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Wang T, Zhai Y, Xue H, Zhou W, Ding Y, Nie H. Regulation of Epithelial Sodium Transport by SARS-CoV-2 Is Closely Related with Fibrinolytic System-Associated Proteins. Biomolecules 2023; 13:biom13040578. [PMID: 37189326 DOI: 10.3390/biom13040578] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/08/2023] [Accepted: 03/21/2023] [Indexed: 05/17/2023] Open
Abstract
Dyspnea and progressive hypoxemia are the main clinical features of patients with coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pulmonary pathology shows diffuse alveolar damage with edema, hemorrhage, and the deposition of fibrinogens in the alveolar space, which are consistent with the Berlin Acute Respiratory Distress Syndrome Criteria. The epithelial sodium channel (ENaC) is a key channel protein in alveolar ion transport and the rate-limiting step for pulmonary edema fluid clearance, the dysregulation of which is associated with acute lung injury/acute respiratory distress syndrome. The main protein of the fibrinolysis system, plasmin, can bind to the furin site of γ-ENaC and induce it to an activation state, facilitating pulmonary fluid reabsorption. Intriguingly, the unique feature of SARS-CoV-2 from other β-coronaviruses is that the spike protein of the former has the same furin site (RRAR) with ENaC, suggesting that a potential competition exists between SARS-CoV-2 and ENaC for the cleavage by plasmin. Extensive pulmonary microthrombosis caused by disorders of the coagulation and fibrinolysis system has also been seen in COVID-19 patients. To some extent, high plasmin (ogen) is a common risk factor for SARS-CoV-2 infection since an increased cleavage by plasmin accelerates virus invasion. This review elaborates on the closely related relationship between SARS-CoV-2 and ENaC for fibrinolysis system-related proteins, aiming to clarify the regulation of ENaC under SARS-CoV-2 infection and provide a novel reference for the treatment of COVID-19 from the view of sodium transport regulation in the lung epithelium.
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Affiliation(s)
- Tingyu Wang
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Yiman Zhai
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Hao Xue
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Wei Zhou
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Yan Ding
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Hongguang Nie
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
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Zebardast A, Latifi T, Shabani M, Hasanzadeh A, Danesh M, Babazadeh S, Sadeghi F. Thrombotic storm in coronavirus disease 2019: from underlying mechanisms to its management. J Med Microbiol 2022; 71. [PMID: 36346830 DOI: 10.1099/jmm.0.001591] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Introduction. Coronavirus disease 2019 (COVID-19) identified in December 2019 in Wuhan, China, is associated with high mortality rates worldwide.Hypothesis/Gap Statement. Thrombotic problems, such as coagulopathy, are common in COVID-19 patients. Despite anticoagulation, thrombosis is more common in patients in the intensive care unit and patients with more severe disease. Although the exact mechanisms of coagulopathy in COVID-19 patients are still unclear, studies showed that overactivation of the renin-angiotensin system (RAS), cytokine storm, endothelial damage, formation of neutrophil extracellular traps (NETs), and also extracellular vesicles (EVs) in response to COVID-19 induced inflammation can lead to systemic coagulation and thrombosis.Aim. The management of COVID-19 patients requires the use of basic and readily available laboratory markers, both on admission and during hospitalization. Because it is critical to understand the pathophysiology of COVID-19 induced coagulopathy and treatment strategies, in this review we attempt to explain the underlying mechanism of COVID-19 coagulopathy, its diagnosis, and the associated successful treatment strategies.Conclusion. The exact mechanisms behind COVID-19-related coagulopathy are still unclear, but several studies revealed some mechanisms. More research is needed to determine the best anticoagulant regimen and to study other therapeutic options.
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Affiliation(s)
- Arghavan Zebardast
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Student Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Tayebeh Latifi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Shabani
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Hasanzadeh
- Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Golestan, Iran
| | - Manizheh Danesh
- Assistant Professor, Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sara Babazadeh
- Department of Pathology, Ayatollah Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran
| | - Farzin Sadeghi
- Cellular & Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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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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Warchoł-Celińska E, Prejbisz A, Dobrowolski P, Wypasek E, Kądziela J, Kołodziejczyk-Kruk S, Kabat M, Undas A, Januszewicz A. Fibrin clot properties and fibrinolysis in patients with endocrine hypertension due to aldosterone or catecholamines excess. Clin Endocrinol (Oxf) 2022; 96:114-122. [PMID: 34778982 DOI: 10.1111/cen.14638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/12/2021] [Accepted: 10/30/2021] [Indexed: 11/29/2022]
Abstract
OBJECTIVE The aim of the study was to investigate a new possible background of increased risk of cardiovascular events in two forms of endocrine hypertension: in primary aldosteronism (PA) and pheochromocytoma/paraganglioma (PPGL) in comparison to essential hypertension (EHT). CONTEXT Prothrombotic properties of the fibrin clot structure, impaired fibrinolysis and enhanced thrombin generation have been reported to be associated with increased cardiovascular risk. DESIGN Patients with PA and PPGL were evaluated at baseline and re-evaluated 3 months after causative treatment. At baseline PA and PPGL patients were compared to matched EHT patients and to healthy controls. PATIENTS The study included 35 patients with PA, 16 patients with PPGL and two reference groups of patients with EHT (32 and 22 patients) and healthy controls (35 and 23 subjects). MEASUREMENTS All subjects underwent evaluation according to the study protocol that included plasma fibrin clot permeability (Ks), clot lysis time, endogenous thrombin potential. RESULTS There were no differences in clot structure and fibrinolytic activity in PA and PPGL patients as compared to matched patients with EHT, whereas all hypertensive groups were characterized by more compact fibrin clot structure, faster clot formation and enhanced thrombin generation in comparison to healthy controls. Both in PA and PPGL patients, fibrin clot properties and fibrinolytic parameters remained stable after the causative treatment. CONCLUSIONS Patients with PA and PPGL are at a prothrombic state comparable to patients with EHT. The results suggest the higher risk of cardiovascular events observed in hypertensive PA and PPGL as compared to EHT is not mediated through investigated prothrombic mechanisms.
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Affiliation(s)
| | - Aleksander Prejbisz
- Department of Hypertension, National Institute of Cardiology, Warsaw, Poland
| | - Piotr Dobrowolski
- Department of Hypertension, National Institute of Cardiology, Warsaw, Poland
| | - Ewa Wypasek
- Innovative Laboratory Diagnostic Centre, John Paul II Hospital, Cracow, Poland
- Cracow Centre for Medical Research and Technologies, John Paul II Hospital, Cracow, Poland
- Department of Physiology and Pathophysiology, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Cracow, Poland
| | - Jacek Kądziela
- Department of Experimental Cardiac Surgery, Anesthesiology and Cardiology, Institute of Cardiology, Jagiellonian University Medical College, Cracow, Poland
| | | | - Marek Kabat
- Department of Hypertension, National Institute of Cardiology, Warsaw, Poland
| | - Anetta Undas
- Innovative Laboratory Diagnostic Centre, John Paul II Hospital, Cracow, Poland
- Cracow Centre for Medical Research and Technologies, John Paul II Hospital, Cracow, Poland
- Department of Invasive Cardiology and Angiology, National Institute of Cardiology, Warsaw, Poland
| | - Andrzej Januszewicz
- Department of Hypertension, National Institute of Cardiology, Warsaw, Poland
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Nagelkirk PR, Soave K, Altherr C, Del Pozzi A. Regular Resistance Training Enhances Fibrinolytic Potential but Does Not Affect Coagulation. Med Sci Sports Exerc 2021; 53:2318-2323. [PMID: 34115732 DOI: 10.1249/mss.0000000000002724] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
PURPOSE This study aimed to identify effects of an 8-wk, whole-body RT program on coagulation and fibrinolysis. METHODS Sixteen healthy women and men (23 ± 5 yr) completed an RT program three times per week for 8 wk. Exercises included 2-3 sets of 8-12 repetitions performed at approximately 60%-80% of a one repetition maximum. Strength, body composition, and body circumferences were assessed before and after training. Plasma samples were obtained before and after training, and analyzed for active tissue plasminogen activator (tPA activity), total tissue plasminogen activator (tPA antigen), active plasminogen activator inhibitor-1 (PAI-1 activity), total plasminogen activator inhibitor-1 (PAI-1 antigen), fibrinogen, and coagulation factors VII (FVII) and VIII (FVIII). RESULTS Significant increases in lean mass, arm and thigh circumferences, maximal chest press (PRE: 57.8 ± 37.5 kg, POST: 73.3 ± 43.2 kg), and leg press (PRE: 189.5 ± 96.0 kg, POST: 256.7 ± 97.9 kg) were observed (P < 0.05 for all). PAI-1 activity (PRE: 20.3 ± 32.5 IU·mL-1, POST 9.5 ± 20.9 IU·mL-1) and PAI-1 antigen decreased (PRE: 10.2 ± 9.0 ng·dL-1, POST: 7.2 ± 5.7 ng·dL-1; both, P < 0.05). No change in tPA activity or tPA antigen occurred. Fibrinogen, FVII, and FVIII did not change after training. CONCLUSIONS Inhibition of fibrinolysis was decreased after training, and coagulation was unaffected. These results suggest that regular RT may beneficially influence the risk of a thrombotic event. More research is warranted to understand the mechanisms through which RT affects hemostasis.
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Affiliation(s)
- Paul R Nagelkirk
- Integrative Exercise Physiology Laboratory, Ball State University, Muncie, IN
| | - Kayla Soave
- Integrative Exercise Physiology Laboratory, Ball State University, Muncie, IN
| | | | - Andrew Del Pozzi
- Integrative Exercise Physiology Laboratory, Ball State University, Muncie, IN
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Dysregulation of the renin-angiotensin system in septic shock: Mechanistic insights and application of angiotensin II in clinical management. Pharmacol Res 2021; 174:105916. [PMID: 34597810 DOI: 10.1016/j.phrs.2021.105916] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/18/2021] [Accepted: 09/26/2021] [Indexed: 12/12/2022]
Abstract
Synergistic physiologic mechanisms involving the renin-angiotensin system (RAS), the sympathetic nervous system, and the arginine-vasopressin system play an integral role in blood pressure homeostasis. A subset of patients with sepsis experience septic shock with attendant circulatory, cellular, and metabolic abnormalities. Septic shock is associated with increased mortality because of an inadequacy to maintain mean arterial blood pressure (MAP) despite volume resuscitation and the use of vasopressors. Vasodilatory shock raises the dose of vasopressors required to maintain a MAP of > 65 mm Hg. The diminished response to endogenous angiotensin II in sepsis-induced vasoplegia may be related to the aberrant RAS activation that stimulates a proinflammatory beneficial antibacterial response, increasing the secretion of proinflammatory cytokines that downregulate AT-1 receptors expression. Moreover, excessive systemic upregulation of nitric oxide synthase, stimulation of prostaglandin synthesis, and activation of ATP-sensitive potassium channels followed by reduced vascular entry of calcium ions are putative mechanisms in the reduced responsiveness to vasopressors. However, intravenous angiotensin II in catecholamine-resistant septic shock patients showed substantial evidence of raising the MAP to target hemodynamic levels, thus allowing time to treat underlying conditions. Nevertheless, evidence of catecholamine-sparing effect by adding angiotensin II, aimed at increasing the therapeutic index of vasopressor therapy, does not show an attenuation of end-organ damage. The use of angiotensin II in septic shock has not been evaluated in patients who are not catecholamine resistant. This, in conjunction with an evolving definition of catecholamine resistance, provides an opportunity for further evaluation of exogenous angiotensin II in septic shock.
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Ekholm M, Kahan T. The Impact of the Renin-Angiotensin-Aldosterone System on Inflammation, Coagulation, and Atherothrombotic Complications, and to Aggravated COVID-19. Front Pharmacol 2021; 12:640185. [PMID: 34220496 PMCID: PMC8245685 DOI: 10.3389/fphar.2021.640185] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 06/07/2021] [Indexed: 12/20/2022] Open
Abstract
Atherosclerosis is considered a disease caused by a chronic inflammation, associated with endothelial dysfunction, and several mediators of inflammation are up-regulated in subjects with atherosclerotic disease. Healthy, intact endothelium exhibits an antithrombotic, protective surface between the vascular lumen and vascular smooth muscle cells in the vessel wall. Oxidative stress is an imbalance between anti- and prooxidants, with a subsequent increase of reactive oxygen species, leading to tissue damage. The renin-angiotensin-aldosterone system is of vital importance in the pathobiology of vascular disease. Convincing data indicate that angiotensin II accelerates hypertension and augments the production of reactive oxygen species. This leads to the generation of a proinflammatory phenotype in human endothelial and vascular smooth muscle cells by the up-regulation of adhesion molecules, chemokines and cytokines. In addition, angiotensin II also seems to increase thrombin generation, possibly via a direct impact on tissue factor. However, the mechanism of cross-talk between inflammation and haemostasis can also contribute to prothrombotic states in inflammatory environments. Thus, blocking of the renin-angiotensin-aldosterone system might be an approach to reduce both inflammatory and thrombotic complications in high-risk patients. During COVID-19, the renin-angiotensin-aldosterone system may be activated. The levels of angiotensin II could contribute to the ongoing inflammation, which might result in a cytokine storm, a complication that significantly impairs prognosis. At the outbreak of COVID-19 concerns were raised about the use of angiotensin converting enzyme inhibitors and angiotensin receptor blocker drugs in patients with COVID-19 and hypertension or other cardiovascular comorbidities. However, the present evidence is in favor of continuing to use of these drugs. Based on experimental evidence, blocking the renin-angiotensin-aldosterone system might even exert a potentially protective influence in the setting of COVID-19.
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Affiliation(s)
- M Ekholm
- Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden
| | - T Kahan
- Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden
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Gando S, Wada T. Thromboplasminflammation in COVID-19 Coagulopathy: Three Viewpoints for Diagnostic and Therapeutic Strategies. Front Immunol 2021; 12:649122. [PMID: 34177896 PMCID: PMC8226122 DOI: 10.3389/fimmu.2021.649122] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 05/28/2021] [Indexed: 01/08/2023] Open
Abstract
Thromboplasminflammation in coronavirus disease 2019 (COVID-19) coagulopathy consists of angiotensin II (Ang II)-induced coagulopathy, activated factor XII (FXIIa)- and kallikrein, kinin system-enhanced fibrinolysis, and disseminated intravascular coagulation (DIC). All three conditions induce systemic inflammation via each pathomechanism-developed production of inflammatory cytokines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) downregulates angiotensin-converting enzyme 2, leading to an increase in Ang II levels. Ang II-induced coagulopathy comprising platelet activation, thrombin generation, plasminogen activator inhibitor-1 expression and endothelial injury causes thrombosis via the angiotensin II type 1 receptor. SARS-CoV-2 RNA and neutrophil extracellular trap (NET) DNA activate FXII, resulting in plasmin generation through FXIIa- and kallikrein-mediated plasminogen conversion to plasmin and bradykinin-induced tissue-type plasminogen activator release from the endothelium via the kinin B2 receptor. NETs induce immunothrombosis at the site of infection (lungs), through histone- and DNA-mediated thrombin generation, insufficient anticoagulation control, and inhibition of fibrinolysis. However, if the infection is sufficiently severe, immunothrombosis disseminates into the systemic circulation, and DIC, which is associated with the endothelial injury, occurs. Inflammation, and serine protease networks of coagulation and fibrinolysis, militate each other through complement pathways, which exacerbates three pathologies of COVID-19 coagulopathy. COVID-19 coagulopathy causes microvascular thrombosis and bleeding, resulting in multiple organ dysfunction and death in critically ill patients. Treatment targets for improving the prognosis of COVID-19 coagulopathy include thrombin, plasmin, and inflammation, and SARS-CoV-2 infection. Several drugs are candidates for controlling these conditions; however, further advances are required to establish robust treatments based on a clear understanding of molecular mechanisms of COVID-19 coagulopathy.
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Affiliation(s)
- Satoshi Gando
- Acute and Critical Center, Department of Acute and Critical Care Medicine, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan.,Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Takeshi Wada
- Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan
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Han M, Pandey D. ZMPSTE24 Regulates SARS-CoV-2 Spike Protein-enhanced Expression of Endothelial Plasminogen Activator Inhibitor-1. Am J Respir Cell Mol Biol 2021; 65:300-308. [PMID: 34003736 PMCID: PMC8485999 DOI: 10.1165/rcmb.2020-0544oc] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Endothelial dysfunction is implicated in the thrombotic events reported in COVID-19 patients, but underlying molecular mechanisms are unknown. Circulating levels of the coagulation cascade activator PAI-1 are substantially higher in COVID-19 patients with severe respiratory dysfunction than in patients with bacterial-sepsis and ARDS. Indeed, the elevation of PAI-1 is recognized as an early marker of endothelial dysfunction. Here, we report that recombinant SARS-CoV-2-S1 stimulated robust production of PAI-1 by HPMEC. We examined the role of protein degradation in this SARS-CoV-2-S1 induction of PAI-1 and found that the proteasomal degradation inhibitor bortezomib inhibited SARS-CoV-2-S1 mediated changes in PAI-1. Our data further show that bortezomib upregulated KLF2, a shear-stress-regulated transcription factor that suppresses PAI-1 expression. Aging and metabolic disorders are known to increase the mortality and morbidity in COVID-19 patients. We therefore examined the role of ZMPSTE24, a metalloprotease with a demonstrated role in host defense against RNA viruses that is decreased in the elderly and in metabolic syndrome, in the induction of PAI-1 in HPMEC by SARS-CoV-2-S1. Indeed, overexpression of ZMPSTE24 blunted enhancement of PAI-1 production in spike protein-exposed HPMEC. Additionally, we found that membrane expression of the SARS-CoV-2 entry receptor ACE2 was reduced by ZMPSTE24-mediated cleavage and shedding of the ACE2 ectodomain, leading to accumulation of ACE2 decoy fragments that may bind SARS-CoV-2. These data indicate that decreases in ZMPSTE24 with age and comorbidities may increase vulnerability to vascular endothelial injury by SARS-CoV-2 viruses and that enhanced production of endothelial PAI-1 might play role in prothrombotic events in COVID-19 patients. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Affiliation(s)
- Mingming Han
- Johns Hopkins University, 1466, Baltimore, Maryland, United States.,University of Science and Technology of China, 12652, Hefei, China
| | - Deepesh Pandey
- Johns Hopkins University, 1466, Baltimore, Maryland, United States;
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10
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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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Ichikawa H, Shimada M, Narita M, Narita I, Kimura Y, Tanaka M, Osanai T, Okumura K, Tomita H. Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease-Activated Receptor Pathway. J Am Heart Assoc 2020; 8:e012195. [PMID: 30957622 PMCID: PMC6507187 DOI: 10.1161/jaha.119.012195] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Background An enhanced renin‐angiotensin system causes hypertensive renal damage. Factor Xa not only functions in the coagulation cascade but also activates intracellular signaling through protease‐activated receptors (PAR). We investigated the effects of rivaroxaban, a factor Xa inhibitor, on hypertensive renal damage in hypertensive mice overexpressing renin (Ren‐TG). Methods and Results The 12‐ to 16‐week‐old Ren‐TG and wild‐type mice were orally administered with or without 6 or 12 mg/kg of rivaroxaban for 1 or 4 months. Plasma factor Xa was significantly increased in the Ren‐TG compared with the wild‐type mice and was reduced by 12 mg/kg of rivaroxaban (P<0.05). Urinary albumin excretion (UAE) was higher in the nontreated 8‐month‐old Ren‐TG than in the wild‐type mice (69.6±29 versus 20.1±8.2 μg/day; P<0.01). Treatment with 12 mg/kg of rivaroxaban for 4 months decreased the UAE to 38.1±13.2 μg/day (P<0.01). Moreover, rivaroxaban treatment attenuated histologic changes of glomerular hypertrophy, mesangial matrix expansion, effacement of the podocyte foot process, and thickened glomerular basement membrane in the Ren‐TG. The renal expression of PAR‐2 was increased in the Ren‐TG, but was inhibited with rivaroxaban treatment. In vitro study using the human podocytes showed that the expressions of PAR‐2 and inflammatory genes and nuclear factor–‐κB activation were induced by angiotensin II stimulation, but were inhibited by rivaroxaban. PAR‐2 knockdown by small interfering RNA also attenuated the PAR‐2‐related inflammatory gene expressions. Conclusions These findings indicate that rivaroxaban exerts protective effects against angiotensin II–induced renal damage, partly through inhibition of the PAR‐2 signaling‐mediated inflammatory response.
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Affiliation(s)
- Hiroaki Ichikawa
- 1 Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki Japan
| | - Michiko Shimada
- 1 Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki Japan
| | - Masato Narita
- 1 Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki Japan
| | - Ikuyo Narita
- 1 Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki Japan
| | - Yoshihiro Kimura
- 1 Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki Japan
| | - Makoto Tanaka
- 2 Department of Stroke and Cerebrovascular Medicine Hirosaki University Graduate School of Medicine Hirosaki Japan
| | - Tomohiro Osanai
- 3 Department of Nursing Science Hirosaki University Graduate School of Health Sciences Hirosaki Japan
| | - Ken Okumura
- 4 Division of Cardiology Saiseikai Kumamoto Hospital Kumamoto Japan
| | - Hirofumi Tomita
- 1 Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki Japan.,2 Department of Stroke and Cerebrovascular Medicine Hirosaki University Graduate School of Medicine Hirosaki Japan
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12
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Leong DP, McMurray JJV, Joseph PG, Yusuf S. From ACE Inhibitors/ARBs to ARNIs in Coronary Artery Disease and Heart Failure (Part 2/5). J Am Coll Cardiol 2020; 74:683-698. [PMID: 31370961 DOI: 10.1016/j.jacc.2019.04.068] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 04/17/2019] [Accepted: 04/17/2019] [Indexed: 11/15/2022]
Abstract
The pharmacological inhibition of the renin-angiotensin-aldosterone system as a therapeutic strategy is one of the most significant advances in the treatment and prevention of cardiovascular disease in heart failure with reduced ejection fraction and in coronary artery disease. Recently, the addition of neprilysin inhibition to angiotensin receptor blockade has been shown to be even more effective than angiotensin-converting enzyme inhibition alone in heart failure with reduced ejection fraction, marking an important new milestone in heart failure treatment. This review summarizes the major trials that have informed the clinical role of inhibition of the renin-angiotensin-aldosterone and neprilysin pathways, as well as the limitations of these strategies.
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Affiliation(s)
- Darryl P Leong
- The Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
| | - John J V McMurray
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Philip G Joseph
- The Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada
| | - Salim Yusuf
- The Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada
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Miesbach W. Pathological Role of Angiotensin II in Severe COVID-19. TH OPEN 2020; 4:e138-e144. [PMID: 32607467 PMCID: PMC7319800 DOI: 10.1055/s-0040-1713678] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 05/19/2020] [Indexed: 01/08/2023] Open
Abstract
The activated renin-angiotensin system induces a prothrombotic state resulting from the imbalance between coagulation and fibrinolysis. Angiotensin II is the central effector molecule of the activated renin-angiotensin system and is degraded by the angiotensin-converting enzyme 2 to angiotensin (1-7). The novel coronavirus infection (classified as COVID-19) is caused by the new coronavirus SARS-CoV-2 and is characterized by an exaggerated inflammatory response that can lead to severe manifestations such as acute respiratory distress syndrome, sepsis, and death in a proportion of patients, mostly elderly patients with preexisting comorbidities. SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor to enter the target cells, resulting in activation of the renin-angiotensin system. After downregulating the angiotensin-converting enzyme 2, the vasoconstrictor angiotensin II is increasingly produced and its counterregulating molecules angiotensin (1-7) reduced. Angiotensin II increases thrombin formation and impairs fibrinolysis. Elevated levels were strongly associated with viral load and lung injury in patients with severe COVID-19. Therefore, the complex clinical picture of patients with severe complications of COVID-19 is triggered by the various effects of highly expressed angiotensin II on vasculopathy, coagulopathy, and inflammation. Future treatment options should focus on blocking the thrombogenic and inflammatory properties of angiotensin II in COVID-19 patients.
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Affiliation(s)
- Wolfgang Miesbach
- Department of Haemostaseology and Haemophilia Center, Institute of Transfusion Medicine, Medical Clinic 2, University Hospital Frankfurt, Frankfurt, Germany
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14
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Targeted gene expression study using TaqMan low density array to gain insights into venous thrombo-embolism (VTE) pathogenesis at high altitude. Blood Cells Mol Dis 2020; 82:102421. [PMID: 32171843 DOI: 10.1016/j.bcmd.2020.102421] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/05/2020] [Accepted: 03/05/2020] [Indexed: 12/23/2022]
Abstract
Venous thrombo-embolism (VTE) is multi-factorial disease involving several genetic and acquired risk factors responsible for its onset. It may occur spontaneously upon climbing at High Altitude (HA). Several studies demonstrated that hypoxic conditions prevailing at HA pose an independent risk factor for VTE; however, molecular mechanism remains unknown. Present study aims to identify genes associated with HA-induced VTE pathophysiology using real time TaqMan Low-Density Array (TLDA) of known candidate genes. Gene expression of total 93 genes were studied and analyzed in patients of VTE from HA (HA-VTE) and from sea level (SL-VTE) in comparison to respective controls. Both HA-VTE and SL-VTE patients showed up-regulation of 37 genes involved in blood coagulation cascade, clot formation, platelet formation, endothelial response, angiogenesis, cell adhesion and calcium channel activity. Seven genes including ACE, EREG, C8A, DLG2, USF1, F2 and PCDHA7 were up-regulated in both HA-controls and VTE patients (both HA-VTE and SL-VTE) indicating their role during VTE event and also upon HA exposure. Ten genes; CDH18, FGA, EDNBR, GATA2, MAPK9, BCAR1, FRK, F11, PCDHA1 and ST8SIA4 were uniquely up-regulated in HA-VTE. The differentially expressed genes from the present study could be determining factors for HA-VTE susceptibility and provide insights into VTE occurrence at HA.
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Ancion A, Tridetti J, Nguyen Trung ML, Oury C, Lancellotti P. A Review of the Role of Bradykinin and Nitric Oxide in the Cardioprotective Action of Angiotensin-Converting Enzyme Inhibitors: Focus on Perindopril. Cardiol Ther 2019; 8:179-191. [PMID: 31578675 PMCID: PMC6828891 DOI: 10.1007/s40119-019-00150-w] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Indexed: 12/13/2022] Open
Abstract
The functional integrity of the endothelium is essential for vascular health. In addition to maintaining a delicate balance between vasodilation and vasoconstriction, the endothelium has numerous other complex roles involved in the maintenance of vascular homeostasis. Chronic exposure to cardiovascular risk factors and oxidative stress results in an imbalance in these functions, creating an environment that favors reduced vasodilation and a proinflammatory and prothrombic state. The involvement of endothelial dysfunction in all stages of the cardiovascular continuum makes it an important target for treatment. One of the major endothelial-derived factors involved in the maintenance of endothelial function is nitric oxide (NO). Angiotensin-converting enzyme (ACE) inhibitors increase NO production both directly and indirectly by preventing production of angiotensin II (which diminishes NO production) and inhibiting the degradation of bradykinin (which stimulates local release of NO). Among the ACE inhibitors, perindopril appears to have the greatest effects on bradykinin and has demonstrated efficacy in a number of markers of endothelial dysfunction including arterial stiffness and progression of atherosclerosis. There is also strong evidence supporting the use of perindopril-based therapy for the treatment of hypertension and for reducing the risk of cardiovascular morbidity and mortality in a wide range of patients across the cardiovascular continuum.Funding: The journal's Rapid Service Fee was funded by Servier.
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Affiliation(s)
- Arnaud Ancion
- University of Liège Hospital, GIGA Cardiovascular Sciences, Division of Cardiology, Acute Care Unit, Heart Failure Clinic, CHU Sart Tilman, Liège, Belgium
| | - Julien Tridetti
- University of Liège Hospital, GIGA Cardiovascular Sciences, Division of Cardiology, Acute Care Unit, Heart Failure Clinic, CHU Sart Tilman, Liège, Belgium
| | - Mai-Linh Nguyen Trung
- University of Liège Hospital, GIGA Cardiovascular Sciences, Division of Cardiology, Acute Care Unit, Heart Failure Clinic, CHU Sart Tilman, Liège, Belgium
| | - Cécile Oury
- University of Liège Hospital, GIGA Cardiovascular Sciences, Division of Cardiology, Acute Care Unit, Heart Failure Clinic, CHU Sart Tilman, Liège, Belgium
| | - Patrizio Lancellotti
- University of Liège Hospital, GIGA Cardiovascular Sciences, Division of Cardiology, Acute Care Unit, Heart Failure Clinic, CHU Sart Tilman, Liège, Belgium.
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Braschi A. Acute exercise-induced changes in hemostatic and fibrinolytic properties: analogies, similarities, and differences between normotensive subjects and patients with essential hypertension. Platelets 2019; 30:675-689. [DOI: 10.1080/09537104.2019.1615611] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Braschi A. Potential Protective Role of Blood Pressure-Lowering Drugs on the Balance between Hemostasis and Fibrinolysis in Hypertensive Patients at Rest and During Exercise. Am J Cardiovasc Drugs 2019; 19:133-171. [PMID: 30714087 DOI: 10.1007/s40256-018-00316-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In patients with hypertension, the triad represented by endothelial dysfunction, platelet hyperactivity, and altered fibrinolytic function disturbs the equilibrium between hemostasis and fibrinolysis and translates into a hypercoagulable state, which underlies the risk of thrombotic complications. This article reviews the scientific evidence regarding some biological effects of antihypertensive drugs, which can protect patients from the adverse consequences of hypertensive disease, improving endothelial function, enhancing antioxidant activity, and restoring equilibrium between hemostatic and fibrinolytic factors. These protective effects appear not to be mediated through blood pressure reduction and are not shared by all molecules of the same pharmacological class.
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Affiliation(s)
- Annabella Braschi
- Ambulatory of Cardiovascular Diseases, Via col. Romey n.10, 91100, Trapani, Italy.
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18
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Su MT, Lin SH, Chen YC, Kuo PL. Genetic association studies of ACE and PAI-1 genes in women with recurrent pregnancy loss. Thromb Haemost 2017. [DOI: 10.1160/th12-08-0584] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
SummaryA fine balance between coagulation and fibrinolysis is critical in early pregnancy. Plasminogen activator inhibitor-1 (PAI-1) and angiotensin converting enzyme (ACE) are involved in the fibrinolytic process, and several studies have reported the association between their gene polymorphisms and recurrent pregnancy loss (RPL). This study was conducted to investigate the association between PAI-1 and ACE polymorphisms and idiopathic RPL, using meta-analyses. A systematic review of the published literature from the MEDLINE and EMBASE databases before April 2012 was conducted. Of 209 potentially relevant studies, 22 case-control studies comprising a total of 2,820 RPL patients and 3,009 controls were included. Among these studies were 11 reports of PAI-1 4G/5G and 11 of ACE I/D polymorphisms in patients with RPL. A significant association was found withthe ACE I/D polymorphism [summary odds ratio 1.29 (95% confidence interval 1.02–1.62)] in studies including more than two recurrent abortions. Subgroup analysis did not show significant associations with RPL in Caucasian and non-Caucasian patients. Meta-analyses of PAI-1 4G/5G polymorphism were not found associations with RPL in studies including more than two or three recurrent abortions, and in studies of Caucasian and non-Caucasian patients. In conclusion, meta-analyses showed a significant association between the ACE I/D polymorphism and idiopathic RPL. High clinical heterogeneity existed among studies of PAI-1 4G/5G, and the aggregated data failed to confer higher susceptibility to idiopathic RPL. More well-designed studies with different ethnic populations are required for future integration.
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Ethnic differences in the association between angiotensin-converting enzyme gene insertion/deletion polymorphism and peripheral vascular disease: A meta-analysis. Chronic Dis Transl Med 2017; 3:230-241. [PMID: 29354806 PMCID: PMC5747497 DOI: 10.1016/j.cdtm.2017.07.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Indexed: 11/30/2022] Open
Abstract
Background Several studies have investigated the association of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with peripheral vascular disease (PVD); however, the results remain controversial. Therefore, we conducted the current meta-analysis to evaluate this relationship in the general population of different ethnicities. Methods We searched PubMed, Embase, Web of Science, Wanfang Database, and CNKI to identify eligible studies. Random-effect models were applied to estimate the pooled odds ratio (OR) with a 95% confidence interval (CI), regardless of between-study heterogeneity. Results A total of 13 studies with 1966 cases and 6129 controls were included in this meta-analysis. The pooled ORs for the association between ACE I/D polymorphism and PVD risk were not statistically significant in the overall population under all genetic models. In further ethnicity-stratified analyses, we found a statistically significant association of ACE I/D polymorphism with PVD susceptibility in Asians under most models. However, the association among Caucasians did not reach statistical significance. Conclusion ACE I/D polymorphism might be associated with susceptibility to PVD in the Asian population, but there was no clear evidence indicating a similar significant relationship among Caucasians.
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20
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Bezgin T, Kaymaz C, Akbal Ö, Yılmaz F, Tokgöz HC, Özdemir N. Thrombophilic Gene Mutations in Relation to Different Manifestations of Venous Thromboembolism: A Single Tertiary Center Study. Clin Appl Thromb Hemost 2016; 24:100-106. [PMID: 27729560 DOI: 10.1177/1076029616672585] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Venous thromboembolism (VTE) is a common and potentially lethal disorder that manifests mainly as deep vein thrombosis (DVT) of the extremities or pulmonary embolism (PE) and occurs as a consequence of genetic and environmental risk factors. We aimed to assess the role of inherited thrombophilia as a causative or additive factor in the development of VTE. METHODS The study included 310 patients (female: 154; mean age: 52.3 ± 16.9 years) with a first episode of VTE and 289 age- and sex-matched healthy controls. All participants underwent screening for thrombophilia-associated polymorphisms including factor V Leiden (FVL), prothrombin G20210A (PTG), factor V H1299 R (factor V HR2), factor XIII V34 L, β-fibrinogen-455 G>A, plasminogen activator inhibitor-1 4G/5G, human platelet antigen-1 a/b, methylene tetrahydrofolate reductase (MTHFR) C677 T, MTHFR A1298C, angiotensin-converting enzyme I/D, apolipoprotein B R3500Q, and apolipoprotein E (Apo E). In addition, serum homocysteine (Hcy) levels were measured. RESULTS In the patient group, 247 (80%) had isolated DVT, 43 (14%) had DVT plus PE, and 20 (6%) had isolated PE. The mean Hcy levels were similar in VTE subgroups and controls. Compared to controls, patients with isolated DVT, DVT plus PE, and isolated PE showed significantly higher frequencies for the following-heterozygous FVL mutation, isolated DVT (28.3%), DVT plus PE (44.2%), isolated PE (50%), controls (8.3%; P < .001); heterozygous PTG mutation, isolated DVT (11.3%), DVT plus PE (20.9%), isolated PE (25%), controls (5.9%; P < .01); Apo E 2/4, isolated DVT (9.7%), DVT plus PE (9.3%), isolated PE (5%), controls (1%; P < .01).The MTHFR A1298C mutation showed a significantly higher frequency in isolated patients with PE than in those with isolated DVT ( P = .006) and in controls ( P = .008). The frequencies of other genetic mutations or polymorphisms showed similar frequencies in all comparisons. In logistic regression analysis, heterozygous FVL mutation was the only independent predictor of VTE (odds ratio: 3.9, 95% confidence interval: 1.3-11.2; P = .012). CONCLUSION Except than FVL, PTG, and Apo E 2/4 mutations, many of aforementioned thrombophilic factors known to be associated with VTE did not demonstrate any relationship with VTE. Heterozygous mutation of FVL was an independent predictor for VTE.
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Affiliation(s)
- Tahir Bezgin
- 1 Kartal Koşuyolu Heart and Research Hospital, Cardiology Clinic, Istanbul, Turkey
| | - Cihangir Kaymaz
- 1 Kartal Koşuyolu Heart and Research Hospital, Cardiology Clinic, Istanbul, Turkey
| | - Özgür Akbal
- 1 Kartal Koşuyolu Heart and Research Hospital, Cardiology Clinic, Istanbul, Turkey
| | - Fatih Yılmaz
- 1 Kartal Koşuyolu Heart and Research Hospital, Cardiology Clinic, Istanbul, Turkey
| | - Hacer Ceren Tokgöz
- 1 Kartal Koşuyolu Heart and Research Hospital, Cardiology Clinic, Istanbul, Turkey
| | - Nihal Özdemir
- 1 Kartal Koşuyolu Heart and Research Hospital, Cardiology Clinic, Istanbul, Turkey
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21
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Infusion of angiotensin II increases fibrinolysis in healthy individuals but not in patients with familial combined hyperlipidemia. Blood Coagul Fibrinolysis 2016; 27:113-6. [PMID: 26340459 DOI: 10.1097/mbc.0000000000000393] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Impaired fibrinolysis is related to insulin resistance, also a characteristic feature of familial combined hyperlipidemia (FCHL). The renin-angiotensin (Ang) system is upregulated with insulin resistance, and there is crosstalk between Ang II and insulin-signalling pathways. We studied the fibrinolytic effects of a 3-h systemic Ang II infusion in 16 patients with FCHL and 16 controls, and placebo infusion in eight individuals. Baseline plasminogen activator inhibitor-1 (PAI-1) activity, plasmin-antiplasmin complex, insulin resistance and C-reactive protein were higher in patients with FCHL than in controls. PAI-1 activity decreased during Ang II, similar in patients with FCHL and controls, and by placebo. Plasmin-antiplasmin complex was unaffected by Ang II in FCHL but increased in controls. Patients with FCHL show signs of insulin resistance, low-grade inflammation and impaired fibrinolysis. Ang II enhances fibrinolysis in controls but not in patients with FCHL, suggesting that patients with FCHL are not capable of increasing tissue plasminogen activator activity in response to Ang II. Ang II has no short-term effects on PAI-1 activity.
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22
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Düsing R. Pharmacological interventions into the renin-angiotensin system with ACE inhibitors and angiotensin II receptor antagonists: effects beyond blood pressure lowering. Ther Adv Cardiovasc Dis 2016; 10:151-61. [PMID: 27122491 DOI: 10.1177/1753944716644130] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Hypertension is recognized as an important risk factor for cardiovascular morbidity and mortality. Lowering of blood pressure has been shown to minimize the risk of cardiovascular events, with the majority of antihypertensives demonstrating a similar ability to reduce coronary events and stroke for a given reduction in blood pressure. Agents that modify the activity of the renin-angiotensin system (RAS) have been proposed to exhibit additional effects that might go beyond simple blood pressure lowering. The RAS is a crucial system that regulates extracellular fluid volume and blood pressure. Proposed potential benefits of RAS blockade that go beyond blood pressure lowering include a reduction in platelet aggregation and thrombosis, blunting of cardiac and vascular remodeling, favorable metabolic effects and reno- and cerebro-protection. However, factors such as treatment adherence, duration of action of antihypertensive agents and differences in effects on central versus brachial blood pressure may also result in apparent differences in efficacy of different antihypertensives. The aim of this review article is to examine the available data from clinical studies of antihypertensive drugs for evidence of effects that might legitimately be claimed to go beyond simple blood pressure lowering.
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Affiliation(s)
- Rainer Düsing
- Hypertoniezentrum Bonn, Am Burgweiher 52-54, 53123 Bonn, Germany
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23
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de Carvalho SS, Simões e Silva AC, Sabino ADP, Evangelista FCG, Gomes KB, Dusse LMS, Rios DRA. Influence of ACE I/D Polymorphism on Circulating Levels of Plasminogen Activator Inhibitor 1, D-Dimer, Ultrasensitive C-Reactive Protein and Transforming Growth Factor β1 in Patients Undergoing Hemodialysis. PLoS One 2016; 11:e0150613. [PMID: 27022914 PMCID: PMC4811575 DOI: 10.1371/journal.pone.0150613] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Accepted: 02/16/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND There is substantial evidence that chronic renal and cardiovascular diseases are associated with coagulation disorders, endothelial dysfunction, inflammation and fibrosis. Angiotensin-Converting Enzyme Insertion/Deletion polymorphism (ACE I/D polymorphism) has also be linked to cardiovascular diseases. Therefore, this study aimed to compare plasma levels of ultrassensible C-reactive protein (usCRP), PAI-1, D-dimer and TGF-β1 in patients undergoing HD with different ACE I/D polymorphisms. METHODS The study was performed in 138 patients at ESRD under hemodialysis therapy for more than six months. The patients were divided into three groups according to the genotype. Genomic DNA was extracted from blood cells (leukocytes). ACE I/D polymorphism was investigated by single polymerase chain reaction (PCR). Plasma levels of D-dimer, PAI-1 and TGF-β1 were measured by enzyme-linked immunosorbent assay (ELISA), and the determination of plasma levels of usCRP was performed by immunonephelometry. Data were analyzed by the software SigmaStat 2.03. RESULTS Clinical characteristics were similar in patients with these three ACE I/D polymorphisms, except for interdialytic weight gain. I allele could be associated with higher interdialytic weight gain (P = 0.017). Patients genotyped as DD and as ID had significantly higher levels of PAI-1 than those with II genotype. Other laboratory parameters did not significantly differ among the three subgroups (P = 0.033). Despite not reaching statistical significance, plasma levels of usCRP were higher in patients carrying the D allele. CONCLUSION ACE I/D polymorphisms could be associated with changes in the regulation of sodium, fibrinolytic system, and possibly, inflammation. Our data showed that high levels of PAI-1 are detected when D allele is present, whereas greater interdialytic gain is associated with the presence of I allele. However, further studies with different experimental designs are necessary to elucidate the mechanisms involved in these associations.
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Affiliation(s)
- Sara Santos de Carvalho
- Campus Centro Oeste Dona Lindu, Universidade Federal de São João del-Rei, Divinópolis/MG – Brazil
| | - Ana Cristina Simões e Silva
- Department of Pediatrics, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine – Universidade Federal de Minas Gerais, Belo Horizonte/MG – Brazil
| | - Adriano de Paula Sabino
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy - Universidade Federal de Minas Gerais, Belo Horizonte/MG – Brazil
| | | | - Karina Braga Gomes
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy - Universidade Federal de Minas Gerais, Belo Horizonte/MG – Brazil
| | - Luci Maria SantAna Dusse
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy - Universidade Federal de Minas Gerais, Belo Horizonte/MG – Brazil
| | - Danyelle Romana Alves Rios
- Campus Centro Oeste Dona Lindu, Universidade Federal de São João del-Rei, Divinópolis/MG – Brazil
- * E-mail:
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Li S, Wang YN, Niimi M, Ning B, Chen Y, Kang D, Wang Z, Yu Q, Waqar AB, Liu E, Zhang J, Shiomi M, Chen YE, Fan J. Angiotensin II Destabilizes Coronary Plaques in Watanabe Heritable Hyperlipidemic Rabbits. Arterioscler Thromb Vasc Biol 2016; 36:810-816. [PMID: 26988589 DOI: 10.1161/atvbaha.115.306871] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 02/29/2016] [Indexed: 01/02/2023]
Abstract
OBJECTIVE Increased plasma concentrations of angiotensin II (Ang II) have been implicated in many cardiovascular diseases, such as atherosclerosis, aortic aneurysms, and myocardial infarction, in humans. However, it is not known whether high levels of plasma Ang II affect coronary plaque stability and subsequent myocardial infarction. This study was designed to examine whether elevated plasma Ang II can directly induce coronary events, such as acute coronary syndrome. APPROACH AND RESULTS To examine the above hypothesis, we infused Ang II (100 ng/min per kg [low group] and 200 ng/min per kg [high group]) or saline vehicle via osmotic minipumps into Watanabe heritable hyperlipidemic rabbits, a model of human familial hypercholesterolemia and atherosclerosis. Infusion of Ang II resulted in mortality rates of 50% and 92% in the low- and high-Ang II groups, respectively, whereas there were no deaths in the vehicle group. Pathological analysis revealed that Ang II-infused Watanabe heritable hyperlipidemic rabbits that died showed myocardial infarction. Furthermore, Ang II-infused Watanabe heritable hyperlipidemic rabbits exhibited coronary plaque erosion and rupture that were associated with thrombosis. CONCLUSIONS These findings suggest that increased blood levels of Ang II can destabilize coronary plaques and trigger the thrombosis, which possibly induces myocardial infarction. The model described in this study provides a novel means for the study of human acute coronary syndrome.
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Affiliation(s)
- Shen Li
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Yan-Ning Wang
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Manabu Niimi
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Bo Ning
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Yajie Chen
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Dedong Kang
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Ziyun Wang
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Qi Yu
- Department of Pathology, Xi'an Medical University, Xi'an, China
| | - Ahmed Bilal Waqar
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan
| | - Enqi Liu
- Research Institute of Atherosclerotic Disease and Laboratory Animal Center, Xi'an Jiaotong University School of Medicine, Xi'an, China
| | - Jifeng Zhang
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Masashi Shiomi
- Institute for Experimental Animals, Kobe University School of Medicine, Kobe, Japan
| | - Y Eugene Chen
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Jianglin Fan
- Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi 409-3898, Japan
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25
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Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 2015; 7:719-741. [PMID: 26635921 PMCID: PMC4660468 DOI: 10.4330/wjc.v7.i11.719] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/23/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.
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26
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van Thiel BS, van der Pluijm I, te Riet L, Essers J, Danser AHJ. The renin-angiotensin system and its involvement in vascular disease. Eur J Pharmacol 2015; 763:3-14. [PMID: 25987425 DOI: 10.1016/j.ejphar.2015.03.090] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Revised: 01/15/2015] [Accepted: 03/24/2015] [Indexed: 10/24/2022]
Abstract
The renin-angiotensin system (RAS) plays a critical role in the pathogenesis of many types of cardiovascular diseases including cardiomyopathy, valvular heart disease, aneurysms, stroke, coronary artery disease and vascular injury. Besides the classical regulatory effects on blood pressure and sodium homoeostasis, the RAS is involved in the regulation of contractility and remodelling of the vessel wall. Numerous studies have shown beneficial effect of inhibition of this system in the pathogenesis of cardiovascular diseases. However, dysregulation and overexpression of the RAS, through different molecular mechanisms, also induces, the initiation of vascular damage. The key effector peptide of the RAS, angiotensin II (Ang II) promotes cell proliferation, apoptosis, fibrosis, oxidative stress and inflammation, processes known to contribute to remodelling of the vasculature. In this review, we focus on the components that are under the influence of the RAS and contribute to the development and progression of vascular disease; extracellular matrix defects, atherosclerosis and ageing. Furthermore, the beneficial therapeutic effects of inhibition of the RAS on the vasculature are discussed, as well as the need for additive effects on top of RAS inhibition.
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Affiliation(s)
- Bibi S van Thiel
- Department of Internal Medicine, Division of Pharmacology and Vascular Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Genetics, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands
| | - Ingrid van der Pluijm
- Department of Genetics, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands
| | - Luuk te Riet
- Department of Internal Medicine, Division of Pharmacology and Vascular Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands
| | - Jeroen Essers
- Department of Genetics, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands; Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands
| | - A H Jan Danser
- Department of Internal Medicine, Division of Pharmacology and Vascular Medicine, Erasmus MC, Rotterdam, The Netherlands.
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Ekholm M, Kahan T, Jörneskog G, Brinck J, Wallén NH. Haemostatic and inflammatory alterations in familial hypercholesterolaemia, and the impact of angiotensin II infusion. J Renin Angiotensin Aldosterone Syst 2015; 16:328-38. [PMID: 25908220 DOI: 10.1177/1470320315575848] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 01/30/2015] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION We examined potential prothrombotic and proinflammatory effects of angiotensin II in 16 otherwise healthy familial hypercholesterolaemia subjects and 16 matched controls. METHODS Markers of fibrinolysis, thrombin generation and inflammation were assessed in plasma before, during and 1h after a 3h intravenous infusion of angiotensin II. In addition, placebo experiments with saline infusion were carried out. RESULTS Baseline plasminogen activator inhibitor type-1 activity and plasmin-antiplasmin-complex concentrations were similar in FH and controls, as were interleukin-6, leukocyte counts and C-reactive protein. Fibrinogen levels were higher in FH, and we observed a greater thrombin generating potential in FH (calibrated automated thrombogram), but no signs of elevated thrombin generation in vivo (prothrombin fragment 1+2). During angiotensin infusion plasminogen activator inhibitor type-1 activity decreased and plasmin-antiplasmin-complex concentrations increased similarly in FH and controls. Total and maximal amount of thrombin generated was unchanged, as were prothrombin-fragment-1+2 levels. Interleukin-6 and leukocyte counts increased similarly in both groups during angiotensin infusion, while fibrinogen tended to increase in FH and increased in controls. During saline infusion plasminogen activator inhibitor type-1 activity and prothrombin fragment 1+2 concentrations fell, whereas other markers were unchanged. CONCLUSIONS FH exhibits an increased thrombin generation potential, an intact fibrinolysis, and has no convincing signs of inflammation. Angiotensin has proinflammatory effects, and might have minor profibrinolytic and procoagulatory effects.
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Affiliation(s)
- Mikael Ekholm
- Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden Department of Internal Medicine, Ryhov County Hospital, Jönköping, Sweden
| | - Thomas Kahan
- Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden
| | - Gun Jörneskog
- Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Internal Medicine, Stockholm, Sweden
| | - Jonas Brinck
- Department of Medicine, Karolinska University Hospital, Huddinge, Sweden
| | - N Håkan Wallén
- Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden
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Senchenkova EY, Russell J, Esmon CT, Granger DN. Roles of Coagulation and fibrinolysis in angiotensin II-enhanced microvascular thrombosis. Microcirculation 2015; 21:401-7. [PMID: 24495184 DOI: 10.1111/micc.12120] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Accepted: 01/29/2014] [Indexed: 11/28/2022]
Abstract
OBJECTIVE AngII-induced HTN is associated with accelerated thrombus development in arterioles. This study assessed the contributions of different components of the coagulation cascade and fibrinolysis to AngII-mediated microvascular thrombosis. METHODS Light/dye-induced thrombus formation (the time of onset and flow cessation) was quantified in cremaster muscle arterioles of AngII infused (two weeks) WT/AngII mice, EPCR-TgN, and mice deficient in PAI-1. WT/AngII mice were also treated with either tissue factor antibody, antithrombin III, heparin, hirudin, or murine APC. RESULTS TF immunoblockade or hirudin treatment did not prevent the AngII-induced acceleration of thrombosis. While antithrombin III treatment prevented the acceleration in both thrombus onset and flow cessation, heparin only improved the time for blood flow cessation. Neither WT mice treated with murine APC nor EPCR-TgN were protected against AngII-induced thrombus development. A similar lack of protection was noted in PAI-1deficient mice. CONCLUSION These findings implicate a role for thrombin generation pathway in the accelerated thrombosis induced by AngII and suggest that an impaired protein C pathway and increased PAI-1 do not make a significant contribution to this model of microvascular thrombosis.
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Affiliation(s)
- Elena Y Senchenkova
- Department of Molecular & Cellular Physiology, LSU Health Sciences Center, Shreveport, Louisiana, USA; Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Saint-Petersburg, Russia
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Sakhteh M, Poopak B, Amirizadeh N, Shamshiri A, Bagheri A, Faranoush M. Polymorphism and synergism of angiotensin-converting enzyme (ACE) and plasminogen activator inhibitor-1 (PAI-1) genes in coronary artery disease. J Renin Angiotensin Aldosterone Syst 2014; 16:1168-74. [PMID: 25501306 DOI: 10.1177/1470320314561247] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Accepted: 09/20/2014] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Among the genetic factors for coronary artery diseases, PAI-1 4G/5G and ACE I/D polymorphisms can be noted. This study was carried out to investigate the association of these two polymorphisms and their synergism in coronary artery disease (CAD) from a sample of the Iranian population. MATERIALS AND METHODS Sixty-one patients with a history of CAD and 92 healthy controls participated in our study. After DNA extraction from leukocytes, PCR was performed to characterize PAI-1 4G/5G and ACE I/D polymorphisms, using an amplification refractory mutation system technique. RESULTS In the studied patients, PAI-1 polymorphisms were 24.6%, 45.9%, and 29.5% for 4G/4G, 4G/5G and 5G/5G, respectively; the values for controls were 20.7%, 42.2% and 37.0%. The distribution rates of genotypes I/I, I/D and D/D in patients accounted for 29.5%, 45.9% and 24.6%; in the control group these figures were estimated to be 40.2%, 40.2% and 19.6%. CONCLUSION Single and multivariate analyses showed a significant difference for the conventional risk factors, including hypertension, diabetes, hyperlipidemia, smoking and family history, for CAD between patients and controls (p value ≤ 0.001). However, no significant correlation was demonstrated considering ACE and PAI-1 polymorphisms either in association with 4G/4G or D/D genotypes or a combination of them in the Iranian population in the current study.
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Affiliation(s)
- Maryam Sakhteh
- High Institute of Iranian Blood Transfusion Organization Research Center, Tehran, Iran
| | | | - Naser Amirizadeh
- High Institute of Iranian Blood Transfusion Organization Research Center, Tehran, Iran
| | - Ahmadreza Shamshiri
- Thrombosis and Hemostasis Research Center,Imam Khomeini Hospital Complex,Tehran University of Medical Sciences, Iran
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Zhang X, Wu M, Jiang H, Hao J, Zhang Q, Zhu Q, Saren G, Zhang Y, Meng X, Yue X. Angiotensin II upregulates endothelial lipase expression via the NF-kappa B and MAPK signaling pathways. PLoS One 2014; 9:e107634. [PMID: 25250890 PMCID: PMC4175466 DOI: 10.1371/journal.pone.0107634] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 08/18/2014] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Angiotensin II (AngII) participates in endothelial damage and inflammation, and accelerates atherosclerosis. Endothelial lipase (EL) is involved in the metabolism and clearance of high density lipoproteins (HDL), the serum levels of which correlate negatively with the onset of cardiovascular diseases including atherosclerosis. However, the relationship between AngII and EL is not yet fully understood. In this study, we investigated the effects of AngII on the expression of EL and the signaling pathways that mediate its effects in human umbilical vein endothelial cells (HUVECs). METHODS AND FINDINGS HUVECs were cultured in vitro with different treatments as follows: 1) The control group without any treatment; 2) AngII treatment for 0 h, 4 h, 8 h, 12 h and 24 h; 3) NF-κB activation inhibitor pyrrolidine dithiocarbamate (PDTC) pretreatment for 1 h before AngII treatment; and 4) mitogen-activated protein kinase (MAPK) p38 inhibitor (SB203580) pretreatment for 1 h before AngII treatment. EL levels in each group were detected by immunocytochemical staining and western blotting. HUVECs proliferation was detected by MTT and proliferating cell nuclear antigen (PCNA) immunofluorescence staining. NF-kappa B (NF-κB) p65, MAPK p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and phosphorylated extracellular signal-regulated kinase (p-ERK) expression levels were assayed by western blotting. The results showed that the protein levels of EL, NF-κB p65, MAPK p38, JNK, and p-ERK protein levels, in addition to the proliferation of HUVECs, were increased by AngII. Both the NF-kB inhibitor (PDTC) and the MAPK p38 inhibitor (SB203580) partially inhibited the effects of AngII on EL expression. CONCLUSION AngII may upregulate EL protein expression via the NF-κB and MAPK signaling pathways.
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Affiliation(s)
- Xiaoli Zhang
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital, Jinan, China
| | - Minghui Wu
- Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Medicine, Shandong University, Jinan, China
| | - Hong Jiang
- Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Medicine, Shandong University, Jinan, China
| | - Jing Hao
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital, Jinan, China
| | - Qingli Zhang
- Department of Morphology Laboratory, School of Medicine, Shandong University, Jinan, China
| | - Qing Zhu
- Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Medicine, Shandong University, Jinan, China
| | - Gaowa Saren
- Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Medicine, Shandong University, Jinan, China
| | - Yun Zhang
- Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Medicine, Shandong University, Jinan, China
| | - Xiaohui Meng
- Institute of Diagnostics, School of Medicine, Shandong University, Jinan, China
| | - Xin Yue
- Key Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Medicine, Shandong University, Jinan, China
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Kim JJ, Choi YM, Lee SK, Yang KM, Paik EC, Jeong HJ, Jun JK, Han AR, Hong MA. The PAI-1 4G/5G and ACE I/D polymorphisms and risk of recurrent pregnancy loss: a case-control study. Am J Reprod Immunol 2014; 72:571-6. [PMID: 25078885 DOI: 10.1111/aji.12302] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 07/13/2014] [Indexed: 11/28/2022] Open
Abstract
PROBLEM Thrombophilia has been postulated to be a contributor to the pathophysiology of recurrent pregnancy loss (RPL). We investigated the role of the plasminogen activator inhibitor type 1 (PAI-1) 4G/5G and angiotensin converting enzyme (ACE) I/D polymorphisms in Korean patients with RPL. METHOD OF STUDY Genotyping was performed using the TaqMan assay in 227 RPL patients and 304 controls. RESULTS The genotype distributions of both polymorphisms in the RPL group did not differ from those of controls. Because the frequency of being homozygous for ACE D/D and the PAI-I 4G/4G combination has been reported to be significantly higher in RPL patients, this was also analyzed. However, no significant difference was noted; 3.1% of RPL patients had both ACE D/D and PAI-I 4G/4G, as did 4.9% of controls (P = 0.791). CONCLUSION The current study suggests that both polymorphisms, either alone or in combination, are not major determinants of the development of RPL in Korean women.
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Affiliation(s)
- Jin Ju Kim
- Department of Obstetrics and Gynecology, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea; The Institute of Reproductive Medicine and Population, Medical Research Centre, Seoul National University College of Medicine, Seoul, Korea
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Doesch C, Süselbeck T, Haghi D, Streitner F, Schoenberg SO, Borggrefe M, Papavassiliu T. The relationship between the severity of coronary artery disease and epicardial adipose tissue depends on the left ventricular function. PLoS One 2012; 7:e48330. [PMID: 23133630 PMCID: PMC3487764 DOI: 10.1371/journal.pone.0048330] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2012] [Accepted: 09/24/2012] [Indexed: 11/23/2022] Open
Abstract
Background Epicardial adipose tissue (EAT) is an active metabolic and endocrine organ. Previous studies focusing mainly on patients with preserved left ventricular function (LVF) could show a correlation between increased amounts of EAT and the extent and activity of coronary artery disease (CAD). However, to date, there are no data available about the relationship between EAT and the severity of CAD with respect to the whole spectrum of LVF impairment. Therefore, we evaluated this relationship in patients with CAD. Methods 250 patients with CAD and 50 healthy controls underwent CMR examination to assess EAT. The severity of CAD was defined using the angiographic Gensini score (GSS). Results The GSS ranged from 2–364. Linear regression analysis revealed a significant correlation between EAT and GSS (r = 0.177, p = 0.01). Patients with mild (GSS≤10) and moderate CAD (GSS>10−≤40) showed comparable EAT to healthy controls. However, in patients with severe CAD (GSS>40) EAT was significantly reduced (p<0.0001) compared to healthy controls. Interestingly, patients with the same GSS revealed different EAT depending on the left ventricular function (LVF). Patients with preserved LVF (LVF≥50%) showed more EAT mass compared to those with reduced LVF (LVF<50%) regardless of the GSS. In patients with preserved LVF and mild CAD, EAT was comparable to healthy controls (61.8±19.4 g vs. 62.9±14.4 g, p = 0.8). In patients with moderate CAD, EAT rose significantly to 83.1±24.9 g (p = 0.01) and started to decline to 66.4±23.6 g in patients with severe CAD (p = 0.03). Contrary, in CAD patients with reduced LVF, EAT was already significantly reduced in patients with mild CAD as compared to healthy controls (p = 0.001) and showed a stepwise decline with increasing CAD severity. Conclusion The relationship between EAT and the severity of CAD depends on LVF. These findings emphasize the multifactorial interaction between EAT and the severity of CAD.
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Affiliation(s)
- Christina Doesch
- Department of Medicine, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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Brown NJ, Vaughan DE. The Renin-Angiotensin and fibrinolytic systems co-conspirators in the pathogenesis of ischemic cardiovascular disease. Trends Cardiovasc Med 2012; 6:239-43. [PMID: 21232303 DOI: 10.1016/s1050-1738(96)00091-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
In vitro and in vivo data provide evidence for an interaction between the renin-angiotensin and fibrinolytic systems. Angiotensin-converting enzyme (ACE) is strategically poised to regulate this interaction. ACE catalyzes the conversion of angiotensin I to angiotensin II (Ang), and Ang II stimulates release of PAI-1, the major inhibitor of tissue-type plasminogen activator (t-PA) and urokinase in the vasculature. Conversely, ACE catalyzes the breakdown of bradykinin, a potent stimulus of t-PA secretion. This interaction between the renin-angiotensin and fibrinolytic systems may partially explain the clinical observation that stimulation or suppression of the renin-angiotensin system can alter the risk of ischemic cardiovascular events. © 1996, Elsevier Science Inc. (Trends Cardiovasc Med 1996;6:239-243).
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Affiliation(s)
- N J Brown
- Clinical Pharmacology Division, Departments of Medicine and Pharmacology, Vanderbilt University Medical Center,Nashville, TN 37232-1720,USA
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Zhang Z, Xu G, Liu D, Fan X, Zhu W, Liu X. Angiotensin-converting enzyme insertion/deletion polymorphism contributes to ischemic stroke risk: a meta-analysis of 50 case-control studies. PLoS One 2012; 7:e46495. [PMID: 23049705 PMCID: PMC3462189 DOI: 10.1371/journal.pone.0046495] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Accepted: 09/05/2012] [Indexed: 01/06/2023] Open
Abstract
Background Many studies have investigated the association between the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and risk of ischemic stroke. However, the evidence is inadequate to draw robust conclusions because most studies were generally small and conducted in heterogeneous populations. To shed light on these inconclusive findings, we conducted a large meta-analysis of studies relating the ACE I/D polymorphism to the risk of ischemic stroke. Methods Relevant studies were identified by searching PubMed and Embase through February 2012 and by reviewing the references of retrieved articles. We included studies that reported odds ratio (OR) with 95% confidence interval (CI) for the association between this polymorphism and ischemic stroke risk. Results Fifty independent publications, with 10 070 stroke cases and 22 103 controls, were included. The results indicated that the DD homozygote carriers had a 37% higher risk of ischemic stroke when compared with the homozygotes II and heterozygote ID [odds ratio (OR) = 1.37, 95% confidence interval (CI): 1.22–1.53]. Subgroup analyses indicated that this higher risk was more pronounced among Asians, hospital-based studies, and small vessel disease (SVD). Potential publication bias may exist, but correction for this bias using a formal statistical method did not materially alter the combined risk estimate. Conclusion The results of our meta-analysis indicate that the D allele of ACE I/D polymorphism is a low-penetrance susceptibility marker of ischemic stroke.
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Affiliation(s)
- Zhizhong Zhang
- Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Jiangsu Province, China
| | - Gelin Xu
- Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Jiangsu Province, China
| | - Dezhi Liu
- Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Jiangsu Province, China
| | - Xinying Fan
- Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Jiangsu Province, China
| | - Wusheng Zhu
- Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Jiangsu Province, China
| | - Xinfeng Liu
- Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Jiangsu Province, China
- * E-mail:
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Billings FT, Balaguer JM, C Y, Wright P, Petracek MR, Byrne JG, Brown NJ, Pretorius M. Comparative effects of angiotensin receptor blockade and ACE inhibition on the fibrinolytic and inflammatory responses to cardiopulmonary bypass. Clin Pharmacol Ther 2012; 91:1065-73. [PMID: 22549281 PMCID: PMC3822756 DOI: 10.1038/clpt.2011.356] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor blockade (ARB) on fibrinolysis and inflammation following cardiopulmonary bypass (CPB) are uncertain. This study tested the hypothesis that ACE inhibition enhances fibrinolysis and inflammation to greater extent than ARB in patients undergoing CPB.One week to five days prior to surgery, patients were randomized to ramipril 5mg/day,candesartan 16mg/day or placebo.ACE inhibition increased intraoperative bradykinin and tissue-type plasminogen activator (t-PA) concentrations compared to ARB. Both ACE inhibition and ARB decreased plasma transfusion compared to placebo, but only ACE inhibition decreased length of stay. Neither ACE inhibition nor ARB significantly affectedplasminogen activator inhibitor-1 (PAI-1), interleukin (IL)-6, IL-8, or IL-10 concentrations. ACE inhibition enhanced intraoperative fibrinolysis without increasing red cell transfusion risk. In contrast, neither ACE inhibition nor ARB affected the inflammatory response. ACE inhibitors and ARB may be safely continued until the day of surgery.
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Affiliation(s)
- F T Billings
- Department of Anesthesiology, Vanderbilt University Medical School, Nashville, Tennessee, USA
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Angiotensin-converting enzyme inhibition alters the inflammatory and fibrinolytic response to cardiopulmonary bypass in children. Pediatr Crit Care Med 2011; 12:532-8. [PMID: 20975611 PMCID: PMC3690292 DOI: 10.1097/pcc.0b013e3181fe3925] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
OBJECTIVE Many children with a congenital heart defect undergo surgical correction requiring cardiopulmonary bypass. One-sixth of these patients take an angiotensin-converting enzyme inhibitor for heart failure treatment. The effect of angiotensin-converting enzyme inhibition on the fibrinolytic and inflammatory response in children undergoing cardiopulmonary bypass is unknown. In adults, angiotensin-converting enzyme inhibition attenuates the increase in plasminogen activator inhibitor-1 after cardiopulmonary bypass, whereas the effect on the interleukin-6 response is uncertain. This study tests the hypothesis that preoperative angiotensin-converting enzyme inhibition attenuates postoperative plasminogen activator inhibitor-1 and interleukin-6 expression after cardiopulmonary bypass in children. DESIGN Single-center prospective, randomized, nonblinded study. SETTING University-affiliated pediatric hospital. PATIENTS Children undergoing elective surgical correction of a congenital heart defect requiring cardiopulmonary bypass and taking an angiotensin-converting enzyme inhibitor. INTERVENTIONS Children were randomized to continue angiotensin-converting enzyme inhibitor until the morning of surgery (angiotensin-converting enzyme inhibitor group, n = 11) or to discontinue therapy 72 hrs before surgery (no angiotensin-converting enzyme inhibitor group, n = 9). MEASUREMENT AND MAIN RESULTS Blood samples were collected at baseline before cardiopulmonary bypass, at 30 mins of cardiopulmonary bypass, on arrival to the intensive care unit, and on postoperative day 1. Baseline bradykinin concentrations were significantly higher and angiotensin-converting enzyme activity significantly lower in the angiotensin-converting enzyme inhibitor group compared with the no angiotensin-converting enzyme inhibitor group (p = .04 and .001, respectively). Plasminogen activator inhibitor-1 antigen increased 15-fold after cardiopulmonary bypass and peaked on postoperative day 1 (from 4.6 ± 1.2 to 67.7 ± 9.5 ng/mL; p < .001). Postoperative day 1 plasminogen activator inhibitor-1 antigen correlated significantly with cardiopulmonary bypass time (r2 = 0.40, p = .03) and was significantly lower in the angiotensin-converting enzyme inhibitor group compared with the no angiotensin-converting enzyme inhibitor group (p = .03). The proinflammatory markers interleukin-6 and interleukin-8 as well as the anti-inflammatory marker interleukin-10 increased significantly after cardiopulmonary bypass (all p < .001). Interleukin-6 concentrations were significantly higher in the angiotensin-converting enzyme inhibitor group after cardiopulmonary bypass (p = .02) even after controlling for potential confounding factors such as age, cardiopulmonary bypass time, and transfusion volume. CONCLUSION Angiotensin-converting enzyme inhibition attenuates the increase in postoperative plasminogen activator inhibitor-1 but enhances the interleukin-6 response in children undergoing cardiopulmonary bypass.
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Fogari R, Zoppi A, Mugellini A, Maffioli P, Lazzari P, Derosa G. Role of angiotensin II in plasma PAI-1 changes induced by imidapril or candesartan in hypertensive patients with metabolic syndrome. Hypertens Res 2011; 34:1321-6. [PMID: 21814211 DOI: 10.1038/hr.2011.137] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
To evaluate the relationship between plasma plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) changes during treatment with imidapril and candesartan in hypertensive patients with metabolic syndrome. A total of 84 hypertensive patients with metabolic syndrome were randomized to imidapril 10 mg or candesartan 16 mg for 16 weeks. At weeks 4 and 8, there was a dose titration to imidapril 20 mg and candesartan 32 mg in nonresponders (systolic blood pressure (SBP) >140 and/or diastolic blood pressure (DBP) >90 mm Hg). We evaluated, at baseline and after 2, 4, 8, 12 and 16 weeks, clinic blood pressure, Ang II and PAI-1 antigen. Both imidapril and candesartan induced a similar SBP/DBP reduction (-19.4/16.8 and -19.5/16.3 mm Hg, respectively, P<0.001 vs. baseline). Both drugs decreased PAI-1 antigen after 4 weeks of treatment, but only the PAI-1 lowering effect of imidapril was sustained throughout the 16 weeks (-9.3 ng ml(-1), P<0.01 vs. baseline), whereas candesartan increased PAI-1 (+6.5 ng ml(-1), P<0.05 vs. baseline and P<0.01 vs. imidapril). Imidapril significantly decreased Ang II levels (-14.6 pg ml(-1) at week 16, P<0.05 vs. baseline), whereas candesartan increased them (+24.2 pg ml(-1), P<0.01 vs. baseline and vs. imidapril). In both groups there was a positive correlation between Ang II and PAI-1 changes (r=0.61, P<0.001 at week 16 for imidapril, and r=0.37, P<0.005 at week 16 for candesartan). Imidapril reduced plasma PAI-1 and Ang II levels, whereas candesartan increased them. This suggests that the different effect of angiotensin-converting enzyme inhibitors and Ang II blockers on Ang II production has a role in their different influence on fibrinolysis.
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Affiliation(s)
- Roberto Fogari
- Department of Internal Medicine and Therapeutics, Centro Ipertensione e Fisiopatologia Cardiovascolare, University of Pavia, Pavia, Italy.
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The Angiotensin Receptor Blocker, Azilsartan Medoxomil (TAK-491), Suppresses Vascular Wall Expression of Plasminogen Activator Inhibitor Type-I Protein Potentially Facilitating the Stabilization of Atherosclerotic Plaques. J Cardiovasc Pharmacol 2011; 58:143-8. [DOI: 10.1097/fjc.0b013e31821dcbea] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Penrod NM, Poku KA, Vaughn DE, Asselbergs FW, Brown NJ, Moore JH, Williams SM. Epistatic interactions in genetic regulation of t-PA and PAI-1 levels in a Ghanaian population. PLoS One 2011; 6:e16639. [PMID: 21304999 PMCID: PMC3031598 DOI: 10.1371/journal.pone.0016639] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Accepted: 01/06/2011] [Indexed: 11/19/2022] Open
Abstract
The proteins, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1), act in concert to balance thrombus formation and degradation, thereby modulating the development of arterial thrombosis and excessive bleeding. PAI-1 is upregulated by the renin-angiotensin system (RAS), specifically by angiotensin II, the product of angiotensin converting enzyme (ACE) cleavage of angiotensin I, which is produced by the cleavage of angiotensinogen (AGT) by renin (REN). ACE indirectly stimulates the release of t-PA which, in turn, activates the corresponding fibrinolytic system. Single polymorphisms in these pathways have been shown to significantly impact plasma levels of t-PA and PAI-1 differently in Ghanaian males and females. Here we explore the involvement of epistatic interactions between the same polymorphisms in central genes of the RAS and fibrinolytic systems on plasma t-PA and PAI-1 levels within the same population (n = 992). Statistical modeling of pairwise interactions was done using two-way ANOVA between polymorphisms in the ETNK2, RENIN, ACE, PAI-1, t-PA, and AGT genes. The most significant interactions that associated with t-PA levels were between the ETNK2 A6135G and the REN T9435C polymorphisms in females (p = 0.006) and the REN T9435C and the TPA I/D polymorphisms (p = 0.005) in males. The most significant interactions for PAI-1 levels were with REN T9435C and the TPA I/D polymorphisms (p = 0.001) in females, and the association of REN G6567T with the TPA I/D polymorphisms (p = 0.032) in males. Our results provide evidence for multiple genetic effects that may not be detected using single SNP analysis. Because t-PA and PAI-1 have been implicated in cardiovascular disease these results support the idea that the genetic architecture of cardiovascular disease is complex. Therefore, it is necessary to consider the relationship between interacting polymorphisms of pathway specific genes that predict t-PA and PAI-1 levels.
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Affiliation(s)
- Nadia M. Penrod
- Department of Genetics, Dartmouth Medical School, Lebanon, New Hampshire, United States of America
| | - Kwabena A. Poku
- Human Services Management and Public Administration, Business School, University of Ghana, Legon, Ghana
| | - Douglas E. Vaughn
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical School, Nashville, Tennessee, United States of America
| | - Folkert W. Asselbergs
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Nancy J. Brown
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical School, Nashville, Tennessee, United States of America
| | - Jason H. Moore
- Department of Genetics, Dartmouth Medical School, Lebanon, New Hampshire, United States of America
- Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, New Hampshire, United States of America
| | - Scott M. Williams
- Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America
- * E-mail:
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Fogari R, Zoppi A, Salvadeo SAT, Mugellini A, Lazzari P, Santoro T, Derosa G. Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension. Hypertens Res 2010; 34:509-15. [DOI: 10.1038/hr.2010.260] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Bentley JP, Asselbergs FW, Coffey CS, Hebert PR, Moore JH, Hillege HL, van Gilst WH. Cardiovascular risk associated with interactions among polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems. PLoS One 2010; 5:e12757. [PMID: 20856803 PMCID: PMC2939877 DOI: 10.1371/journal.pone.0012757] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2010] [Accepted: 08/24/2010] [Indexed: 11/19/2022] Open
Abstract
Background Vascular fibrinolytic balance is maintained primarily by interplay of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1). Previous research has shown that polymorphisms in genes from the renin-angiotensin (RA), bradykinin, and fibrinolytic systems affect plasma concentrations of both t-PA and PAI-1 through a set of gene-gene interactions. In the present study, we extend this finding by exploring the effects of polymorphisms in genes from these systems on incident cardiovascular disease, explicitly examining two-way interactions in a large population-based study. Methodology/Principal Findings Data from the population-based PREVEND study in Groningen, The Netherlands (n = 8,138) were analyzed. The effects of the polymorphisms and their interactions on cardiovascular events were analyzed via Cox proportional hazards models. There was no association between five of the six polymorphisms singly and risk of cardiovascular disease. There was a significant main effect for the ACE I/D polymorphism for both dominant and additive coding schemes. There were significant interactions between the following polymorphism pairs even after adjustment for known risk factors: ACE I/D & PAI-1 4G/5G (p = 0.012), BDKRB2 C181T & ACE I/D (p = 0.016), BDKRB2 C58T & ACE I/D (p = 0.025), BDKRB2 exon 1 I/D & AT1R A1166C (p = 0.017), and BDKRB2 C58T & AT1R A1166C (p = 0.015). Conclusions/Significance This study suggests possible interactions between genes from the RA, bradykinin, and fibrinolytic systems on the risk of cardiovascular disease, extending previous research that has demonstrated that interactions among genes from these systems influence plasma concentrations of both t-PA and PAI-1. Further explorations of these interactions are needed.
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Affiliation(s)
- John P. Bentley
- Department of Pharmacy Administration, School of Pharmacy, University of Mississippi, University, Mississippi, United States of America
| | - Folkert W. Asselbergs
- Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- * E-mail:
| | - Christopher S. Coffey
- Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa, United States of America
| | - Patricia R. Hebert
- Charles E. Schmidt College of Biomedical Science, Florida Atlantic University, Boca Raton, Florida, United States of America
| | - Jason H. Moore
- Departments of Genetics and Community and Family Medicine, Dartmouth Medical School, Lebanon, New Hampshire, United States of America
| | - Hans L. Hillege
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Wiek H. van Gilst
- Department of Experimental Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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TIRYAKI OZLEM, USALAN CELALETTIN, BUYUKHATIPOGLU HAKAN. Effect of combined angiotensin-converting enzyme and aldosterone inhibition on plasma plasminogen activator inhibitor type 1 levels in chronic hypertensive patients. Nephrology (Carlton) 2010; 15:211-5. [DOI: 10.1111/j.1440-1797.2009.01181.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Tiryaki O, Buyukhatipoglu H, Usalan C. Plasma plasminogen activator inhibitor 1 (PAI-1) and P-selectin levels in urgent hypertension: effect of single dose captopril and nifedipine on fibrinolytic activity. Clin Exp Hypertens 2010; 32:347-51. [PMID: 21028997 DOI: 10.3109/10641961003628478] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
In this study, we primarily aimed to identify the acute effects of hypertension on fibrinolytic function in previously untreated urgent hypertensive patients and to evaluate the influence of two commonly used, short-acting, anti-hypertensive agents, captopril and nifedipine, in these patients. Patient groups were selected homogeneously, i.e., only previously untreated patients amidst an urgent hypertensive episode and having no co-morbid disease were included-and randomly assigned to receive either captopril or nifedipine for immediate management. These two treatment groups were matched for age, gender, and mean arterial blood pressure. Study results demonstrated that lowering blood pressure with either agent improved fibrinolytic function; however, in those patients given captopril, this beneficial effect was more prominent, providing evidence supporting the preferential use of short-acting, angiotensin-converting enzyme (ACE) inhibitors in this setting.
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Affiliation(s)
- Ozlem Tiryaki
- Gaziantep University School of Medicine, Department of Nephrology, Gaziantep, Turkey
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Lack of change in insulin levels as a biological marker of PAI-1 lowering in GH-deficient adults on r-HGH replacement therapy. Thromb Res 2009; 124:711-3. [DOI: 10.1016/j.thromres.2009.06.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2008] [Revised: 05/29/2009] [Accepted: 06/03/2009] [Indexed: 11/23/2022]
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Hanif K, Bid HK, Konwar R. Reinventing the ACE inhibitors: some old and new implications of ACE inhibition. Hypertens Res 2009; 33:11-21. [PMID: 19911001 DOI: 10.1038/hr.2009.184] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Since their inception, angiotensin-converting enzyme (ACE) inhibitors have been used as first-line therapy for the treatment of cardiovascular and renal diseases. They restore the balance between the vasoconstrictive salt-retentive and hypertrophy-causing peptide angiotensin II (Ang II) and bradykinin, a vasodilatory and natriuretic peptide. As ACE is a promiscuous enzyme, ACE inhibitors alter the metabolism of a number of other vasoactive substances. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have been proven effective in the treatment of hypertension, and reduce mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction. They inhibit ischemic events and stabilize plaques. Furthermore, they delay the progression of diabetic nephropathy and neuropathy and act as antioxidants. Ongoing studies have elucidated protective roles for them in both memory-related disorders and cancer. Lastly, N- and C-domain selective ACE inhibitors have led to new uses for ACE inhibitors.
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Affiliation(s)
- Kashif Hanif
- Division of Pharmacology, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh, India.
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Pratte KA, Barón AE, Ogden LG, Hassell KL, Rewers M, Hokanson JE. Plasminogen activator inhibitor-1 is associated with coronary artery calcium in Type 1 diabetes. J Diabetes Complications 2009; 23:387-93. [PMID: 18768333 DOI: 10.1016/j.jdiacomp.2008.07.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2008] [Revised: 06/27/2008] [Accepted: 07/12/2008] [Indexed: 11/22/2022]
Abstract
BACKGROUND Elevated levels of plasminogen activator inhibitor-1 (PAI-1), the major inhibitor of fibrinolysis, is associated with coronary artery disease (CAD). This association may not be independent of factors related to insulin resistance (IR). Patients with Type 1 diabetes mellitus have increased CAD and an increase in sub-clinical CAD which develops earlier in life. It is not known if PAI-1 is associated with sub-clinical CAD in Type 1 diabetes or if this association is independent of IR. METHODS AND RESULTS Type 1 diabetes patients (n=560) and participants without diabetes (n=693) were assessed for coronary artery calcium (CAC), a surrogate for subclinical CAD, by electron-beam computed tomography. PAI-1 was associated with CAC in both Type 1 diabetes (OR=1.32, 95% CI=1.12-1.58) and non-diabetes (OR=1.34, 95% CI=1.13-1.58), after controlling for traditional risk factors not associated with IR. In Type 1 diabetes, the relationship between PAI-1 and CAC was strongest for younger participants (P=.02 for PAI-1-by-age interaction) after controlling for factors related to IR. PAI-1 was positively associated with CAC for Type 1 diabetes participants younger than 45 years of age. CONCLUSION PAI-1 levels are independently related to CAC in younger Type 1 diabetes participants. PAI-1 levels were not independently related to CAC in non-diabetes participants.
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Affiliation(s)
- Katherine A Pratte
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Denver, CO 80262, USA
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Boman K, Boman JH, Andersson J, Olofsson M, Dahlöf B. Effects of atenolol or losartan on fibrinolysis and von Willebrand factor in hypertensive patients with left ventricular hypertrophy. Clin Appl Thromb Hemost 2009; 16:146-52. [PMID: 19825910 DOI: 10.1177/1076029609349501] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVES To compare the effects of the beta-blocker atenolol with the angiotensin receptor blocker (ARB) losartan on plasma tissue-type plasminogen activator (tPA) activity and mass concentration, plasminogen activator inhibitor-1 (PAI-1) activity, tPA/PAI-1 complex, and von Willebrand factor (VWF). DESIGN A prespecified, explorative substudy in 22 patients with hypertension and left ventricular hypertrophy (LVH) performed within randomized multicenter, double-blind prospective study. RESULTS After a median of 36 weeks of treatment, there were significant differences between the treatment groups, atenolol versus losartan, in plasma median levels of tPA mass (11.9 vs 7.3 ng/mL, P = .019), PAI-1 activity (20.7 vs 4.8 IU/mL, P = .030), and tPA/PAI-1 complex (7.1 vs 2.5 ng/mL, P = .015). In patients treated with atenolol, median levels of tPA mass (8.9-11.9 ng/mL, P = .021) and VWF (113.5%-134.3%, P = .021) increased significantly, indicating a change toward a more prothrombotic state. No significant changes occurred in the losartan group. CONCLUSION Losartan treatment was associated with preserved fibrinolytic balance compared to a more prothrombotic fibrinolytic and hemostatic state in the atenolol group. These findings suggest different fibrinolytic and hemostatic responses to treatment in hypertensive patients with LVH.
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Affiliation(s)
- Kurt Boman
- University Umeå and Department of Medicine-Geriatric, Skellefteå County Hospital, Umeå, Sweden.
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Goodman C, Hur J, Goodman CS, Jeyendran RS, Coulam C. Are polymorphisms in the ACE and PAI-1 genes associated with recurrent spontaneous miscarriages? Am J Reprod Immunol 2009; 62:365-70. [PMID: 19821806 DOI: 10.1111/j.1600-0897.2009.00744.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
PROBLEM To determine whether the ACE D/D genotype or the combination of PAI-1 4G/4G and ACE D/D genotypes may serve as a risk factor for recurrent pregnancy loss. METHOD OF STUDY Buccal swabs were obtained from 120 women experiencing recurrent pregnancy loss and from 84 fertile control women. DNA was extracted from the buccal swab samples using the Qiagen DNA Mini Kit (Qiagen), followed by multiplex polymerase chain reaction (PCR). PCR products were analyzed for the ACE gene polymorphism, which consists of the insertion or deletion (I/D) of a 287-bp fragment in intron 16, and the PAI-1 4G/4G genotype. RESULTS No significant differences in specific ACE gene mutations were observed when patients experiencing recurrent miscarriage were compared with control women. When the frequencies of homozygous mutations for ACE D/D and PAI-I 4G/4G were compared between recurrent aborters and controls, again no significant differences in the prevalence of the combination of these gene mutations were noted. CONCLUSION Homozygosity for the D allele of the ACE gene and the combination of the D/D genotype with two 4G alleles of the PAI-1 promoter gene are not associated with a significant increase in the risk of recurrent miscarriage.
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Simoni J, Simoni G, Moeller JF, Tsikouris JP, Wesson DE. Evaluation of Angiotensin Converting Enzyme (ACE)-Like Activity of Acellular Hemoglobin. ACTA ACUST UNITED AC 2009; 35:191-210. [PMID: 17453704 DOI: 10.1080/10731190601188273] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Despite the tremendous progress in research on hemoglobin (Hb) cellular and molecular responses, the current understanding of Hb's overall intrinsic toxicity is still limited. The complete mechanism of Hb-induced vasoconstriction has not yet been established, particularly the involvement of the renin-angiotensin system (RAS). Some studies emphasized that Hb may augment the vascular responsiveness to angiotensin (Ang)-II. It was also reported that Hb, as well as Ang-II, influences the synthesis of 8-iso prostaglandin F2 alpha, which has an impact on renal flow and possibly RAS. Hb in the presence of H(2)O(2) gains enzymatic activity. Thus, it is possible that Hb directly and/or indirectly can activate RAS. In this study, we monitored the effect of ferrous- and ferryl-Hb, and H(2)O(2) alone, on conversion of Ang-I to its active metabolites. The structural and immunological identity of the resulting products were evaluated by reversed phase C-18 HPLC and ELISA, respectively. Additionally, ACE-like activity of Hbs was measured spectrophotometrically by determining their ability to react with the ACE substrate, the synthetic tripeptide N-[3-(2-furyl)acryloyl]-L-phenylalanylglycylglycine. Results indicate that while ferrous-Hb can serve as a receptor for Ang-I, its ferryl form possesses ACE-like activity, being able to convert, within minutes, Ang-I to Ang-II, Ang-III, Ang-IV, Ang (1-7) and other unresolved fragments. H(2)O(2) itself had a very limited hydrolyzing effect on Ang-I. Based on this study, it can be concluded that ACE-like activity of Hb with rapid formation of active angiotensins may be a contributor to the still unexplained vasoconstrictive response observed immediately after Hb administration.
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Affiliation(s)
- Jan Simoni
- Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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Waeber B. Position of fixed‐dose combinations containing an AT1‐receptor blocker and a thiazide diuretic. Blood Press 2009; 14:324-36. [PMID: 16403686 DOI: 10.1080/08037050500390534] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Treatment of hypertension remains a difficult task despite the availability of different types of medications lowering blood pressure by different mechanisms. In order to reach the target blood pressures recommended today combination therapy is required in most patients. The co-administration of two drugs with different impacts on the cardiovascular system markedly increases the antihypertensive effectiveness without altering adversely tolerability. Fixed low-dose combinations are becoming a valuable option not only as second-line, but also as first-line therapy. In this respect the co-administration of thiazide diuretic with an AT(1)-receptor blocker is particularly appealing. The diuretic-induced decrease in total body sodium activates the renin-angiotensin system, thus rendering blood pressure maintenance angiotensin II-dependent. During blockade of the renin-angiotensin system low doses of thiazides generally suffice, allowing the prevention of undesirable metabolic effects. Also, blockade of the AT(1)-receptor, particularly when angiotensin II production is enhanced in response to diuretic therapy, is expected to be beneficial, since angiotensin II seems to contribute importantly to the pathogenesis of cardiovascular and renal complications of hypertension.
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Affiliation(s)
- B Waeber
- Division of Clinical Pathophysiology, Department of Medicine, University Hospital, Lausanne, Switzerland.
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