RAS) inhibitors, mounting evidence suggests that various other widely administered drugs used in the treatment of hypertension, heart failure, diabetes mellitus, hyperlipidemias, coagulation disorders, and pulmonary disease may also present a varied risk for COVID-19. Specifically, we summarize mechanisms on how heparin, statins, steroids and phytochemicals, besides their established therapeutic effects, may also interfere with SARS-CoV-2 viral entry into cells. We also describe evidence on the effect of several vitamins, phytochemicals, and naturally occurring compounds on ACE2 expression and activity in various tissues and disease models. This comprehensive review aims to provide a timely compendium on the potential impact of commonly prescribed drugs and pharmacologically active compounds on COVID-19 pathology and risk through regulation of ACE2 and RAS signaling.
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Key Words
- adam17, a disintegrin and metalloprotease 17
- ace, angiotensin i converting enzyme
- ace-inh., angiotensin i converting enzyme inhibitor
- ampk, amp-activated protein kinase
- ang-ii, angiotensin ii
- arb, angiotensin ii type 1-receptor blocker
- ards, acute respiratory distress syndrome
- at1-r, angiotensin ii type 1-receptor
- βarb, β-adrenergic receptor blockers
- bk, bradykinin
- ccb, calcium channel blockers
- ch25h, cholesterol-25-hydroxylase
- copd, chronic obstructive lung disease
- cox, cyclooxygenase
- covid-19, coronavirus disease-2019
- dabk, [des-arg9]-bradykinin
- erk, extracellular signal-regulated kinase
- 25hc, 25-hydroxycholesterol
- hs, heparan sulfate
- hspg, heparan sulfate proteoglycan
- ibd, inflammatory bowel disease
- map, mitogen-activated protein
- mers, middle east respiratory syndrome
- mrb, mineralocorticoid receptor blocker
- nos, nitric oxide synthase
- nsaid, non-steroid anti-inflammatory drug
- ras, renin-angiotensin system
- sars-cov, severe acute respiratory syndrome coronavirus
- sh, spontaneously hypertensive
- s protein, spike protein
- sirt1, sirtuin 1
- t2dm, type 2 diabetes mellitus
- tcm, traditional chinese medicine
- tmprss2, transmembrane protease, serine 2
- tnf, tumor necrosis factor
- ufh, unfractionated heparin
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Affiliation(s)
- Murat Oz
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait.
| | - Dietrich Ernst Lorke
- Department of Anatomy and Cellular Biology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates; Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Nadine Kabbani
- School of Systems Biology, George Mason University, Fairfax, VA 22030, USA
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14
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Tsai HJ, Shih CC, Chang KY, Liao MH, Liaw WJ, Wu CC, Tsao CM. Angiotensin-(1-7) treatment blocks lipopolysaccharide-induced organ damage, platelet dysfunction, and IL-6 and nitric oxide production in rats. Sci Rep 2021; 11:610. [PMID: 33436885 PMCID: PMC7804205 DOI: 10.1038/s41598-020-79902-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 12/14/2020] [Indexed: 12/29/2022] Open
Abstract
Sepsis can lead to shock, multiple organ failure, and even death. Platelets play an active role in the pathogenesis of sepsis-induced multiple organ failure. Angiotensin (Ang)-(1–7), a biologically active peptide, counteracts various effects of Ang II and attenuates inflammatory responses, reactive oxygen species production, and apoptosis. We evaluated the effects of Ang-(1–7) on organ injury and platelet dysfunction in rats with endotoxaemia. We treated male Wistar rats with saline or lipopolysaccharide (LPS, 10 mg, intravenously) then Ang-(1–7) (1 mg/kg, intravenous infusion for 3 h beginning 30 min after LPS administration). We analysed several haemodynamic, biochemical, and inflammatory parameters, as well as platelet counts and aggregation. Ang-(1–7) improved hypotension and organ dysfunction, and attenuated plasma interleukin-6, chemokines and nitric oxide production in rats after LPS administration. The LPS-induced reduction in platelet aggregation, but not the decreased platelet count, was restored after Ang-(1–7) treatment. The protein expression of iNOS and IκB, but not phosphorylated ERK1/2 and p38, was diminished in Ang-(1–7)-treated LPS rats. The histological changes in liver and lung were significantly attenuated in Ang-(1–7)-treated LPS rats. Our results suggest that Ang-(1–7) ameliorates endotoxaemic-induced organ injury and platelet dysfunction, likely through the inhibition of the inflammatory response and nitric oxide production.
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Affiliation(s)
- Hsin-Jung Tsai
- Department of Anesthesiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 112, Taiwan
| | - Chih-Chin Shih
- Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan
| | - Kuang-Yi Chang
- Department of Anesthesiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 112, Taiwan.,Department of Anesthesiology, National Yang-Ming University, Taipei, Taiwan
| | - Mei-Hui Liao
- Department of Nursing, Oriental Institute of Technology, New Taipei City, Taiwan
| | - Wen-Jinn Liaw
- Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.,Department of Anesthesiology, Chung Shan Medical University and Hospital, Taichung, Taiwan
| | - Chin-Chen Wu
- Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan
| | - Cheng-Ming Tsao
- Department of Anesthesiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 112, Taiwan. .,Department of Anesthesiology, National Yang-Ming University, Taipei, Taiwan. .,Department of Anesthesiology, National Defense Medical Center, Taipei, Taiwan.
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15
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ACE2 in the renin-angiotensin system. Clin Sci (Lond) 2020; 134:3063-3078. [PMID: 33264412 DOI: 10.1042/cs20200478] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/12/2020] [Accepted: 11/19/2020] [Indexed: 01/01/2023]
Abstract
In 2020 we are celebrating the 20th anniversary of the angiotensin-converting enzyme 2 (ACE2) discovery. This event was a landmark that shaped the way that we see the renin-angiotensin system (RAS) today. ACE2 is an important molecular hub that connects the RAS classical arm, formed mainly by the octapeptide angiotensin II (Ang II) and its receptor AT1, with the RAS alternative or protective arm, formed mainly by the heptapeptides Ang-(1-7) and alamandine, and their receptors, Mas and MrgD, respectively. In this work we reviewed classical and modern literature to describe how ACE2 is a critical component of the protective arm, particularly in the context of the cardiac function, coagulation homeostasis and immune system. We also review recent literature to present a critical view of the role of ACE2 and RAS in the SARS-CoV-2 pandemic.
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16
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Chueh TI, Zheng CM, Hou YC, Lu KC. Novel Evidence of Acute Kidney Injury in COVID-19. J Clin Med 2020; 9:E3547. [PMID: 33153216 PMCID: PMC7692179 DOI: 10.3390/jcm9113547] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/29/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023] Open
Abstract
The coronavirus 2019 (COVID-19) pandemic has caused a huge impact on health and economic issues. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes cellular damage by entry mediated by the angiotensin-converting enzyme 2 of the host cells and its conjugation with spike proteins of SARS-CoV-2. Beyond airway infection and acute respiratory distress syndrome, acute kidney injury is common in SARS-CoV-2-associated infection, and acute kidney injury (AKI) is predictive to multiorgan dysfunction in SARS-CoV-2 infection. Beyond the cytokine storm and hemodynamic instability, SARS-CoV-2 might directly induce kidney injury and cause histopathologic characteristics, including acute tubular necrosis, podocytopathy and microangiopathy. The expression of apparatus mediating SARS-CoV-2 entry, including angiotensin-converting enzyme 2, transmembrane protease serine 2 (TMPRSS2) and a disintegrin and metalloprotease 17 (ADAM17), within the renal tubular cells is highly associated with acute kidney injury mediated by SARS-CoV-2. Both entry from the luminal and basolateral sides of the renal tubular cells are the possible routes for COVID-19, and the microthrombi associated with severe sepsis and the dysregulated renin-angiotensin-aldosterone system worsen further renal injury in SARS-CoV-2-associated AKI. In the podocytes of the glomerulus, injured podocyte expressed CD147, which mediated the entry of SARS-CoV-2 and worsen further foot process effacement, which would worsen proteinuria, and the chronic hazard induced by SARS-CoV-2-mediated kidney injury is still unknown. Therefore, the aim of the review is to summarize current evidence on SARS-CoV-2-associated AKI and the possible pathogenesis directly by SARS-CoV-2.
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Affiliation(s)
- Ti-I Chueh
- Department of Medical Laboratory, Cardinal-Tien Hospital, New Taipei City 231, Taiwan;
- Department of Education, Cardinal Tien Junior College of Healthcare and Management, New Taipei City 231, Taiwan
| | - Cai-Mei Zheng
- Research Center of Urology and Kidney, Taipei Medical University, Taipei 110, Taiwan;
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University, Shuang Ho Hospital, Ministry of New Taipei City 235, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Yi-Chou Hou
- Division of Nephrology, Department of Medicine, Cardinal-Tien Hospital, New Taipei City 231, Taiwan;
- School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Kuo-Cheng Lu
- Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
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17
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Fang C, Schmaier AH. Novel anti-thrombotic mechanisms mediated by Mas receptor as result of balanced activities between the kallikrein/kinin and the renin-angiotensin systems. Pharmacol Res 2020; 160:105096. [PMID: 32712319 PMCID: PMC7378497 DOI: 10.1016/j.phrs.2020.105096] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 07/16/2020] [Accepted: 07/19/2020] [Indexed: 12/17/2022]
Abstract
The risk of thrombosis, a globally growing challenge and a major cause of death, is influenced by various factors in the intravascular coagulation, vessel wall, and cellular systems. Among the contributors to thrombosis, the contact activation system and the kallikrein/kinin system, two overlapping plasma proteolytic systems that are often considered as synonymous, regulate thrombosis from different aspects. On one hand, components of the contact activation system such as factor XII initiates activation of the coagulation proteins promoting thrombus formation on artificial surfaces through factor XI- and possibly prekallikrein-mediated intrinsic coagulation. On the other hand, physiological activation of plasma prekallikrein in the kallikrein/kinin system on endothelial cells liberates bradykinin from associated high-molecular-weight kininogen to stimulate the constitutive bradykinin B2 receptor to generate nitric oxide and prostacyclin to induce vasodilation and counterbalance angiotensin II signaling from the renin-angiotensin system which stimulates vasoconstriction. In addition to vascular tone regulation, this interaction between the kallikrein/kinin and renin-angiotensin systems has a thrombo-regulatory role independent of the contact pathway. At the level of the G-protein coupled receptors of these systems, defective bradykinin signaling due to attenuated bradykinin formation and/or decreased B2 receptor expression, as seen in murine prekallikrein and B2 receptor null mice, respectively, leads to compensatory overexpressed Mas, the receptor for angiotensin-(1-7) of the renin-angiotensin system. Mas stimulation and/or its increased expression contributes to maintaining a healthy vascular homeostasis by generating graded elevation of plasma prostacyclin which reduces thrombosis through two independent pathways: (1) increasing the vasoprotective transcription factor Sirtuin 1 to suppress tissue factor expression, and (2) inhibiting platelet activation. This review will summarize the recent advances in this field that support these understandings. Appreciating these subtle mechanisms help to develop novel anti-thrombotic strategies by targeting the vascular receptors in the renin-angiotensin and the kallikrein/kinin systems to maintain healthy vascular homeostasis.
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Affiliation(s)
- Chao Fang
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology and the Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, 430030, China.
| | - Alvin H. Schmaier
- Division of Hematology and Oncology, Department of Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, 44106, USA
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18
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Alsufyani HA, Alrefaie Z. Renin-Angiotensin System Implications to COVID-19 Comorbidities. J Microsc Ultrastruct 2020; 8:148-151. [PMID: 33623738 PMCID: PMC7883491 DOI: 10.4103/jmau.jmau_105_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 11/11/2020] [Indexed: 01/08/2023] Open
Abstract
The role of the renin-angiotensin system (RAS) and its pharmacological modulators in the susceptibility and outcomes of SARS CoV-2 pandemic (COVID-19) has been much discussed recently. Angiotensin-converting enzyme type 2 (ACE2) has attracted much attention and debate in relevance to COVID-19. It not only acts as the receptor to which the SARS CoV-2 virus binds to be introduced into cells but also balances the effects of angiotensin II offering anti-inflammatory and antifibrotic protective actions to different organs. This mini-review aims to shed some light on the possible involvement of ACE2 and RAS alternate pathways in the comorbidities and clinical findings observed in COVID-19 patients.
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Affiliation(s)
- Hadeel A. Alsufyani
- Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Zienab Alrefaie
- Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
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19
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Shahjouei S, Naderi S, Li J, Khan A, Chaudhary D, Farahmand G, Male S, Griessenauer C, Sabra M, Mondello S, Cernigliaro A, Khodadadi F, Dev A, Goyal N, Ranji-Burachaloo S, Olulana O, Avula V, Ebrahimzadeh SA, Alizada O, Hancı MM, Ghorbani A, Vaghefi Far A, Ranta A, Punter M, Ramezani M, Ostadrahimi N, Tsivgoulis G, Fragkou PC, Nowrouzi-Sohrabi P, Karofylakis E, Tsiodras S, Neshin Aghayari Sheikh S, Saberi A, Niemelä M, Rezai Jahromi B, Mowla A, Mashayekhi M, Bavarsad Shahripour R, Sajedi SA, Ghorbani M, Kia A, Rahimian N, Abedi V, Zand R. Risk of stroke in hospitalized SARS-CoV-2 infected patients: A multinational study. EBioMedicine 2020; 59:102939. [PMID: 32818804 PMCID: PMC7429203 DOI: 10.1016/j.ebiom.2020.102939] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/04/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND There is an increased attention to stroke following SARS-CoV-2. The goal of this study was to better depict the short-term risk of stroke and its associated factors among SARS-CoV-2 hospitalized patients. METHODS This multicentre, multinational observational study includes hospitalized SARS-CoV-2 patients from North and South America (United States, Canada, and Brazil), Europe (Greece, Italy, Finland, and Turkey), Asia (Lebanon, Iran, and India), and Oceania (New Zealand). The outcome was the risk of subsequent stroke. Centres were included by non-probability sampling. The counts and clinical characteristics including laboratory findings and imaging of the patients with and without a subsequent stroke were recorded according to a predefined protocol. Quality, risk of bias, and heterogeneity assessments were conducted according to ROBINS-E and Cochrane Q-test. The risk of subsequent stroke was estimated through meta-analyses with random effect models. Bivariate logistic regression was used to determine the parameters with predictive outcome value. The study was reported according to the STROBE, MOOSE, and EQUATOR guidelines. FINDINGS We received data from 26,175 hospitalized SARS-CoV-2 patients from 99 tertiary centres in 65 regions of 11 countries until May 1st, 2020. A total of 17,799 patients were included in meta-analyses. Among them, 156(0.9%) patients had a stroke-123(79%) ischaemic stroke, 27(17%) intracerebral/subarachnoid hemorrhage, and 6(4%) cerebral sinus thrombosis. Subsequent stroke risks calculated with meta-analyses, under low to moderate heterogeneity, were 0.5% among all centres in all countries, and 0.7% among countries with higher health expenditures. The need for mechanical ventilation (OR: 1.9, 95% CI:1.1-3.5, p = 0.03) and the presence of ischaemic heart disease (OR: 2.5, 95% CI:1.4-4.7, p = 0.006) were predictive of stroke. INTERPRETATION The results of this multi-national study on hospitalized patients with SARS-CoV-2 infection indicated an overall stroke risk of 0.5%(pooled risk: 0.9%). The need for mechanical ventilation and the history of ischaemic heart disease are the independent predictors of stroke among SARS-CoV-2 patients. FUNDING None.
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Affiliation(s)
- Shima Shahjouei
- Neurology Department, Neuroscience Institute, Geisinger Health System, Danville, PA, USA
| | - Soheil Naderi
- Neurology Department, Neuroscience Institute, Geisinger Health System, Danville, PA, USA; Neurosurgery Department, Tehran University of Medical Sciences, Tehran, Iran
| | - Jiang Li
- Department of Molecular and Functional Genomics, Geisinger Health System, Danville, PA, USA
| | - Ayesha Khan
- Neurology Department, Neuroscience Institute, Geisinger Health System, Danville, PA, USA
| | - Durgesh Chaudhary
- Neurology Department, Neuroscience Institute, Geisinger Health System, Danville, PA, USA
| | - Ghasem Farahmand
- Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Neurology Department, Tehran University of Medical Sciences, Tehran, Iran
| | - Shailesh Male
- Neurology Department, Vidant Medical Center, Greenville, NC, USA
| | - Christoph Griessenauer
- Neurology Department, Neuroscience Institute, Geisinger Health System, Danville, PA, USA
| | - Mirna Sabra
- Neurosciences Research Center (NRC), Lebanese University/ Medical School, Beirut, Lebanon
| | - Stefania Mondello
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | | | | | | | - Nitin Goyal
- Neurology Department, University of Tennessee Health Science Center, Tennessee, USA
| | - Sakineh Ranji-Burachaloo
- Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Neurology Department, Tehran University of Medical Sciences, Tehran, Iran
| | - Oluwaseyi Olulana
- Neurology Department, Neuroscience Institute, Geisinger Health System, Danville, PA, USA
| | - Venkatesh Avula
- Neurology Department, Neuroscience Institute, Geisinger Health System, Danville, PA, USA
| | | | - Orkhan Alizada
- Neurosurgery Department, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey
| | - Mehmet Murat Hancı
- Neurosurgery Department, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey
| | - Askar Ghorbani
- Neurology Department, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Annemarei Ranta
- Department of Neurology, Wellington Hospital, Wellington, New Zealand; Department of Medicine, University of Otago, Wellington, New Zealand
| | - Martin Punter
- Department of Neurology, Wellington Hospital, Wellington, New Zealand; Department of Medicine, University of Otago, Wellington, New Zealand
| | - Mahtab Ramezani
- Neurology Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nima Ostadrahimi
- Neurosurgery Department, Tehran University of Medical Sciences, Tehran, Iran
| | - Georgios Tsivgoulis
- Neurology Department, University of Tennessee Health Science Center, Tennessee, USA; Second Department of Neurology, National and Kapodistrian University of Athens, School of Medicine, "Attikon" University Hospital, Athens, Greece
| | - Paraskevi C Fragkou
- Fourth Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Emmanouil Karofylakis
- Fourth Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Sotirios Tsiodras
- Fourth Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Alia Saberi
- Neurology Department, Poursina Hospital, Guilan University of Medical Sciences, Guilan, Iran
| | - Mika Niemelä
- Department of Neurosurgery, Helsinki University Hospital, Helsinki, Finland
| | | | - Ashkan Mowla
- Division of Stroke and Endovascular Neurosurgery, Department of Neurological Surgery, Keck School of Medicine, University of Southern California, California, USA
| | - Mahsa Mashayekhi
- Internal medicine Department, Tabriz University of medical sciences, Tabriz, Iran
| | | | - Seyed Aidin Sajedi
- Neuroscience Research Center, Department of Neurology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mohammad Ghorbani
- Divisions of Vascular and Endovascular Neurosurgery and Neurology, Firoozgar Hospital and Rasoul-Akram hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Arash Kia
- Icahn school of medicine at Mount Sinai, Department of Population Health Science and Policy, Institute for Healthcare Delivery Science, New York, USA
| | | | - Vida Abedi
- Department of Molecular and Functional Genomics, Geisinger Health System, Danville, PA, USA; Biocomplexity Institute, Virginia Tech, Blacksburg, Virginia, USA
| | - Ramin Zand
- Neurology Department, Neuroscience Institute, Geisinger Health System, Danville, PA, USA; Neurology Department, University of Tennessee Health Science Center, Tennessee, USA.
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20
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Mahmudpour M, Roozbeh J, Keshavarz M, Farrokhi S, Nabipour I. COVID-19 cytokine storm: The anger of inflammation. Cytokine 2020; 133:155151. [PMID: 32544563 PMCID: PMC7260598 DOI: 10.1016/j.cyto.2020.155151] [Citation(s) in RCA: 319] [Impact Index Per Article: 63.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/20/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023]
Abstract
Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.
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Affiliation(s)
- Mehdi Mahmudpour
- The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Jamshid Roozbeh
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohsen Keshavarz
- The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Shokrollah Farrokhi
- Department of Immunology and Allergy, The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Iraj Nabipour
- The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran; Future Studies Group, The Academy of Medical Sciences of the I.R., Iran.
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21
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Shi W, Lv J, Lin L. Coagulopathy in COVID-19: Focus on vascular thrombotic events. J Mol Cell Cardiol 2020; 146:32-40. [PMID: 32681845 PMCID: PMC7362808 DOI: 10.1016/j.yjmcc.2020.07.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/28/2020] [Accepted: 07/11/2020] [Indexed: 02/06/2023]
Abstract
SARS-CoV-2 causes a phenotype of pneumonia with diverse manifestation, which is termed as coronavirus disease 2019 (COVID-19). An impressive high transmission rate allows COVID-19 conferring enormous challenge for clinicians worldwide, and developing to a pandemic level. Combined with a series of complications, a part of COVID-19 patients progress into severe cases, which critically contributes to the risk of fatality. To date, coagulopathy has been found as a prominent feature of COVID-19 and severe coagulation dysfunction may be associated with poor prognosis. Coagulopathy in COVID-19 may predispose patients to hypercoagulability-related disorders including thrombosis and even fatal vascular events. Inflammatory storm, uncontrolled inflammation-mediated endothelial injury and renin angiotensin system (RAS) dysregulation are the potential mechanisms. Ongoing efforts made to develop promising therapies provide several potential strategies for hypercoagulability in COVID-19. In this review, we introduce the clinical features of coagulation and the increased vascular thrombotic risk conferred by coagulopathy according to present reports about COVID-19. The potential underlying mechanisms and emerging therapeutic avenues are discussed, emphasizing an urgent need for effective interventions.
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Affiliation(s)
- Wei Shi
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
| | - Jiagao Lv
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
| | - Li Lin
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
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Ahmed S, Zimba O, Gasparyan AY. Thrombosis in Coronavirus disease 2019 (COVID-19) through the prism of Virchow's triad. Clin Rheumatol 2020; 39:2529-2543. [PMID: 32654082 PMCID: PMC7353835 DOI: 10.1007/s10067-020-05275-1] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 06/26/2020] [Accepted: 06/30/2020] [Indexed: 02/07/2023]
Abstract
The pathogenesis of Coronavirus disease 2019 (COVID-19) is gradually being comprehended. A high number of thrombotic episodes are reported, along with the mortality benefits of heparin. COVID-19 can be viewed as a prothrombotic disease. We overviewed the available evidence to explore this possibility. We identified various histopathology reports and clinical case series reporting thromboses in COVID-19. Also, multiple coagulation markers support this. COVID-19 can be regarded as a risk factor for thrombosis. Applying the principles of Virchow's triad, we described abnormalities in the vascular endothelium, altered blood flow, and platelet function abnormalities that lead to venous and arterial thromboses in COVID-19. Endothelial dysfunction, activation of the renin-angiotensin-aldosterone system (RAAS) with the release of procoagulant plasminogen activator inhibitor (PAI-1), and hyperimmune response with activated platelets seem to be significant contributors to thrombogenesis in COVID-19. Stratifying risk of COVID-19 thromboses should be based on age, presence of comorbidities, D-dimer, CT scoring, and various blood cell ratios. Isolated heparin therapy may not be sufficient to combat thrombosis in this disease. There is an urgent need to explore newer avenues like activated protein C, PAI-1 antagonists, and tissue plasminogen activators (tPA). These should be augmented with therapies targeting RAAS, antiplatelet drugs, repurposed antiinflammatory, and antirheumatic drugs. Key Points • Venous and arterial thromboses in COVID-19 can be viewed through the prism of Virchow's triad. • Endothelial dysfunction, platelet activation, hyperviscosity, and blood flow abnormalities due to hypoxia, immune reactions, and hypercoagulability lead to thrombogenesis in COVID-19. • There is an urgent need to stratify COVID-19 patients at risk for thrombosis using age, comorbidities, D-dimer, and CT scoring. • Patients with COVID-19 at high risk for thrombosis should be put on high dose heparin therapy.
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Affiliation(s)
- Sakir Ahmed
- Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences (KIMS), KIIT University, Bhubaneswar, India
| | - Olena Zimba
- Department of Internal Medicine No. 2, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
| | - Armen Yuri Gasparyan
- Departments of Rheumatology and Research and Development, Dudley Group NHS Foundation Trust (Teaching Trust of the University of Birmingham, UK) Russells Hall Hospital, Pensnett Road, Dudley, West Midlands DY1 2HQ UK
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23
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Domingo P, Mur I, Pomar V, Corominas H, Casademont J, de Benito N. The four horsemen of a viral Apocalypse: The pathogenesis of SARS-CoV-2 infection (COVID-19). EBioMedicine 2020; 58:102887. [PMID: 32736307 PMCID: PMC7387269 DOI: 10.1016/j.ebiom.2020.102887] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/23/2020] [Accepted: 06/25/2020] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of coronavirus disease 2019 (COVID-19) may be envisaged as the dynamic interaction between four vicious feedback loops chained or happening at once. These are the viral loop, the hyperinflammatory loop, the non-canonical renin-angiotensin system (RAS) axis loop, and the hypercoagulation loop. Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 lights the wick by infecting alveolar epithelial cells (AECs) and downregulating the angiotensin converting enzyme-2 (ACE2)/angiotensin (Ang-1-7)/Mas1R axis. The viral feedback loop includes evading the host's innate response, uncontrolled viral replication, and turning on a hyperactive adaptative immune response. The inflammatory loop is composed of the exuberant inflammatory response feeding back until exploding in an actual cytokine storm. Downregulation of the ACE2/Ang-(1-7)/Mas1R axis leaves the lung without a critical defense mechanism and turns the scale to the inflammatory side of the RAS. The coagulation loop is a hypercoagulable state caused by the interplay between inflammation and coagulation in an endless feedback loop. The result is a hyperinflammatory and hypercoagulable state producing acute immune-mediated lung injury and eventually, adult respiratory distress syndrome.
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Affiliation(s)
- Pere Domingo
- Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Institut de Recerca del Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni Mª Claret, 167, 08025 Barcelona, Spain.
| | - Isabel Mur
- Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Institut de Recerca del Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni Mª Claret, 167, 08025 Barcelona, Spain
| | - Virginia Pomar
- Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Institut de Recerca del Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni Mª Claret, 167, 08025 Barcelona, Spain
| | - Héctor Corominas
- Departments of Rheumatology, Hospital de la Santa Creu i Sant Pau, Institut de Recerca del Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Jordi Casademont
- Internal Medicine, Hospital de la Santa Creu i Sant Pau, Institut de Recerca del Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Natividad de Benito
- Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Institut de Recerca del Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni Mª Claret, 167, 08025 Barcelona, Spain
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24
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Nuche J, Segura de la Cal T, Jiménez López Guarch C, López-Medrano F, Delgado CPO, Ynsaurriaga FA, Delgado JF, Ibáñez B, Oliver E, Subías PE. Effect of Coronavirus Disease 2019 in Pulmonary Circulation. The Particular Scenario of Precapillary Pulmonary Hypertension. Diagnostics (Basel) 2020; 10:E548. [PMID: 32752129 PMCID: PMC7459745 DOI: 10.3390/diagnostics10080548] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 07/30/2020] [Accepted: 07/30/2020] [Indexed: 02/06/2023] Open
Abstract
The Coronavirus Disease of 2019 (COVID-19) has supposed a global health emergency affecting millions of people, with particular severity in the elderly and patients with previous comorbidities, especially those with cardiovascular disease. Patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) could represent an especially vulnerable population because of the high mortality rates reported for respiratory infections. However, the number of COVID-19 cases reported among PAH and CTEPH patients is surprisingly low. Furthermore, the clinical picture that has been described in these patients is far from the severity that experts would expect. Endothelial dysfunction is a common feature between patients with PAH/CTEPH and COVID-19, leading to ventilation/perfusion mismatch, vasoconstriction, thrombosis and inflammation. In this picture, the angiotensin-converting enzyme 2 plays an essential role, being directly involved in the pathophysiology of both clinical entities. Some of these common characteristics could explain the good adaptation of PAH and CTEPH patients to COVID-19, who could also have obtained a benefit from the disease's specific treatments (anticoagulant and pulmonary vasodilators), probably due to its protective effect on the endothelium. Additionally, these common features could also lead to PAH/CTEPH as a potential sequelae of COVID-19. Throughout this comprehensive review, we describe the similarities and differences between both conditions and the possible pathophysiological and therapeutic-based mechanisms leading to the low incidence and severity of COVID-19 reported in PAH/CTEPH patients to date. Nevertheless, international registries should look carefully into this population for better understanding and management.
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Affiliation(s)
- Jorge Nuche
- Centro de Investigaciones Biomédicas En Red de enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.N.); (C.J.L.G.); (F.A.Y.); (J.F.D.); (B.I.)
- Servicio de Cardiología, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), 28041 Madrid, Spain; (T.S.d.l.C.); (C.P.-O.D.)
- Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain
- Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain;
| | - Teresa Segura de la Cal
- Servicio de Cardiología, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), 28041 Madrid, Spain; (T.S.d.l.C.); (C.P.-O.D.)
| | - Carmen Jiménez López Guarch
- Centro de Investigaciones Biomédicas En Red de enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.N.); (C.J.L.G.); (F.A.Y.); (J.F.D.); (B.I.)
- Servicio de Cardiología, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), 28041 Madrid, Spain; (T.S.d.l.C.); (C.P.-O.D.)
- Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain;
| | - Francisco López-Medrano
- Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain;
- Department of Infectious Diseases, Hospital Universitario 12 de Octubre, Instituto de Investigacioón Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Carmen Pérez-Olivares Delgado
- Servicio de Cardiología, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), 28041 Madrid, Spain; (T.S.d.l.C.); (C.P.-O.D.)
| | - Fernando Arribas Ynsaurriaga
- Centro de Investigaciones Biomédicas En Red de enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.N.); (C.J.L.G.); (F.A.Y.); (J.F.D.); (B.I.)
- Servicio de Cardiología, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), 28041 Madrid, Spain; (T.S.d.l.C.); (C.P.-O.D.)
- Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain;
| | - Juan F. Delgado
- Centro de Investigaciones Biomédicas En Red de enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.N.); (C.J.L.G.); (F.A.Y.); (J.F.D.); (B.I.)
- Servicio de Cardiología, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), 28041 Madrid, Spain; (T.S.d.l.C.); (C.P.-O.D.)
- Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain;
| | - Borja Ibáñez
- Centro de Investigaciones Biomédicas En Red de enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.N.); (C.J.L.G.); (F.A.Y.); (J.F.D.); (B.I.)
- Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain
- IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain
| | - Eduardo Oliver
- Centro de Investigaciones Biomédicas En Red de enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.N.); (C.J.L.G.); (F.A.Y.); (J.F.D.); (B.I.)
- Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain
| | - Pilar Escribano Subías
- Centro de Investigaciones Biomédicas En Red de enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.N.); (C.J.L.G.); (F.A.Y.); (J.F.D.); (B.I.)
- Servicio de Cardiología, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), 28041 Madrid, Spain; (T.S.d.l.C.); (C.P.-O.D.)
- Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain;
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Ahmed S, Anirvan P. Reply to Rheumatologists' perspective on coronavirus disease 19: is heparin the dark horse for COVID-19? Clin Rheumatol 2020; 39:2099-2100. [PMID: 32388748 PMCID: PMC7211055 DOI: 10.1007/s10067-020-05145-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 04/18/2020] [Accepted: 05/01/2020] [Indexed: 11/27/2022]
Affiliation(s)
- Sakir Ahmed
- Department of Clinical Immunology & Rheumatology, Kalinga Institute of Medical Sciences (KIMS), KIIT University, Bhubaneswar, 751024, India.
| | - Prajna Anirvan
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College and Hospital, Cuttack, 753007, India
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26
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Associations of ACE I/D polymorphism with the levels of ACE, kallikrein, angiotensin II and interleukin-6 in STEMI patients. Sci Rep 2019; 9:19719. [PMID: 31873176 PMCID: PMC6927979 DOI: 10.1038/s41598-019-56263-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 12/09/2019] [Indexed: 12/11/2022] Open
Abstract
This study aimed to compare the plasma levels of angiotensin-I converting enzyme (ACE), Angiotensin II (AngII), kallikrein (KLK1) and interleukin-6 (IL-6) in ST segment elevation myocardial infarction (STEMI) patients with different ACE Insertion/deletion (I/D) polymorphisms in a Chinese population. The ACE genotypes were determined in the 199 STEMI patients and 216 control subjects. STEMI patients were divided into three groups based on the ACE genotypes. Single polymerase chain reaction (PCR) was performed to characterize ACE I/D polymorphisms. Plasma levels of ACE, AngII, KLK1 and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). We found that the DD or ID genotype was significantly independently associated with high ACE (OR = 4.697; 95% CI = 1.927–11.339), KLK1 (3.339; 1.383–8.063) and IL-6 levels (OR = 2.10; 1.025–4.327) in STEMI patients. However, there was no statistical significance between the ACE I/D polymorphism and AngII plasma levels whether in univariate or multivariate logistic regression. Additionally, we detected a significantly positive correlation between plasma KLK1 levels and IL-6 levels in STEMI patients (r = 0.584, P < 0.001). The study showed high levels of ACE, KLK1 and IL-6 were detected when the D allele was present, but AngII plasma levels was not influenced by the ACE I/D polymorphism.
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27
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Xu X, Shi L, Ma X, Su H, Ma G, Wu X, Ying K, Zhang R. RhoA-Rho associated kinase signaling leads to renin-angiotensin system imbalance and angiotensin converting enzyme 2 has a protective role in acute pulmonary embolism. Thromb Res 2019; 176:85-94. [PMID: 30784777 DOI: 10.1016/j.thromres.2019.02.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 01/31/2019] [Accepted: 02/13/2019] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Acute pulmonary embolism (APE) is a cardiovascular disease with high morbidity and mortality. Although the anatomical obstruction of the pulmonary vascular bed initiates APE, recent studies have suggested that vasoconstrictors in the renin-angiotensin system (RAS) play a role in the severity of APE. MATERIALS AND METHODS We performed a 5-year retrospective clinical study to analyze the key RAS components in APE patients, including angiotensin converting enzyme (ACE), ACE2, angiotensin II (Ang II) and angiotensin 1-7(Ang(1-7)). The role of RhoA-Rho associated kinase (ROCK) signaling in regulating RAS vasoconstrictors was detected in rat pulmonary artery endothelial cells and in an APE rat model. RESULTS In clinical study, we found that the levels of RAS vasoconstrictors were correlated with the clinical classification of APE patients, ACE and Ang II were unregulated, whereas ACE2 and Ang(1-7) were downregulated in the high-risk group compared to the healthy volunteers. In animal study, we found that activated RhoA-ROCK signaling was responsible for the imbalance in RAS vasoconstrictors both in vitro and in vivo, and further evidence indicated that ROCK inhibitors (Y27632 or HA1077) and an ACE2 activator (Resorcinol naphthalein) restored the dysregulated RAS vasoconstrictors significantly and had a protective role in an APE rat model. CONCLUSIONS Our study revealed that RhoA-ROCK signaling leads to RAS imbalance in APE patients, and ACE2 activation might be a novel therapeutic target in APE treatment.
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Affiliation(s)
- Xiaoling Xu
- Department of Pulmonary and Critical Care Medicine, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Liuhong Shi
- Department of Ultrasound, the Second Affiliated Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Xiuqing Ma
- Department of Pulmonary and Critical Care Medicine, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Hua Su
- Department of Pulmonary and Critical Care Medicine, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Guofeng Ma
- Department of Pulmonary and Critical Care Medicine, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Xiaohong Wu
- Department of Pulmonary and Critical Care Medicine, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Kejing Ying
- Department of Pulmonary and Critical Care Medicine, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Ruifeng Zhang
- Department of Pulmonary and Critical Care Medicine, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
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Forrester SJ, Booz GW, Sigmund CD, Coffman TM, Kawai T, Rizzo V, Scalia R, Eguchi S. Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiol Rev 2018; 98:1627-1738. [PMID: 29873596 DOI: 10.1152/physrev.00038.2017] [Citation(s) in RCA: 714] [Impact Index Per Article: 102.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (AT1R) is believed to mediate most functions of ANG II in the system. AT1R utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between AT1R signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. AT1R remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.
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Affiliation(s)
- Steven J Forrester
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - George W Booz
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Curt D Sigmund
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Thomas M Coffman
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Tatsuo Kawai
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Victor Rizzo
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Rosario Scalia
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Satoru Eguchi
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
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Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, Campagnole-Santos MJ. The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7). Physiol Rev 2018; 98:505-553. [PMID: 29351514 PMCID: PMC7203574 DOI: 10.1152/physrev.00023.2016] [Citation(s) in RCA: 762] [Impact Index Per Article: 108.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 05/09/2017] [Accepted: 06/18/2017] [Indexed: 12/16/2022] Open
Abstract
The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1-7)/MAS, whose end point is the metabolite ANG-(1-7). ACE2 and other enzymes can form ANG-(1-7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1-7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1-7) in physiology and disease, with particular emphasis on the brain.
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Affiliation(s)
- Robson Augusto Souza Santos
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
| | - Walkyria Oliveira Sampaio
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
| | - Andreia C Alzamora
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
| | - Daisy Motta-Santos
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
| | - Natalia Alenina
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
| | - Michael Bader
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
| | - Maria Jose Campagnole-Santos
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
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Yu X, Cui L, Hou F, Liu X, Wang Y, Wen Y, Chi C, Li C, Liu R, Yin C. Angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis prevents pancreatic acinar cell inflammatory response via inhibition of the p38 mitogen-activated protein kinase/nuclear factor-κB pathway. Int J Mol Med 2017; 41:409-420. [PMID: 29138810 DOI: 10.3892/ijmm.2017.3252] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 11/07/2017] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the role of the angiotensin-converting enzyme (ACE)2-angiotensin‑(Ang)-(1-7)-Mas axis in the pathogenesis of pancreatitis and the association between this axis and the p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor (NF-κB) signaling pathway in pancreatic acinar cells. Mouse pancreatic acinar cancer (MPC-83) cells were stimulated with 10 nM caerulein (CAE) to create an in vitro model of acute pancreatitis, and collected for analysis at 2, 6, 12, 24 and 48 h post stimulation. In addition, cells were pretreated with different concentrations of Ang‑(1‑7), Ang‑(1‑7) antagonist A779, p38 MAPK inhibitor SB203580 or ACE2 inhibitor DX600 for 30 min, and then stimulated with CAE for 24 h. The ACE2, Mas receptor, p38 MAPK, phosphorylated (p)-p38 MAPK and NF-κB expression levels were evaluated using western blotting and immunofluorescence. p38 MAPK, NF-κB, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8 and IL-10 mRNA expression levels were assessed using reverse transcription-quantitative polymerase chain reaction. The results of the immunofluorescence assay demonstrated that ACE2 and p38 MAPK were present mainly in the cytoplasm, while the Mas receptor was located mainly in the cell membrane. ACE2, p38 MAPK and p-p38 MAPK protein levels were significantly increased (P<0.05) following stimulation with CAE compared with those in the control group and peaked at 24 h. Mas receptor protein levels were significantly upregulated (P<0.05) between 6 and 24 h, peaking at 12 h. Ang‑(1‑7) and SB203580 downregulated p-p38 MAPK and NF-κB expression and the mRNA levels of inflammatory factors IL-6, TNF-α and IL-8, but upregulated the mRNA level of inflammatory factor IL-10 compared with those treated with CAE alone. These results were supported by the opposite outcomes observed for cells treated with A779 or DX600. Therefore, it was concluded that the ACE2-Ang‑(1‑7)-Mas axis significantly inhibits pancreatitis by inhibition of the p38 MAPK/NF-κB signaling pathway.
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Affiliation(s)
- Xiaozheng Yu
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
| | - Lijian Cui
- Department of Emergency, Beijing Chaoyang Hospital (Jingxi Campus), Capital Medical University, Beijing 100043, P.R. China
| | - Fei Hou
- Department of Infectious Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Xiaoya Liu
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
| | - Yan Wang
- Department of Infectious Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Yan Wen
- Department of Infectious Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Cheng Chi
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
| | - Chunyun Li
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
| | - Ruixia Liu
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
| | - Chenghong Yin
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
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Ning ZW, Luo XY, Wang GZ, Li Y, Pan MX, Yang RQ, Ling XG, Huang S, Ma XX, Jin SY, Wang D, Li X. MicroRNA-21 Mediates Angiotensin II-Induced Liver Fibrosis by Activating NLRP3 Inflammasome/IL-1β Axis via Targeting Smad7 and Spry1. Antioxid Redox Signal 2017; 27:1-20. [PMID: 27502441 PMCID: PMC5488354 DOI: 10.1089/ars.2016.6669] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
AIMS Angiotensin II (AngII), a vasoconstrictive peptide of the renin-angiotensin system (RAS), promotes hepatic fibrogenesis and induces microRNA-21(mir-21) expression. Angiotensin-(1-7) [Ang-(1-7)] is a peptide of the RAS, which attenuates liver fibrosis. Recently, it was reported that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome participated in liver fibrosis. However, it remains unclear how mir-21 mediates AngII-induced NLRP3 inflammasome activation. We investigate the role of AngII-induced mir-21 in the regulation of NLRP3 inflammasome/IL-1β axis in liver fibrosis. RESULTS In vivo, circulating mir-21 was upregulated in patients with liver fibrosis and was positively correlated with liver fibrosis and oxidation. Treatment with Ang-(1-7) inhibited mir-21, NLRP3 inflammasome, and liver fibrosis after bile duct ligation (BDL) or AngII infusion. Inhibition of mir-21 suppressed the Smad7/Smad2/3/NOX4, Spry1/ERK/NF-κB pathway, NLRP3 inflammasome, and liver fibrosis induced by AngII infusion. In vitro, AngII upregulated mir-21 expression via targeting Smad7 and Spry1 in primary hepatic stellate cells (HSCs). In contrast, Ang-(1-7) suppressed mir-21 expression and oxidation induced by AngII. Overexpression of mir-21 promoted oxidation, and collagen production enhanced the effect of AngII on NLRP3 inflammasome activation via the Spry1/ERK/NF-κB, Smad7/Smad2/3/NOX4 pathways. However, downregulation of mir-21 exerted the opposite effects. Innovation and Conclusions: Mir-21 mediates AngII-activated NLRP3 inflammasome and resultant HSC activation via targeting Spry1 and Smad7. Ang-(1-7) protected against BDL or AngII infusion-induced hepatic fibrosis and inhibited mir-21 expression. Antioxid. Redox Signal. 27, 1-20.
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Affiliation(s)
- Zuo-Wei Ning
- 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Xiao-Ying Luo
- 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Guo-Zhen Wang
- 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Yang Li
- 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Miao-Xia Pan
- 2 Department of Respiratory Diseases, Southern Medical University , Guangzhou, China
| | - Ren-Qiang Yang
- 3 Department of Emergency Medicine, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Xu-Guang Ling
- 3 Department of Emergency Medicine, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Shan Huang
- 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Xiao-Xin Ma
- 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Si-Yi Jin
- 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Dan Wang
- 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Xu Li
- 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China .,4 State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University , Guangzhou, China
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Fernández-Atucha A, Izagirre A, Fraile-Bermúdez AB, Kortajarena M, Larrinaga G, Martinez-Lage P, Echevarría E, Gil J. Sex differences in the aging pattern of renin-angiotensin system serum peptidases. Biol Sex Differ 2017; 8:5. [PMID: 28174624 PMCID: PMC5291971 DOI: 10.1186/s13293-017-0128-8] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 01/31/2017] [Indexed: 01/01/2023] Open
Abstract
Background Serum peptidases, such as angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (ACE2), neutral endopeptidase (NEP), aminopeptidase N (APN), and aminopeptidase A (APA), are important elements of the renin–angiotensin system (RAS). Dysregulation of these enzymes has been associated with hypertension and cardiovascular risk. In the present study, serum activities of RAS peptidases were analyzed to evaluate the existence of sexual differences, with a possible different pattern in pre- and post-andropausal/post-menopausal participants. Methods One hundred and eighteen healthy men and women between 41 and 70 years of age (58 women and 60 men) were recruited to participate in the study. Serum RAS-regulating enzymes were measured by spectrofluorimetry. Enzymatic activity was recorded as units of enzyme per milliliter of serum (U/mL). Results Significantly lower serum APA activity was observed in men with respect to women; no sex differences were detected for ACE, ACE2, NEP, or APN. Significantly lower APA and ACE serum activity were observed in older men compared to older women. In contrast, younger (<55 years) men had significantly higher values of NEP serum activity than younger women. Significantly lower ACE serum activity was detected in older men compared to younger men. In women, significantly higher ACE2 serum activity was observed in older women compared to younger women. Conclusions These results suggest a differential effect of aging on the activity of RAS enzymes in men and women, especially with respect to the breakpoint of andropausia/menopausia, on the critical serum enzymatic activities of the RAS, which could correlate with sexual differences in cardiovascular risk.
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Affiliation(s)
- A Fernández-Atucha
- Department of Nursing I, School of Nursing, University of the Basque Country (UPV/EHU), P.O. Box 699, E-48080 Bilbao, Bizkaia Spain
| | - A Izagirre
- Department of Neurology, CITA-Alzheimer Foundation, San Sebastian, Spain
| | - A B Fraile-Bermúdez
- Department of Nursing I, School of Nursing, University of the Basque Country (UPV/EHU), P.O. Box 699, E-48080 Bilbao, Bizkaia Spain
| | - M Kortajarena
- Department of Nursing I, School of Nursing, University of the Basque Country (UPV/EHU), P.O. Box 699, E-48080 Bilbao, Bizkaia Spain
| | - G Larrinaga
- Department of Nursing I, School of Nursing, University of the Basque Country (UPV/EHU), P.O. Box 699, E-48080 Bilbao, Bizkaia Spain
| | - P Martinez-Lage
- Department of Neurology, CITA-Alzheimer Foundation, San Sebastian, Spain
| | - E Echevarría
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.,Department of Physiology, Faculty of Medicine, University of the Basque Country (UPV/EHU), P.O. Box 699, E-48080 Bilbao, Bizkaia Spain
| | - J Gil
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.,Department of Physiology, Faculty of Medicine, University of the Basque Country (UPV/EHU), P.O. Box 699, E-48080 Bilbao, Bizkaia Spain
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Hoffmann BR, Stodola TJ, Wagner JR, Didier DN, Exner EC, Lombard JH, Greene AS. Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium. Arterioscler Thromb Vasc Biol 2017; 37:433-445. [PMID: 28082260 DOI: 10.1161/atvbaha.116.307787] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 01/02/2017] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Angiotensin II (AngII) has been shown to regulate angiogenesis and at high pathophysiological doses to cause vasoconstriction through the AngII receptor type 1. Angiotensin 1 to 7 (Ang-(1-7)) acting through the Mas1 receptor can act antagonistically to high pathophysiological levels of AngII by inducing vasodilation, whereas the effects of Ang-(1-7) signaling on angiogenesis are less defined. To complicate the matter, there is growing evidence that a subpressor dose of AngII produces phenotypes similar to Ang-(1-7). APPROACH AND RESULTS This study shows that low-dose Ang-(1-7), acting through the Mas1 receptor, promotes angiogenesis and vasodilation similar to a low, subpressor dose of AngII acting through AngII receptor type 1. In addition, we show through in vitro tube formation that Ang-(1-7) augments the angiogenic response in rat microvascular endothelial cells. Using proteomic and genomic analyses, downstream components of Mas1 receptor signaling were identified, including Rho family of GTPases, phosphatidylinositol 3-kinase, protein kinase D1, mitogen-activated protein kinase, and extracellular signal-related kinase signaling. Further experimental antagonism of extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinase signaling inhibited endothelial tube formation and vasodilation when stimulated with equimolar, low doses of either AngII or Ang-(1-7). CONCLUSIONS These results significantly expand the known Ang-(1-7)/Mas1 receptor signaling pathway and demonstrate an important distinction between the pathological effects of elevated and suppressed AngII compared with the beneficial effects of AngII normalization and Ang-(1-7) administration. The observed convergence of Ang-(1-7)/Mas1 and AngII/AngII receptor type 1 signaling at low ligand concentrations suggests a nuanced regulation in vasculature. These data also reinforce the importance of mitogen-activated protein kinase/extracellular signal-related kinase signaling in maintaining vascular function.
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Affiliation(s)
- Brian R Hoffmann
- From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee
| | - Timothy J Stodola
- From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee
| | - Jordan R Wagner
- From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee
| | - Daniela N Didier
- From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee
| | - Eric C Exner
- From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee
| | - Julian H Lombard
- From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee
| | - Andrew S Greene
- From the Department of Medicine, Division of Cardiology (B.R.H.), the Department of Biomedical Engineering (B.R.H., A.S.G.), and the Department of Physiology (T.J.S., J.R.W., J.H.L., D.N.D., E.C.E., A.S.G.), Cardiovascular Center (B.R.H.), Medical College of Wisconsin, Milwaukee.
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Fedson DS. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:421. [PMID: 27942512 DOI: 10.21037/atm.2016.11.03] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
There is an ongoing threat of epidemic or pandemic diseases that could be caused by influenza, Ebola or other emerging viruses. It will be difficult and costly to develop new drugs that target each of these viruses. Statins and angiotensin receptor blockers (ARBs) have been effective in treating patients with sepsis, pneumonia and influenza, and a statin/ARB combination appeared to dramatically reduce mortality during the recent Ebola outbreak. These drugs target (among other things) the endothelial dysfunction found in all of these diseases. Most scientists work on new drugs that target viruses, and few accept the idea of treating the host response with generic drugs. A great deal of research will be needed to show conclusively that these drugs work, and this will require the support of public agencies and foundations. Investigators in developing countries should take an active role in this research. If the next Public Health Emergency of International Concern is caused by an emerging virus, a "top down" approach to developing specific new drug treatments is unlikely to be effective. However, a "bottom up" approach to treatment that targets the host response to these viruses by using widely available and inexpensive generic drugs could reduce mortality in any country with a basic health care system. In doing so, it would make an immeasurable contribution to global equity and global security.
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Affiliation(s)
- David S Fedson
- Formerly, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA
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Captopril improves postresuscitation hemodynamics protective against pulmonary embolism by activating the ACE2/Ang-(1-7)/Mas axis. Naunyn Schmiedebergs Arch Pharmacol 2016; 389:1159-1169. [PMID: 27449068 DOI: 10.1007/s00210-016-1278-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 07/14/2016] [Indexed: 01/07/2023]
Abstract
Acute pulmonary embolism (APE) has a very high mortality rate, especially at cardiac arrest and even after the return of spontaneous circulation (ROSC). This study investigated the protective effect of the angiotensin-converting enzyme (ACE) inhibitor captopril on postresuscitation hemodynamics, in a porcine model of cardiac arrest established by APE. Twenty-nine Beijing Landrace pigs were infused with an autologous thrombus leading to cardiac arrest and subjected to standard cardiopulmonary resuscitation and thrombolysis. Ten resuscitated pigs were randomly and equally apportioned to receive either captopril (22.22 mg/kg) infusion or the same volume saline, 30 min after ROSC. Hemodynamic changes and ACE-Ang II-angiotensin II type 1 receptor (AT1R) and ACE2/Ang-(1-7)/Mas receptor axis levels were determined. APE was associated with a decline in mean arterial pressure and a dramatic increase in pulmonary artery pressure and mean right ventricular pressure. After ROSC, captopril infusion was associated with significantly lower mean right ventricular pressure and systemic and pulmonary vascular resistance, faster heart rate, and higher Ang-(1-7) levels, ACE2/ACE, and Ang-(1-7)/Ang II, compared with the saline infusion. The ACE2/Ang-(1-7)/Mas pathway correlated negatively with external vascular lung water and pulmonary vascular permeability and positively with the right cardiac index. In conclusion, in a pig model of APE leading to cardiac arrest, captopril infusion was associated with less mean right ventricular pressure overload after resuscitation, compared with saline infusion. The reduction in systemic and pulmonary vascular resistance associated with captopril may be by inhibiting the ACE-Ang II-AT1R axis and activating the ACE2/Ang-(1-7)/Mas axis.
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Li W, Li J, Hao P, Chen W, Meng X, Li H, Zhang Y, Zhang C, Yang J. Imbalance between angiotensin II and angiotensin-(1-7) in human coronary atherosclerosis. J Renin Angiotensin Aldosterone Syst 2016; 17:17/3/1470320316659618. [PMID: 27432541 PMCID: PMC5843867 DOI: 10.1177/1470320316659618] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 05/24/2016] [Indexed: 11/24/2022] Open
Abstract
Objective: Our previous studies found that angiotensin-(1–7) (Ang-(1–7)) is an endogenous counter-factor of angiotensin II (Ang-II). However, the balance between Ang-II and Ang-(1–7) in the development of human coronary atherosclerosis is not determined. Methods and results: The plasma levels of Ang-II and Ang-(1–7) were detected by enzyme-linked immunosorbent assay (ELISA) in 112 patients with known or suspected coronary artery disease (CAD) undergoing coronary angiography. Patients were divided into three groups based on the coronary angiography as follows: (1) normal (n = 13); (2) noncritical CAD (<50% stenosis, n = 17); and (3) critical CAD (⩾50% stenosis, n = 82). The plasma levels of Ang-II, Ang-(1–7) and the ratio of Ang-II and Ang-(1–7) (Ang-II/Ang-(1–7) were comparable between the normal and noncritical CAD groups. However, Ang-II, Ang-(1–7), and especially Ang-II/Ang-(1–7), were elevated in patients with critical CAD, compared with patients with normal or noncritical CAD. The level of Ang-II/Ang-(1–7) was positively associated with serious coronary stenosis, and correlated with tumor necrosis factor-alpha (TNF-α) level. Conclusion: Both Ang-II and Ang-(1–7) expression are significantly increased in patients with critical CAD. However, increased Ang-II/Ang-(1–7) ratios may lead to Ang-II over-activation and aggravate atherosclerosis progression.
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Affiliation(s)
- Wenjing Li
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, P.R. China Fine Arts School of Shandong University, P.R. China
| | - Jifu Li
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, P.R. China
| | - Panpan Hao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, P.R. China
| | - Wenqiang Chen
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, P.R. China
| | - Xiao Meng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, P.R. China
| | - Hongxuan Li
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, P.R. China
| | - Yun Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, P.R. China
| | - Cheng Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, P.R. China
| | - Jianmin Yang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, P.R. China
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Sindone A, Erlich J, Lee C, Newman H, Suranyi M, Roger SD. Cardiovascular risk reduction in hypertension: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers. Where are we up to? Intern Med J 2016; 46:364-72. [DOI: 10.1111/imj.12975] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 11/05/2015] [Accepted: 11/16/2015] [Indexed: 11/26/2022]
Affiliation(s)
- A. Sindone
- Heart Failure Unit and Department of Cardiac Rehabilitation; Concord Repatriation General Hospital; Concord New South Wales Australia
| | - J. Erlich
- Faculty of Medicine; University of NSW; Sydney New South Wales Australia
- Department of Nephrology; Prince of Wales Hospital; Sydney New South Wales Australia
| | - C. Lee
- Department of Cardiology; Nepean Hospital; Sydney New South Wales Australia
| | - H. Newman
- Department of Cardiology; Liverpool Hospital; Sydney New South Wales Australia
| | - M. Suranyi
- Liverpool Renal Clinical Research Centre; Liverpool Hospital; Sydney New South Wales Australia
| | - S. D. Roger
- Department of Renal Medicine; Gosford Hospital; Gosford New South Wales Australia
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Diminazene enhances stability of atherosclerotic plaques in ApoE-deficient mice. Vascul Pharmacol 2015; 74:103-113. [PMID: 26304699 DOI: 10.1016/j.vph.2015.08.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 07/22/2015] [Accepted: 08/20/2015] [Indexed: 11/23/2022]
Abstract
Angiotensin (Ang) II contributes to the development of atherosclerosis, while Ang-(1-7) has atheroprotective actions. Accordingly, angiotensin-converting enzyme 2 (ACE2), which breaks-down Ang II and forms Ang-(1-7), has been suggested as a target against atherosclerosis. Here we investigated the actions of diminazene, a recently developed ACE2 activator compound, in a model of vulnerable atherosclerotic plaque. Atherosclerotic plaque formation was induced in the carotid artery of ApoE-deficient mice by a shear stress (SS) modifier device. The animals were treated with diminazene (15mg/kg/day) or vehicle. ACE2 was strongly expressed in the aortic root and low SS-induced carotid plaques, but poorly expressed in the oscillatory SS-induced carotid plaques. Diminazene treatment did not change the lesion size, but ameliorated the composition of aortic root and low SS-induced carotid plaques by increasing collagen content and decreasing both MMP-9 expression and macrophage infiltration. Interestingly, these beneficial effects were not observed in the oscillatory SS-induced plaque. Additionally, diminazene treatment decreased intraplaque ICAM-1 and VCAM-1 expression, circulating cytokine and chemokine levels and serum triglycerides. In summary, ACE2 was distinctively expressed in atherosclerotic plaques, which depends on the local pattern of shear stress. Moreover, diminazene treatment enhances the stability of atherosclerotic plaques.
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Schmaier AH. Thrombosis Prevention without Anticoagulation. Front Med (Lausanne) 2015; 1:12. [PMID: 25705625 PMCID: PMC4335402 DOI: 10.3389/fmed.2014.00012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 04/27/2014] [Indexed: 11/21/2022] Open
Affiliation(s)
- Alvin H Schmaier
- Division of Hematology and Oncology, Department of Internal Medicine, University Hospitals Case Medical Center, Case Western Reserve University , Cleveland, OH , USA
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Fraga‐Silva RA, Costa‐Fraga FP, Montecucco F, Sturny M, Faye Y, Mach F, Pelli G, Shenoy V, da Silva RF, Raizada MK, Santos RA, Stergiopulos N. Diminazene Protects Corpus Cavernosum Against Hypercholesterolemia‐Induced Injury. J Sex Med 2015; 12:289-302. [PMID: 25411084 DOI: 10.1111/jsm.12757] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Riquelme C, Acuña MJ, Torrejón J, Rebolledo D, Cabrera D, Santos RA, Brandan E. ACE2 is augmented in dystrophic skeletal muscle and plays a role in decreasing associated fibrosis. PLoS One 2014; 9:e93449. [PMID: 24695436 PMCID: PMC3973684 DOI: 10.1371/journal.pone.0093449] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 03/04/2014] [Indexed: 02/06/2023] Open
Abstract
Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease and is characterized by absence of the cytoskeletal protein dystrophin, muscle wasting, and fibrosis. We previously demonstrated that systemic infusion or oral administration of angiotensin-(1-7) (Ang-(1-7)), a peptide with opposing effects to angiotensin II, normalized skeletal muscle architecture, decreased local fibrosis, and improved muscle function in mdx mice, a dystrophic model for DMD. In this study, we investigated the presence, activity, and localization of ACE2, the enzyme responsible for Ang-(1-7) production, in wild type (wt) and mdx skeletal muscle and in a model of induced chronic damage in wt mice. All dystrophic muscles studied showed higher ACE2 activity than wt muscle. Immunolocalization studies indicated that ACE2 was localized mainly at the sarcolemma and, to a lesser extent, associated with interstitial cells. Similar results were observed in the model of chronic damage in the tibialis anterior (TA) muscle. Furthermore, we evaluated the effect of ACE2 overexpression in mdx TA muscle using an adenovirus containing human ACE2 sequence and showed that expression of ACE2 reduced the fibrosis associated with TA dystrophic muscles. Moreover, we observed fewer inflammatory cells infiltrating the mdx muscle. Finally, mdx gastrocnemius muscles from mice infused with Ang-(1-7), which decreases fibrosis, contain less ACE2 associated with the muscle. This is the first evidence supporting ACE2 as an important therapeutic target to improve the dystrophic skeletal muscle phenotype.
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Affiliation(s)
- Cecilia Riquelme
- Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile
| | - María José Acuña
- Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile
| | - Javiera Torrejón
- Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile
| | - Daniela Rebolledo
- Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile
| | - Daniel Cabrera
- Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile
| | - Robson A. Santos
- Department of Physiology and Biophysics, Biological Sciences Institute, INCT Nanobio-far, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Enrique Brandan
- Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile
- * E-mail:
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Affiliation(s)
- Robson Augusto Santos
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, CEP 31270-910, Brazil.
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Non-canonical signalling and roles of the vasoactive peptides angiotensins and kinins. Clin Sci (Lond) 2014; 126:753-74. [DOI: 10.1042/cs20130414] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
GPCRs (G-protein-coupled receptors) are among the most important targets for drug discovery due to their ubiquitous expression and participation in cellular events under both healthy and disease conditions. These receptors can be activated by a plethora of ligands, such as ions, odorants, small ligands and peptides, including angiotensins and kinins, which are vasoactive peptides that are classically involved in the pathophysiology of cardiovascular events. These peptides and their corresponding GPCRs have been reported to play roles in other systems and under pathophysiological conditions, such as cancer, central nervous system disorders, metabolic dysfunction and bone resorption. More recently, new mechanisms have been described for the functional regulation of GPCRs, including the transactivation of other signal transduction receptors and the activation of G-protein-independent pathways. The existence of such alternative mechanisms for signal transduction and the discovery of agonists that can preferentially trigger one signalling pathway over other pathways (called biased agonists) have opened new perspectives for the discovery and development of drugs with a higher specificity of action and, therefore, fewer side effects. The present review summarizes the current knowledge on the non-canonical signalling and roles of angiotensins and kinins.
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Ferrari R, Boersma E. The impact of ACE inhibition on all-cause and cardiovascular mortality in contemporary hypertension trials: a review. Expert Rev Cardiovasc Ther 2014; 11:705-17. [DOI: 10.1586/erc.13.42] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Acuña MJ, Pessina P, Olguin H, Cabrera D, Vio CP, Bader M, Muñoz-Canoves P, Santos RA, Cabello-Verrugio C, Brandan E. Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-β signalling. Hum Mol Genet 2013; 23:1237-49. [DOI: 10.1093/hmg/ddt514] [Citation(s) in RCA: 123] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Lu J, Jiang T, Wu L, Gao L, Wang Y, Zhou F, Zhang S, Zhang Y. The expression of angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor axis are upregulated after acute cerebral ischemic stroke in rats. Neuropeptides 2013; 47:289-95. [PMID: 24090950 DOI: 10.1016/j.npep.2013.09.002] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Revised: 08/10/2013] [Accepted: 09/09/2013] [Indexed: 01/23/2023]
Abstract
There is now unequivocal evidence that the angiotensin-converting enzyme 2(ACE2)-Ang-(1-7)-Mas axis is a key component of the renin-angiotensin system (RAS) cascade, which is closely correlated with ischemic insult occurrence. Our previous studies demonstrated that the Ang-(1-7), was an active member of the brain RAS. However, the ACE2-Ang-(1-7)-Mas axis expression after cerebral ischemic injury are currently unclear. In the present study, we investigated the time course of ACE2-Ang-(1-7) and Mas receptor expression in the acute stage of cerebral ischemic stroke. The content of Ang-(1-7) in ischemic tissues and blood serum was measured by specific EIA kits. Real-time PCR and western blot were used to determine messenger RNA (mRNA) and protein levels of the ACE2 and Mas. The cerebral ischemic lesion resulted in a significant increase of regional cerebral and circulating Ang-(1-7) at 6-48 h compared with sham operation group following focal ischemic stroke (12h: 7.276±0.320 ng/ml vs. 2.466±0.410 ng/ml, serum; 1.024±0.056 ng/mg vs. 0.499±0.032, brain) (P<0.05). Both ACE2 and Mas expression were markedly enhanced compared to the control in the ischemic tissues (P<0.05). Mas immunopositive neurons were also seen stronger expression in the ischemic cortex (19.167±2.858 vs. 7.833±2.483) (P<0.05). The evidence collected in our present study will indicate that, ACE2-Ang-(1-7)-Mas axis are upregulated after acute ischemic stroke and would play a pivotal role in the regulation of acute neuron injury in ischemic cerebrovascular diseases.
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Affiliation(s)
- Jie Lu
- Department of Neurology, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, PR China
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Fraga-Silva RA, Montecucco F, Mach F, Santos RAS, Stergiopulos N. Pathophysiological role of the renin-angiotensin system on erectile dysfunction. Eur J Clin Invest 2013; 43:978-85. [PMID: 23909886 DOI: 10.1111/eci.12117] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 05/15/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND The renin-angiotensin system (RAS) has been shown to play an active role within the erectile tissues. The aim of this narrative review is to summarize the literature addressing the pathophysiological role of RAS on erectile function. Additionally, we update evidence on recent findings on the role of the Ang-(1-7) and Mas receptor on the erectile function and its therapeutic potential for treating erectile dysfunction (ED). MATERIALS AND METHODS This narrative review is based on the material searched and obtained via MEDLINE and PubMed up to November 2012. The search terms we used are 'angiotensin, erectile dysfunction, renin, Mas receptor' in combination with 'pathophysiology, fibrosis, pathways'. RESULTS The levels of angiotensin (Ang) II, the main component of this system, are increased in the corpus cavernosum as compared to those found in the systemic circulation. Moreover, emerging evidence indicates that an increased activity of Ang II via AT1 receptor might contribute to the development of ED, whereas the pharmacological blockage of Ang II/AT1 actions has beneficial effects on the erection. On the other hand, the heptapeptide Ang-(1-7), known as a major endogenous counter-regulator of Ang II actions, favours penile erection via the activation of Mas receptor. CONCLUSIONS Ang-(1-7) and Mas receptor pathway might be considered as a promising therapeutic target for the treatment of ED.
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Fraga-Silva RA, Ferreira AJ, Dos Santos RAS. Opportunities for targeting the angiotensin-converting enzyme 2/angiotensin-(1-7)/mas receptor pathway in hypertension. Curr Hypertens Rep 2013; 15:31-8. [PMID: 23212695 DOI: 10.1007/s11906-012-0324-1] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
It is well known that the renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cardiovascular diseases. This is well illustrated by the great success of ACE inhibitors and angiotensin (Ang) II AT(1) blockers in the treatment of hypertension and its complications. In the past decade, the classical concept of RAS orchestrated by a series of enzymatic reactions culminating in the linear generation and action of Ang II has expanded and become more complex. From the discoveries of new components such as the angiotensin converting enzyme 2 and the receptor Mas emerged a novel concept of dual opposite branches of the RAS: one vasoconstrictor and pro-hypertensive composed of ACE/Ang II/AT1; and other vasodilator and anti-hypertensive composed of ACE2/Ang-(1-7)/Mas. In this review we will discuss recent findings concerning the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular system and highlight the initiatives to develop potential therapeutic strategies based on this axis for treating hypertension.
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