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Ribeiro Vitorino T, Ferraz do Prado A, Bruno de Assis Cau S, Rizzi E. MMP-2 and its implications on cardiac function and structure: Interplay with inflammation in hypertension. Biochem Pharmacol 2023; 215:115684. [PMID: 37459959 DOI: 10.1016/j.bcp.2023.115684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 07/12/2023] [Accepted: 07/13/2023] [Indexed: 08/01/2023]
Abstract
Hypertension is one of the leading risk factors for the development of heart failure. Despite being a multifactorial disease, in recent years, preclinical and clinical studies suggest strong evidence of the pivotal role of inflammatory cells and cytokines in the remodeling process and cardiac dysfunction. During the heart remodeling, activation of extracellular matrix metalloproteinases (MMPs) occurs, with MMP-2 being one of the main proteases secreted by cardiomyocytes, fibroblasts, endothelial and inflammatory cells in cardiac tissue. In this review, we will address the process of cardiac remodeling and injury induced by the increase in MMP-2 and the main signaling pathways involving cytokines and inflammatory cells in the process of transcriptional, secretion and activation of MMP-2. In addition, an interaction and coordinated action between MMP-2 and inflammation are explored and significant in maintaining the cardiac cycle. These observations suggest that new therapeutic opportunities targeting MMP-2 could be used to reduce inflammatory biomarkers and reduce cardiac damage in hypertension.
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Affiliation(s)
- Thaís Ribeiro Vitorino
- Unit of Biotechnology, University of Ribeirao Preto, UNAERP, Brazil; Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, UNICAMP, Brazil
| | - Alejandro Ferraz do Prado
- Cardiovascular System Pharmacology and Toxicology, Institute of Biological Sciences, Federal University of Para, UFPA, Brazil
| | - Stefany Bruno de Assis Cau
- Department of Pharmacology, Institute of Biological Science, Federal University of Minas Gerais, UFMG, Brazil.
| | - Elen Rizzi
- Unit of Biotechnology, University of Ribeirao Preto, UNAERP, Brazil.
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2
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Mulorz J, Ibing W, Cappallo M, Braß SM, Takeuchi K, Raaz U, Schellinger IN, Krott KJ, Schelzig H, Aubin H, Oberhuber A, Elvers M, Wagenhäuser MU. Ethanol Enhances Endothelial Rigidity by Targeting VE-Cadherin-Implications for Acute Aortic Dissection. J Clin Med 2023; 12:4967. [PMID: 37568369 PMCID: PMC10420172 DOI: 10.3390/jcm12154967] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
(1) Background: Acute aortic dissection (AAD) is caused by an endothelial entry tear followed by intimomedial delamination of the outer layers of the vessel wall. The established risk factors include hypertension and smoking. Another rising candidate risk factor is excessive alcohol consumption. This experimental study explores the effects of nicotine (Nic), angiotensin II (Ang II), and ethanol (EtOH) on human aortic endothelial cells (hAoEC). (2) Methods: HAoECs were exposed to Nic, Ang II, and EtOH at different dose levels. Cell migration was studied using the scratch assay and live-cell imaging. The metabolic viability and permeability capacity was investigated using the water-soluble tetrazolium (WST)-1 assay and an in vitro vascular permeability assay. Cell adherence was studied by utilizing the hanging drop assay. The transcriptional and protein level changes were analyzed by RT-qPCR, Western blotting and immunohistochemistry for major junctional complexing proteins. (3) Results: We observed reduced metabolic viability following Ang II and EtOH exposure vs. control. Further, cell adherence was enhanced by EtOH exposure prior to trituration and by all risk factors after trituration, which correlated with the increased gene and protein expression of VE-cadherin upon EtOH exposure. The cell migration capacity was reduced upon EtOH exposure vs. controls. (4) Conclusion: Marked functional changes were observed upon exposure to established and potential risk factors for AAD development in hAoECs. Our findings advocate for an enhanced mechanical rigidity in hAoECs in response to the three substances studied, which in turn might increase endothelial rigidity, suggesting a novel mechanism for developing an endothelial entry tear due to reduced deformability in response to increased shear and pulsatile stress.
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Affiliation(s)
- Joscha Mulorz
- Clinic for Vascular and Endovascular Surgery, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
| | - Wiebke Ibing
- Clinic for Vascular and Endovascular Surgery, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
| | - Melanie Cappallo
- Clinic for Vascular and Endovascular Surgery, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
- Clinic for Cardiac Surgery, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
- CURE3D Lab, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
| | - Sönke Maximilian Braß
- Clinic for Vascular and Endovascular Surgery, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
| | - Kiku Takeuchi
- Clinic for Vascular and Endovascular Surgery, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
| | - Uwe Raaz
- Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg-August-University, 37075 Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site, 37075 Göttingen, Germany
- University Heart Center, 37075 Göttingen, Germany
| | - Isabel Nahal Schellinger
- Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg-August-University, 37075 Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site, 37075 Göttingen, Germany
- University Heart Center, 37075 Göttingen, Germany
| | - Kim Jürgen Krott
- Clinic for Vascular and Endovascular Surgery, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
| | - Hubert Schelzig
- Clinic for Vascular and Endovascular Surgery, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
| | - Hug Aubin
- Clinic for Cardiac Surgery, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
- CURE3D Lab, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
| | - Alexander Oberhuber
- Clinic for Vascular and Endovascular Surgery, University Hospital Münster, 48149 Münster, Germany
| | - Margitta Elvers
- Clinic for Vascular and Endovascular Surgery, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
| | - Markus Udo Wagenhäuser
- Clinic for Vascular and Endovascular Surgery, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University, 40225 Duesseldorf, Germany
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Lin CJ, Chiu CY, Liao EC, Wu CJ, Chung CH, Greenberg CS, Lai TS. S-Nitrosylation of Tissue Transglutaminase in Modulating Glycolysis, Oxidative Stress, and Inflammatory Responses in Normal and Indoxyl-Sulfate-Induced Endothelial Cells. Int J Mol Sci 2023; 24:10935. [PMID: 37446114 DOI: 10.3390/ijms241310935] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/23/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Circulating uremic toxin indoxyl sulfate (IS), endothelial cell (EC) dysfunction, and decreased nitric oxide (NO) bioavailability are found in chronic kidney disease patients. NO nitrosylates/denitrosylates a specific protein's cysteine residue(s), forming S-nitrosothios (SNOs), and the decreased NO bioavailability could interfere with NO-mediated signaling events. We were interested in investigating the underlying mechanism(s) of the reduced NO and how it would regulate the S-nitrosylation of tissue transglutaminase (TG2) and its substrates on glycolytic, redox and inflammatory responses in normal and IS-induced EC injury. TG2, a therapeutic target for fibrosis, has a Ca2+-dependent transamidase (TGase) that is modulated by S-nitrosylation. We found IS increased oxidative stress, reduced NADPH and GSH levels, and uncoupled eNOS to generate NO. Immunoblot analysis demonstrated the upregulation of an angiotensin-converting enzyme (ACE) and significant downregulation of the beneficial ACE2 isoform that could contribute to oxidative stress in IS-induced injury. An in situ TGase assay demonstrated IS-activated TG2/TGase aminylated eNOS, NFkB, IkBα, PKM2, G6PD, GAPDH, and fibronectin (FN), leading to caspases activation. Except for FN, TGase substrates were all differentially S-nitrosylated either with or without IS but were denitrosylated in the presence of a specific, irreversible TG2/TGase inhibitor ZDON, suggesting ZDON-bound TG2 was not effectively transnitrosylating to TG2/TGase substrates. The data suggest novel roles of TG2 in the aminylation of its substrates and could also potentially function as a Cys-to-Cys S-nitrosylase to exert NO's bioactivity to its substrates and modulate glycolysis, redox, and inflammation in normal and IS-induced EC injury.
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Affiliation(s)
- Cheng-Jui Lin
- Department of Medicine, MacKay Medical College, New Taipei 25245, Taiwan
- MacKay Junior College of Medicine, Nursing and Management, New Taipei 25245, Taiwan
- Division of Nephrology, Department of Internal Medicine, MacKay Memorial Hospital, New Taipei 25245, Taiwan
| | - Chun Yu Chiu
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei 25245, Taiwan
| | - En-Chih Liao
- Department of Medicine, MacKay Medical College, New Taipei 25245, Taiwan
| | - Chih-Jen Wu
- Department of Medicine, MacKay Medical College, New Taipei 25245, Taiwan
- MacKay Junior College of Medicine, Nursing and Management, New Taipei 25245, Taiwan
- Division of Nephrology, Department of Internal Medicine, MacKay Memorial Hospital, New Taipei 25245, Taiwan
| | - Ching-Hu Chung
- Department of Medicine, MacKay Medical College, New Taipei 25245, Taiwan
| | - Charles S Greenberg
- Division of Hematology/Oncology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Thung-S Lai
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei 25245, Taiwan
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Martinez VR, Martins Lima A, Stergiopulos N, Velez Rueda JO, Islas MS, Griera M, Calleros L, Rodriguez Puyol M, Jaquenod de Giusti C, Portiansky EL, Ferrer EG, De Giusti V, Williams PAM. Effect of the structural modification of Candesartan with Zinc on hypertension and left ventricular hypertrophy. Eur J Pharmacol 2023; 946:175654. [PMID: 36930883 DOI: 10.1016/j.ejphar.2023.175654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 02/25/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023]
Abstract
Hypertension is the most common cause of left ventricular hypertrophy, contributing to heart failure progression. Candesartan (Cand) is an angiotensin receptor antagonist widely used for hypertension treatment. Structural modifications were previously performed by our group using Zinc (ZnCand) as a strategy for improving its pharmacological properties. The measurements showed that ZnCand exerts a stronger interaction with the angiotensin II receptor, type 1 (AT1 receptor), reducing oxidative stress and intracellular calcium flux, a mechanism implied in cell contraction. These results were accompanied by the reduction of the contractile capacity of mesangial cells. In vivo experiments showed that the complex causes a significant decrease in systolic blood pressure after 8 weeks of treatment in spontaneously hypertensive rats (SHR). The reduction of heart hypertrophy was evidenced by echocardiography, the histologic cross-sectional area of cardiomyocytes, collagen content, the B-type natriuretic peptide (BNP) marker and connective tissue growth factor (CTGF) and the matrix metalloproteinase 2 (MMP-2) expression. Besides, the complex restored the redox status. In this study, we demonstrated that the complexation with Zn(II) improves the antihypertensive and cardiac effects of the parental drug.
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Affiliation(s)
- Valeria R Martinez
- CEQUINOR-CONICET-CICPBA-UNLP, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Bv. 120 N◦ 1465, 1900, La Plata, Argentina; CIC-CONICET-UNLP, Facultad de Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina
| | - Augusto Martins Lima
- Laboratory of Hemodynamics & Cardiovascular Technology (LHTC), Institute of Bioengineering (Bâtiment MED), Station 9, École Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland
| | - Nikolaous Stergiopulos
- Laboratory of Hemodynamics & Cardiovascular Technology (LHTC), Institute of Bioengineering (Bâtiment MED), Station 9, École Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland
| | - Jorge O Velez Rueda
- CIC-CONICET-UNLP, Facultad de Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina
| | - Maria S Islas
- Departamento de Química y Bioquímica, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, 7600, Mar del Plata, Argentina
| | - Mercedes Griera
- Departamento de Fisiología, Universidad de Alcalá, Campus Universitario, 28871, Alcalá de Henares, Madrid, Spain
| | - Laura Calleros
- Departamento de Fisiología, Universidad de Alcalá, Campus Universitario, 28871, Alcalá de Henares, Madrid, Spain
| | - Manuel Rodriguez Puyol
- Departamento de Fisiología, Universidad de Alcalá, Campus Universitario, 28871, Alcalá de Henares, Madrid, Spain
| | - Carolina Jaquenod de Giusti
- CIC-CONICET-UNLP, Facultad de Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina
| | - Enrique L Portiansky
- Laboratorio de Análisis de Imágenes-UNLP, Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, 60 y 118, 1900, La Plata, Argentina
| | - Evelina G Ferrer
- CEQUINOR-CONICET-CICPBA-UNLP, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Bv. 120 N◦ 1465, 1900, La Plata, Argentina
| | - Verónica De Giusti
- CIC-CONICET-UNLP, Facultad de Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina.
| | - Patricia A M Williams
- CEQUINOR-CONICET-CICPBA-UNLP, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Bv. 120 N◦ 1465, 1900, La Plata, Argentina.
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5
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Crintea A, Motofelea AC, Șovrea AS, Constantin AM, Crivii CB, Carpa R, Duțu AG. Dendrimers: Advancements and Potential Applications in Cancer Diagnosis and Treatment-An Overview. Pharmaceutics 2023; 15:pharmaceutics15051406. [PMID: 37242648 DOI: 10.3390/pharmaceutics15051406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/17/2023] [Accepted: 04/29/2023] [Indexed: 05/28/2023] Open
Abstract
Cancer is a leading cause of death worldwide, and the main treatment methods for this condition are surgery, chemotherapy, and radiotherapy. These treatment methods are invasive and can cause severe adverse reactions among organisms, so nanomaterials are increasingly used as structures for anticancer therapies. Dendrimers are a type of nanomaterial with unique properties, and their production can be controlled to obtain compounds with the desired characteristics. These polymeric molecules are used in cancer diagnosis and treatment through the targeted distribution of some pharmacological substances. Dendrimers have the ability to fulfill several objectives in anticancer therapy simultaneously, such as targeting tumor cells so that healthy tissue is not affected, controlling the release of anticancer agents in the tumor microenvironment, and combining anticancer strategies based on the administration of anticancer molecules to potentiate their effect through photothermal therapy or photodynamic therapy. The purpose of this review is to summarize and highlight the possible uses of dendrimers regarding the diagnosis and treatment of oncological conditions.
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Affiliation(s)
- Andreea Crintea
- Department of Molecular Sciences, Faculty of Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Alexandru Cătălin Motofelea
- Department of Internal Medicine, Faculty of Medicine, Victor Babeș University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Alina Simona Șovrea
- Department of Morphological Sciences, Faculty of Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Anne-Marie Constantin
- Department of Morphological Sciences, Faculty of Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Carmen-Bianca Crivii
- Department of Morphological Sciences, Faculty of Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400000 Cluj-Napoca, Romania
| | - Rahela Carpa
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Institute for Research-Development-Innovation in Applied Natural Sciences, Babeș-Bolyai University, 400084 Cluj-Napoca, Romania
| | - Alina Gabriela Duțu
- Department of Molecular Sciences, Faculty of Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
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6
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Jayawardena DP, Masciantonio MG, Wang L, Mehta S, DeGurse N, Pape C, Gill SE. Imbalance of Pulmonary Microvascular Endothelial Cell-Expression of Metalloproteinases and Their Endogenous Inhibitors Promotes Septic Barrier Dysfunction. Int J Mol Sci 2023; 24:ijms24097875. [PMID: 37175585 PMCID: PMC10178398 DOI: 10.3390/ijms24097875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 05/15/2023] Open
Abstract
Sepsis is a life-threatening disease characterized by excessive inflammation leading to organ dysfunction. During sepsis, pulmonary microvascular endothelial cells (PMVEC) lose barrier function associated with inter-PMVEC junction disruption. Matrix metalloproteinases (MMP) and a disintegrin and metalloproteinases (ADAM), which are regulated by tissue inhibitors of metalloproteinases (TIMPs), can cleave cell-cell junctional proteins, suggesting a role in PMVEC barrier dysfunction. We hypothesize that septic PMVEC barrier dysfunction is due to a disruption in the balance between PMVEC-specific metalloproteinases and TIMPs leading to increased metalloproteinase activity. The effects of sepsis on TIMPs and metalloproteinases were assessed ex vivo in PMVEC from healthy (sham) and septic (cecal ligation and perforation) mice, as well as in vitro in isolated PMVEC stimulated with cytomix, lipopolysaccharide (LPS), and cytomix + LPS vs. PBS. PMVEC had high basal Timp expression and lower metalloproteinase expression, and septic stimulation shifted expression in favour of metalloproteinases. Septic stimulation increased MMP13 and ADAM17 activity associated with a loss of inter-PMVEC junctional proteins and barrier dysfunction, which was rescued by treatment with metalloproteinase inhibitors. Collectively, our studies support a role for metalloproteinase-TIMP imbalance in septic PMVEC barrier dysfunction, and suggest that inhibition of specific metalloproteinases may be a therapeutic avenue for septic patients.
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Affiliation(s)
- Devika P Jayawardena
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Marcello G Masciantonio
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Lefeng Wang
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Sanjay Mehta
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Natalie DeGurse
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Cynthia Pape
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - Sean E Gill
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Division of Respirology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
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7
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Dong CX, Malecki C, Robertson E, Hambly B, Jeremy R. Molecular Mechanisms in Genetic Aortopathy-Signaling Pathways and Potential Interventions. Int J Mol Sci 2023; 24:ijms24021795. [PMID: 36675309 PMCID: PMC9865322 DOI: 10.3390/ijms24021795] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/02/2023] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
Thoracic aortic disease affects people of all ages and the majority of those aged <60 years have an underlying genetic cause. There is presently no effective medical therapy for thoracic aneurysm and surgery remains the principal intervention. Unlike abdominal aortic aneurysm, for which the inflammatory/atherosclerotic pathogenesis is well established, the mechanism of thoracic aneurysm is less understood. This paper examines the key cell signaling systems responsible for the growth and development of the aorta, homeostasis of endothelial and vascular smooth muscle cells and interactions between pathways. The evidence supporting a role for individual signaling pathways in pathogenesis of thoracic aortic aneurysm is examined and potential novel therapeutic approaches are reviewed. Several key signaling pathways, notably TGF-β, WNT, NOTCH, PI3K/AKT and ANGII contribute to growth, proliferation, cell phenotype and survival for both vascular smooth muscle and endothelial cells. There is crosstalk between pathways, and between vascular smooth muscle and endothelial cells, with both synergistic and antagonistic interactions. A common feature of the activation of each is response to injury or abnormal cell stress. Considerable experimental evidence supports a contribution of each of these pathways to aneurysm formation. Although human information is less, there is sufficient data to implicate each pathway in the pathogenesis of human thoracic aneurysm. As some pathways i.e., WNT and NOTCH, play key roles in tissue growth and organogenesis in early life, it is possible that dysregulation of these pathways results in an abnormal aortic architecture even in infancy, thereby setting the stage for aneurysm development in later life. Given the fine tuning of these signaling systems, functional polymorphisms in key signaling elements may set up a future risk of thoracic aneurysm. Multiple novel therapeutic agents have been developed, targeting cell signaling pathways, predominantly in cancer medicine. Future investigations addressing cell specific targeting, reduced toxicity and also less intense treatment effects may hold promise for effective new medical treatments of thoracic aortic aneurysm.
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Affiliation(s)
- Charlotte Xue Dong
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
| | - Cassandra Malecki
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
- The Baird Institute, Camperdown, NSW 2042, Australia
| | - Elizabeth Robertson
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
| | - Brett Hambly
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
| | - Richmond Jeremy
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
- The Baird Institute, Camperdown, NSW 2042, Australia
- Correspondence:
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8
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Lymperopoulos A, Borges JI, Carbone AM, Cora N, Sizova A. Cardiovascular angiotensin II type 1 receptor biased signaling: Focus on non-Gq-, non-βarrestin-dependent signaling. Pharmacol Res 2021; 174:105943. [PMID: 34662735 DOI: 10.1016/j.phrs.2021.105943] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023]
Abstract
The physiological and pathophysiological roles of the angiotensin II type 1 (AT1) receptor, a G protein-coupled receptor ubiquitously expressed throughout the cardiovascular system, have been the focus of intense investigations for decades. The success of angiotensin converting enzyme inhibitors (ACEIs) and of angiotensin receptor blockers (ARBs), which are AT1R-selective antagonists/inverse agonists, in the treatment of heart disease is a testament to the importance of this receptor for cardiovascular homeostasis. Given the pleiotropic signaling of the cardiovascular AT1R and, in an effort to develop yet better drugs for heart disease, the concept of biased signaling has been exploited to design and develop biased AT1R ligands that selectively activate β-arrestin transduction pathways over Gq protein-dependent pathways. However, by focusing solely on Gq or β-arrestins, studies on AT1R "biased" signaling & agonism tend to largely ignore other non-Gq-, non β-arrestin-dependent signaling modalities the very versatile AT1R employs in cardiovascular tissues, including two very important types of signal transducers/regulators: other G protein types (e.g., Gi/o, G12/13) & the Regulator of G protein Signaling (RGS) proteins. In this review, we provide a brief overview of the current state of cardiovascular AT1R biased signaling field with a special focus on the non-Gq-, non β-arrestin-dependent signaling avenues of this receptor in the cardiovascular system, which usually get left out of the conversation of "biased" AT1R signal transduction.
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Affiliation(s)
- Anastasios Lymperopoulos
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA.
| | - Jordana I Borges
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Alexandra M Carbone
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Natalie Cora
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
| | - Anastasiya Sizova
- Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
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9
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Hong N, Ye Z, Lin Y, Liu W, Xu N, Wang Y. Agomelatine prevents angiotensin II-induced endothelial and mononuclear cell adhesion. Aging (Albany NY) 2021; 13:18515-18526. [PMID: 34292876 PMCID: PMC8351686 DOI: 10.18632/aging.203299] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 06/19/2021] [Indexed: 12/25/2022]
Abstract
Agomelatine is a non-selective melatonin receptor agonist and an atypical antidepressant with anti-inflammatory, neuroprotective, and cardioprotective effects. The renin-angiotensin system modulates blood pressure and vascular homeostasis. Angiotensin II (Ang II) and its receptor Ang II type I receptor (AT1R) are recognized as contributors to the pathogenesis of cardiovascular and cardiometabolic diseases, including diabetes, obesity, and atherosclerosis. The recruitment and attachment of monocytes to the vascular endothelium is a major event in the early stages of atherosclerosis and other cardiovascular diseases. In the present study, we demonstrate that agomelatine reduced Ang II-induced expression of AT1R while significantly inhibiting the attachment of monocytes to endothelial cells induced by Ang II and mediated by ICAM-1 and VCAM-1. Additionally, Ang II inhibited the expression of the chemokines CXCL1, MCP-1, and CCL5, which are critical in the process of immune cell recruitment and invasion. Agomelatine also suppressed the expression of TNF-α, IL-8, and IL-12, which are proinflammatory cytokines that promote endothelial dysfunction and atherogenesis. Importantly, we demonstrate that the inhibitory effect of agomelatine against the expression of adhesion molecules is mediated through the downregulation of Egr-1 signaling. Together, our findings provide evidence of a novel mechanism of agomelatine that may be practicable in the treatment and prevention of cardiovascular diseases.
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Affiliation(s)
- Najiao Hong
- Department of General Medicine, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou 362000, Fujian, China
| | - Zhirong Ye
- Department of General Medicine, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou 362000, Fujian, China
| | - Yongjun Lin
- Department of General Medicine, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou 362000, Fujian, China
| | - Wensen Liu
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun 130122, Jilin, China
| | - Na Xu
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun 130122, Jilin, China
| | - Yan Wang
- Department of Stomatology, Tibet Corps Hospital, Chinese People's Armed Police Forces, Lhasa 850000, Tibet Autonomous Region, China
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Eckenstaler R, Sandori J, Gekle M, Benndorf RA. Angiotensin II receptor type 1 - An update on structure, expression and pathology. Biochem Pharmacol 2021; 192:114673. [PMID: 34252409 DOI: 10.1016/j.bcp.2021.114673] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 07/02/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022]
Abstract
The AT1 receptor, a major effector of the renin-angiotensin system, has been extensively studied in the context of cardiovascular and renal disease. Moreover, angiotensin receptor blockers, sartans, are among the most frequently prescribed drugs for the treatment of hypertension, chronic heart failure and chronic kidney disease. However, precise molecular insights into the structure of this important drug target have not been available until recently. In this context, seminal studies have now revealed exciting new insights into the structure and biased signaling of the receptor and may thus foster the development of novel therapeutic approaches to enhance the efficacy of pharmacological angiotensin receptor antagonism or to enable therapeutic induction of biased receptor activity. In this review, we will therefore highlight these and other seminal publications to summarize the current understanding of the tertiary structure, ligand binding properties and downstream signal transduction of the AT1 receptor.
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Affiliation(s)
| | - Jana Sandori
- Institute of Pharmacy, Martin-Luther-University, Halle, Germany
| | - Michael Gekle
- Julius-Bernstein-Institute of Physiology, Martin-Luther-University, Halle, Germany
| | - Ralf A Benndorf
- Institute of Pharmacy, Martin-Luther-University, Halle, Germany.
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11
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Abstract
Neurohormones and inflammatory mediators have effects in both the heart and the peripheral vasculature. In patients with heart failure (HF), neurohormonal activation and increased levels of inflammatory mediators promote ventricular remodeling and development of HF, as well as vascular dysfunction and arterial stiffness. These processes may lead to a vicious cycle, whereby arterial stiffness perpetuates further ventricular remodeling leading to exacerbation of symptoms. Although significant advances have been made in the treatment of HF, currently available treatment strategies slow, but do not halt, this cycle. The current treatment for HF patients involves the inhibition of neurohormonal activation, which can reduce morbidity and mortality related to this condition. Beyond benefits associated with neurohormonal blockade, other strategies have focused on inhibition of inflammatory pathways implicated in the pathogenesis of HF. Unfortunately, attempts to target inflammation have not yet been successful to improve prognosis of HF. Further work is required to interrupt key maladaptive mechanisms involved in disease progression.
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Gao HL, Yu XJ, Liu KL, Zuo YY, Fu LY, Chen YM, Zhang DD, Shi XL, Qi J, Li Y, Yi QY, Tian H, Wang XM, Yu JY, Zhu GQ, Liu JJ, Kang KB, Kang YM. Chronic Infusion of Astaxanthin Into Hypothalamic Paraventricular Nucleus Modulates Cytokines and Attenuates the Renin-Angiotensin System in Spontaneously Hypertensive Rats. J Cardiovasc Pharmacol 2021; 77:170-181. [PMID: 33538532 DOI: 10.1097/fjc.0000000000000953] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 10/28/2020] [Indexed: 11/26/2022]
Abstract
ABSTRACT Oxidative stress, the renin-angiotensin system (RAS), and inflammation are some of the mechanisms involved in the pathogenesis of hypertension. The aim of this study is to examine the protective effect of the chronic administration of astaxanthin, which is extracted from the shell of crabs and shrimps, into hypothalamic paraventricular nucleus (PVN) in spontaneously hypertensive rats. Animals were randomly assigned to 2 groups and treated with bilateral PVN infusion of astaxanthin or vehicle (artificial cerebrospinal fluid) through osmotic minipumps (Alzet Osmotic Pumps, Model 2004, 0.25 μL/h) for 4 weeks. Spontaneously hypertensive rats had higher mean arterial pressure and plasma level of norepinephrine and proinflammatory cytokine; higher PVN levels of reactive oxygen species, NOX2, NOX4, IL-1β, IL-6, ACE, and AT1-R; and lower PVN levels of IL-10 and Cu/Zn SOD, Mn SOD, ACE2, and Mas receptors than Wistar-Kyoto rats. Our data showed that chronic administration of astaxanthin into PVN attenuated the overexpression of reactive oxygen species, NOX2, NOX4, inflammatory cytokines, and components of RAS within the PVN and suppressed hypertension. The present results revealed that astaxanthin played a role in the brain. Our findings demonstrated that astaxanthin had protective effect on hypertension by improving the balance between inflammatory cytokines and components of RAS.
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Affiliation(s)
- Hong-Li Gao
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Xiao-Jing Yu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Kai-Li Liu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Yi-Yi Zuo
- College of Stomatology, Xi'an Jiaotong University, Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Xi'an, Shaanxi, People's Republic of China
| | - Li-Yan Fu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Yan-Mei Chen
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Dong-Dong Zhang
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Xiao-Lian Shi
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Jie Qi
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Ying Li
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Qiu-Yue Yi
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Hua Tian
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Xiao-Min Wang
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Jia-Yue Yu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Guo-Qing Zhu
- Department of Physiology, Nanjing Medical University, Nanjing, China; and
| | - Jin-Jun Liu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
| | - Kai B Kang
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL
| | - Yu-Ming Kang
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an, China
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TNF-α inhibition decreases MMP-2 activity, reactive oxygen species formation and improves hypertensive vascular hypertrophy independent of its effects on blood pressure. Biochem Pharmacol 2020; 180:114121. [PMID: 32592722 DOI: 10.1016/j.bcp.2020.114121] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/28/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023]
Abstract
Systemic arterial hypertension is a public health problem associated with an increased risk of cardiovascular disease. Matrix metalloproteinases (MMP) are endopeptidases that participate in hypertension-induced cardiovascular remodeling, which may be activated by oxidative stress. Angiotensin II (Ang II), a potent hypertrophic and vasoconstrictor peptide, increases oxidative stress, MMP-2 activity and tumor necrosis factor (TNF-α) expression. In vitro studies have shown that TNF-α is essential for Ang II-induced MMP-2 expression. Thus, this study evaluated whetherTNF-α inhibition decreases the development of hypertension-induced vascular remodeling via reduction of MMP-2 activity and reactive oxygen species (ROS) formation. Two distinct pharmacological approaches were used in the present study: Pentoxifylline (PTX), a non-selective inhibitor of phosphodiesterases that exerts anti- inflammatory effects via inhibition of TNF-α, and Etanercept (ETN), a selective TNF-α inhibitor. 2-kidney and 1-Clip (2K1C). 2-kidney and 1-Clip (2K1C) and Sham rats were treated with Vehicle, PTX (50 mg/Kg and 100 mg/kg daily) or ETN (0.3 mg/Kg and 1 mg/kg; three times per week). Systolic blood pressure (SBP) was measured weekly by tail cuff plethysmography. Plasma TNF-α and IL-1β levels were evaluated by enzyme-linked immunosorbent assay (ELISA) technique. The vascular hypertrophy was examined in the aorta sections stained with hematoxylin/eosin. ROS in aortas was evaluated by dihydroethidium and chemiluminescence lucigenin assay. Aortic MMP-2 levels and activity were evaluated by gel zymography and in situ zymography, respectively. The 2K1C animals showed a progressive increase in SBP levels and was accompanied by significant vascular hypertrophy (p < 0.05 vs Sham). Treatment with PTX at higher doses decreased SBP and vascular remodeling in 2K1C animals (p < 0.05 vs 2K1C vehicle). Although the highest dose of ETN treatment did not reduce blood pressure, the vascular hypertrophy was significantly attenuated in 2K1C animals treated with ETN1 (p < 0.05). The increased cytokine levels and ROS formation were reversed by the highest doses of both PTX and ETN. The increase in MMP-2 levels and activity in 2K1C animals were reduced by PTX100 and ETN1 treatments (p < 0.05 vs vehicle 2K1C). Lower doses of PTX and ETN did not affect any of the evaluated parameters in this study, except for a small reduction in TNF-α levels. The findings of the present study suggest that PTX and ETN treatment exerts immunomodulatory effects, blunted excessive ROS formation, and decreased renovascular hypertension-induced MMP-2 up-regulation, leading to improvement ofvascular remodeling typically found in 2K1C hypertension. Therefore, strategies using anti-hypertensive drugs in combination with TNF alpha inhibitors could be an attractive therapeutic approach to tackle hypertension and its associated vascular remodeling.
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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: 44] [Impact Index Per Article: 7.3] [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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Endothelial dysfunction predicted increased left atrial volume index in newly diagnosed nondiabetic hypertensive patients. Blood Press Monit 2019; 25:75-81. [PMID: 31764010 DOI: 10.1097/mbp.0000000000000419] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Arterial hypertension is associated with cardiovascular morbidity and mortality. It was previously shown that left atrium volume increase associated with mortality and atherosclerotic heart disease. The aim of the present study was to demonstrate the value of endothelial dysfunction in predicting left atrium volume increase in newly diagnosed hypertension patients. METHODS This study included 96 consecutive newly diagnosed hypertensive patients. Left atrium volume and left ventricular ejection fraction were calculated. Pulse wave velocity and brachial artery flow-mediated dilation measurements were obtained from each patient. RESULTS Left Ventricle Mass Index (114 ± 29 g/m, 91 ± 17 g/m, P < 001), left ventricular septum (P < 0.001) and posterior wall thickness (P = 0.001), left ventricular end diastolic diameter (P = 0.016) were significantly higher in patients with higher left atrial volume index. FMD% was lower in patients with higher left atrial volume index those without (9.7 ± 3.5 vs. 13.31 ± 6.01, P = 0.004). Lateral wall E wave velocity was significantly lower (8.68 ± 2.8, 10.2 ± 2.8; P = 0.009), while isovolumetric relaxation time (101.9 ± 19.9 ms, 85.7 ± 15.2 ms; P < 0.001), and ejection time was longer (101.9 ± 19.9 ms, 85.7 ± 15.2 ms; P = 0.077) and Mitral E/ lateral wall E ratio (E/E relation) was significantly higher (P = 0.031) in patients with higher left atrial volume index. CONCLUSION The rate of isovolumetric relaxation time, FMD% and E/E' ratio independently predicted left atrial volume index increase in newly diagnosed hypertension patients.
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Nascimento RA, Possomato-Vieira JS, Bonacio GF, Rizzi E, Dias-Junior CA. Reductions of Circulating Nitric Oxide are Followed by Hypertension during Pregnancy and Increased Activity of Matrix Metalloproteinases-2 and -9 in Rats. Cells 2019; 8:cells8111402. [PMID: 31703340 PMCID: PMC6912623 DOI: 10.3390/cells8111402] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 09/03/2019] [Indexed: 12/14/2022] Open
Abstract
Hypertensive pregnancy has been associated with reduced nitric oxide (NO), bioavailability, and increased activity of matrix metalloproteinases (MMPs). However, it is unclear if MMPs activation is regulated by NO during pregnancy. To this end, we examined activity of MMP-2 and MMP-9 in plasma, placenta, uterus and aorta, NO bioavailability, oxidative stress, systolic blood pressure (SBP), and fetal-placental development at the early, middle, and late pregnancy stages in normotensive and Nω-Nitro-L-arginine methyl-ester (L-NAME)-induced hypertensive pregnancy in rats. Reduced MMP-2 activity in uterus, placenta, and aorta and reduced MMP-9 activity in plasma and placenta with concomitant increased NO levels were found in normotensive pregnant rats. By contrast, increased MMP-2 activity in uterus, placenta, and aorta, and increased MMP-9 activity in plasma and placenta with concomitant reduced NO levels were observed in hypertensive pregnant rats. Also, elevated oxidative stress was displayed by hypertensive pregnant rats at the middle and late stages. These findings in the L-NAME-treated pregnant rats were also followed by increases in SBP and associated with fetal growth restrictions at the middle and late pregnancy stages. We concluded that NO bioavailability may regulate MMPs activation during normal and hypertensive pregnancy.
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Affiliation(s)
- Regina A. Nascimento
- Department of Pharmacology, Biosciences Institute of Botucatu, Sao Paulo State University – UNESP, Botucatu, Sao Paulo 18.618-689, Brazil; (R.A.N.); (J.S.P.-V.)
| | - Jose S. Possomato-Vieira
- Department of Pharmacology, Biosciences Institute of Botucatu, Sao Paulo State University – UNESP, Botucatu, Sao Paulo 18.618-689, Brazil; (R.A.N.); (J.S.P.-V.)
| | - Giselle F. Bonacio
- Unit of Biotechnology, University of Ribeirao Preto, UNAERP, Ribeirao Preto, Sao Paulo 14096-900, Brazil; (G.F.B.); (E.R.)
| | - Elen Rizzi
- Unit of Biotechnology, University of Ribeirao Preto, UNAERP, Ribeirao Preto, Sao Paulo 14096-900, Brazil; (G.F.B.); (E.R.)
| | - Carlos A. Dias-Junior
- Department of Pharmacology, Biosciences Institute of Botucatu, Sao Paulo State University – UNESP, Botucatu, Sao Paulo 18.618-689, Brazil; (R.A.N.); (J.S.P.-V.)
- Correspondence: ; Tel.: +55 14 3880-0214
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Endothelial dysfunction, subclinical atherosclerosis and LDL cholesterol are the independent predictors of left atrial functions in hypertension. Int J Cardiovasc Imaging 2019; 36:69-77. [PMID: 31586295 DOI: 10.1007/s10554-019-01699-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 09/16/2019] [Indexed: 10/25/2022]
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Mulens-Arias V, Balfourier A, Nicolás-Boluda A, Carn F, Gazeau F. Disturbance of adhesomes by gold nanoparticles reveals a size- and cell type-bias. Biomater Sci 2019; 7:389-408. [PMID: 30484789 DOI: 10.1039/c8bm01267a] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gold nanoparticles (AuNP) have been thoroughly studied as multifunctional theranosis agents for cell imaging and cancer therapy as well as sensors due to their tunable physical and chemical properties. Although AuNP have proved to be safe in a wide concentration range, yet other important biological effects can arise in the sublethal window of treatment. This is especially pivotal to understand how AuNP can affect cell biology when labeling steps are needed for cell tracking in vivo, as nanoparticle loading can affect cell migratory/invasion ability, a function mediated by filamentous actin-rich nanometric structures collectively called adhesomes. It is noteworthy that, although numerous research studies have addressed the cell response to AuNP loading, yet none of them focuses on adhesome dynamics as a target of intracellular pathways affected by AuNP. We intend to study the collective dynamics of adhesive F-actin rich structures upon AuNP treatment as an approach to understand the complex AuNP-triggered modulation of migration/invasion related cellular functions. We demonstrated that citrate-coated spherical AuNP of different sizes (3, 11, 16, 30 and 40 nm) disturbed podosome-forming rosettes and the resulting extracellular matrix (ECM) degradation in a murine macrophage model depending on core size. This phenomenon was accompanied by a reduction in metalloproteinase MMP2 and an increment in metalloproteinase inhibitors, TIMP-1/2 and SerpinE1. We also found that AuNP treatment has opposite effects on focal adhesions (FA) in endothelial and mesenchymal stem cells. While endothelial cells reduced their mature FA number and ECM degradation rate upon AuNP treatment, mouse mesenchymal stem cells increased the number and size of mature FA and, therefore, the ECM degradation rate. Overall, AuNP appear to disturb adhesive structures and therefore migratory/invasive cell functions measured as ECM degradation ability, providing new insights into AuNP-cell interaction depending on cell type.
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Affiliation(s)
- Vladimir Mulens-Arias
- Laboratoire Matière et Systèmes Complexes (MSC), UMR 7075, CNRS and Université Paris Diderot, Université Sorbonne Paris Cité (USPC), 10 Rue Alice Domon et Léonie Duquet, 75205 Paris Cedex 13, France.
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Maneesai P, Bunbupha S, Potue P, Berkban T, Kukongviriyapan U, Kukongviriyapan V, Prachaney P, Pakdeechote P. Hesperidin Prevents Nitric Oxide Deficiency-Induced Cardiovascular Remodeling in Rats via Suppressing TGF-β1 and MMPs Protein Expression. Nutrients 2018; 10:E1549. [PMID: 30347737 PMCID: PMC6213402 DOI: 10.3390/nu10101549] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/12/2018] [Accepted: 10/18/2018] [Indexed: 12/12/2022] Open
Abstract
Hesperidin is a major flavonoid isolated from citrus fruits that exhibits several biological activities. This study aims to evaluate the effect of hesperidin on cardiovascular remodeling induced by n-nitro l-arginine methyl ester (l-NAME) in rats. Male Sprague-Dawley rats were treated with l-NAME (40 mg/kg), l-NAME plus hesperidin (15 mg/kg), hesperidin (30 mg/kg), or captopril (2.5 mg/kg) for five weeks (n = 8/group). Hesperidin or captopril significantly prevented the development of hypertension in l-NAME rats. l-NAME-induced cardiac remodeling, i.e., increases in wall thickness, cross-sectional area (CSA), and fibrosis in the left ventricular and vascular remodeling, i.e., increases in wall thickness, CSA, vascular smooth muscle cells, and collagen deposition in the aorta were attenuated by hesperidin or captopril. These were associated with reduced oxidative stress markers, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta 1 (TGF-β1), and enhancing plasma nitric oxide metabolite (NOx) in l-NAME treated groups. Furthermore, up-regulation of tumor necrosis factor receptor type 1 (TNF-R1) and TGF- β1 protein expression and the overexpression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) was suppressed in l-NAME rats treated with hesperidin or captopril. These data suggested that hesperidin had cardioprotective effects in l-NAME hypertensive rats. The possible mechanism may involve antioxidant and anti-inflammatory effects.
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Affiliation(s)
- Putcharawipa Maneesai
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
- Cardiovascular Research Group, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Sarawoot Bunbupha
- Faculty of Medicine, Mahasarakham University, Maha Sarakham 44000, Thailand.
| | - Prapassorn Potue
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Thewarid Berkban
- Faculty of Medicine, Mahasarakham University, Maha Sarakham 44000, Thailand.
| | - Upa Kukongviriyapan
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
- Cardiovascular Research Group, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Veerapol Kukongviriyapan
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Parichat Prachaney
- Cardiovascular Research Group, Khon Kaen University, Khon Kaen 40002, Thailand.
- Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Poungrat Pakdeechote
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
- Cardiovascular Research Group, Khon Kaen University, Khon Kaen 40002, Thailand.
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Krishnaswamy VR, Mintz D, Sagi I. Matrix metalloproteinases: The sculptors of chronic cutaneous wounds. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017; 1864:2220-2227. [PMID: 28797647 DOI: 10.1016/j.bbamcr.2017.08.003] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 08/01/2017] [Accepted: 08/04/2017] [Indexed: 02/07/2023]
Abstract
Cutaneous wound healing is a complex mechanism with multiple processes orchestrating harmoniously for structural and functional restoration of the damaged tissue. Chronic non-healing wounds plagued with infection create a major healthcare burden and is one of the most frustrating clinical problems. Chronic wounds are manifested by prolonged inflammation, defective re-epithelialization and haphazard remodeling. Matrix metalloproteinases (MMPs) are zinc dependent enzymes that play cardinal functions in wound healing. Understanding the pathological events mediated by MMPs during wound healing may pave way in identifying novel drug targets for chronic wounds. Here, we discuss the functions and skewed regulation of different MMPs during infection and chronic tissue repair. This review also points out the potential of MMPs and their inhibitors as therapeutic agents in treating chronic wounds during distinct phases of the wound healing. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
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Affiliation(s)
| | - Dvir Mintz
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 7610001, Israel
| | - Irit Sagi
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 7610001, Israel.
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Masciantonio MG, Lee CKS, Arpino V, Mehta S, Gill SE. The Balance Between Metalloproteinases and TIMPs: Critical Regulator of Microvascular Endothelial Cell Function in Health and Disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 147:101-131. [PMID: 28413026 DOI: 10.1016/bs.pmbts.2017.01.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Endothelial cells (EC), especially the microvascular EC (MVEC), have critical functions in health and disease. For example, healthy MVEC provide a barrier between the fluid and protein found within the blood, and the surrounding tissue. Following tissue injury or infection, the microvascular barrier is often disrupted due to activation and dysfunction of the MVEC. Multiple mechanisms promote MVEC activation and dysfunction, including stimulation by cytokines, mechanical interaction with activated leukocytes, and exposure to harmful leukocyte-derived molecules, which collectively result in a loss of MVEC barrier function. However, MVEC activation is also critical to facilitate recruitment of inflammatory cells, such as neutrophils (PMNs) and monocytes, into the injured or infected tissue. Metalloproteinases, including the matrix metalloproteinases (MMPs) and the closely related, a disintegrin and metalloproteinases (ADAMs), have been implicated in regulating both MVEC barrier function, through cleavage of adherens and tight junctions proteins between adjacent MVEC and through degradation of the extracellular matrix, as well as PMN-MVEC interaction, through shedding of cell surface PMN receptors. Moreover, the tissue inhibitors of metalloproteinases (TIMPs), which collectively inhibit most MMPs and ADAMs, are critical regulators of MVEC activation and dysfunction through their ability to inhibit metalloproteinases and thereby promote MVEC stability. However, TIMPs have been also found to modulate MVEC function through metalloproteinase-independent mechanisms, such as regulation of vascular endothelial growth factor signaling. This chapter is focused on examining the role of the metalloproteinases and TIMPs in regulation of MVEC function in both health and disease.
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Affiliation(s)
- Marcello G Masciantonio
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Christopher K S Lee
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Valerie Arpino
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Sanjay Mehta
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada
| | - Sean E Gill
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
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22
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Uchida T, Mori M, Uzawa A, Masuda H, Muto M, Ohtani R, Kuwabara S. Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: Their possible role on blood–brain barrier disruption. Mult Scler 2016; 23:1072-1084. [DOI: 10.1177/1352458516672015] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background: Inflammation in neuromyelitis optica (NMO) is triggered by a serum antibody against the aquaporin-4 (AQP4). This process requires antibody penetration of the blood–brain barrier (BBB), but the mechanisms for BBB disruption in NMO remain unknown. Objective: We examined whether changes in cerebrospinal fluid (CSF) and serum matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and cytokines are associated with BBB disruption in NMO. Methods: The concentrations 9 MMPs, 4 TIMPs, and 14 cytokines were measured by multiplex assay in CSF and serum samples from 29 NMO patients, 29 relapsing-remitting multiple sclerosis (MS) patients, and 27 patients with other neurological disorders. We also performed immunohistochemistry for MMP-2 and TIMP-1 expression in post-mortem brain tissues from NMO patients. Results: NMO patients exhibited significantly elevated MMP-2, TIMP-1, interleukin-6, and MMP-2/TIMP-2 ratio in CSF (but not sera) than the other groups. The CSF/serum albumin ratio, an index of BBB permeability, was most strongly correlated with CSF MMP-2 concentration, which in turn correlated with CSF interleukin-6 levels. Immunohistochemistry revealed MMP-2- and TIMP-1-positive cells surrounding vessels in NMO lesions. Conclusion: In NMO, increased CSF MMP-2, likely induced by interleukin-6 signaling, may disrupt the BBB and enable serum anti-AQP-4 antibodies migration into the central nervous system (CNS).
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Affiliation(s)
- Tomohiko Uchida
- Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masahiro Mori
- Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Akiyuki Uzawa
- Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroki Masuda
- Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Mayumi Muto
- Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryohei Ohtani
- Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Satoshi Kuwabara
- Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
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Wang X, Fan YZ, Yao L, Wang JM. Anti-proliferative effect of olmesartan on Tenon's capsule fibroblasts. Int J Ophthalmol 2016; 9:669-76. [PMID: 27275419 DOI: 10.18240/ijo.2016.05.05] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 12/05/2015] [Indexed: 11/23/2022] Open
Abstract
AIM To evaluate the inhibitive effect of olmesartan to fibroblast proliferation and the anti-scarring effect in Tenon's capsule, both in vitro and in vivo. METHODS Human primary Tenon's capsule fibroblasts were cultured in vitro, treated with up titrating concentrations of olmesartan. The rate of inhibition was tested with methyl thiazol tetrazolium (MTT) method. Real-time PCR was performed to analyze changes in mRNA expressions of the fibrosis-related factors: matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase (TIMP-1,2) and proliferating cell nuclear antigen (PCNA). Thirty rabbits were divided into 5 groups (3, 7, 14, 21, and 28d). A rabbit conjunctiva flap model was created in each eye. Olmesartan solution was injected subconjunctivally and then evaluated its anti-proliferation and anti-fibrosis effects through the histological morphology and immunohistochemistry of MMP-2 and PCNA in each group. Only the 7d group was treated with Masson's trichrome to compare the neovascularization in the subconjunctiva area. RESULTS In vitro, cultured Tenon's capsule human fibroblasts showed a dose dependent inhibition by olmesartan in MTT. Olmesartan reduced mRNA expressions of MMP-2 and PCNA but increased mRNA expressions of TIMP-1 and TIMP-2. In vivo, the rabbit eyes treated with olmesartan at 3(rd), 7(th), 14(th) and 21(st) days demonstrated a significant reduced expressions of MMP-2 and PCNA compared with control eye, no significant difference observed in 28(th) day group. The cellular proliferation and neovascularization was suppressed by olmesartan in Masson's trichrome observation. CONCLUSION By inhibiting fibroblasts in vitro and in vivo, olmesartan prevents the proliferation and activity of fibroblasts in scar tissue formation, which might benefit glaucoma filtering surgery.
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Affiliation(s)
- Xuan Wang
- Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Ya-Zhi Fan
- Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Liang Yao
- Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Jian-Ming Wang
- Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
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24
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Cross talk between MMP2-Spm-Cer-S1P and ERK1/2 in proliferation of pulmonary artery smooth muscle cells under angiotensin II stimulation. Arch Biochem Biophys 2016; 603:91-101. [PMID: 27210740 DOI: 10.1016/j.abb.2016.05.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 05/14/2016] [Accepted: 05/17/2016] [Indexed: 11/20/2022]
Abstract
The aim of the present study is to establish the mechanism associated with the proliferation of PASMCs under ANG II stimulation. The results showed that treatment of PASMCs with ANG II induces an increase in cell proliferation and 100 nM was the optimum concentration for maximum increase in proliferation of the cells. Pretreatment of the cells with AT1, but not AT2, receptor antagonist inhibited ANG II induced cell proliferation. Pretreatment with pharmacological and genetic inhibitors of sphingomyelinase (SMase) and sphingosine kinase (SPHK) prevented ANG II-induced cell proliferation. ANG II has also been shown to induce SMase activity, SPHK phosphorylation and S1P production. In addition, ANG II caused an increase in proMMP-2 expression and activation, ERK1/2 phosphorylation and NADPH oxidase activation. Upon inhibition of MMP-2, SMase activity and S1P level were curbed leading to inhibition of cell proliferation. SPHK was phosphorylated by ERK1/2 during ET-1 stimulation of the cells. ANG II-induced ERK1/2 phosphorylation and proMMP-2 expression and activation in the cells were abrogated upon inhibition of NADPH oxidase activity. Overall, NADPH oxidase plays an important role in proMMP-2 expression and activation and that MMP-2 mediated SMC proliferation occurs through the involvement of Spm-Cer-S1P signaling axis under ANG II stimulation of PASMCs.
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25
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Chang M. Restructuring of the extracellular matrix in diabetic wounds and healing: A perspective. Pharmacol Res 2016; 107:243-248. [DOI: 10.1016/j.phrs.2016.03.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 03/10/2016] [Indexed: 12/15/2022]
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26
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Chakrabarti S, Wu J. Bioactive peptides on endothelial function. FOOD SCIENCE AND HUMAN WELLNESS 2016. [DOI: 10.1016/j.fshw.2015.11.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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27
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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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28
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Otto S, Deussen A, Zatschler B, Müller B, Neisser A, Barth K, Morawietz H, Kopaliani I. A novel role of endothelium in activation of latent pro-membrane type 1 MMP and pro-MMP-2 in rat aorta. Cardiovasc Res 2015; 109:409-18. [PMID: 26598508 DOI: 10.1093/cvr/cvv256] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 11/14/2015] [Indexed: 11/13/2022] Open
Abstract
AIMS Aortic stiffness is an independent risk factor for progression of cardiovascular diseases. Degradation of elastic fibres in aorta due to angiotensin II (ANGII)-stimulated overactivation of latent membrane type 1 matrix metalloproteinase (MT1MMP) and matrix metalloproteinase-2 (MMP2) is regarded to represent an important cause of aortic stiffness. Therefore, clarification of the causal mechanisms triggering the overactivation of these MMPs is of utmost importance. This study addresses the endothelium as a novel key activator of latent pro-MT1MMP and pro-MMP2 in rat aorta. METHODS AND RESULTS Using a co-culture model of rat aortic endothelial cells (ECs) and smooth muscle cells (SMCs), we found that ANGII stimulation resulted in activation of latent pro-MT1MMP and pro-MMP2 in SMCs exclusively when co-cultured with ECs (assessed with western blot and gelatin zymography, respectively). EC-specific AT1 receptor stimulation triggered endothelin-1 release and paracrine action on SMCs. Endothelin-1 increased expression and activity of pro-protein convertase furin in SMCs via endothelin receptor type A (assessed with qPCR and furin activity assay, respectively). Consequently, furin acted in two ways. First, it increased the activation of latent pro-MT1MMP and, second, it activated pro-αvβ3 integrin. Both pathways led to overactivation of latent pro-MMP2. In vitro findings in the co-culture model were fully consistent with the ex vivo findings obtained in isolated rat aorta. CONCLUSIONS We propose that the endothelium under ANGII stimulation acts as a novel and key activator of latent pro-MT1MMP and pro-MMP2 in SMCs of rat aorta. Therefore, endothelium may critically contribute to pathophysiology of aortic stiffness.
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Affiliation(s)
- Sören Otto
- Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany
| | - Andreas Deussen
- Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany
| | - Birgit Zatschler
- Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany
| | - Bianca Müller
- Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany
| | - Anja Neisser
- Department of Anatomy, Faculty of Medicine, Technische Universität Dresden, Germany
| | - Kathrin Barth
- Department of Anatomy, Faculty of Medicine, Technische Universität Dresden, Germany
| | - Henning Morawietz
- Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University, Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Germany
| | - Irakli Kopaliani
- Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany
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Pernomian L, do Prado AF, Gomes MS, Pernomian L, da Silva CH, Gerlach RF, de Oliveira AM. MAS receptors mediate vasoprotective and atheroprotective effects of candesartan upon the recovery of vascular angiotensin-converting enzyme 2–angiotensin-(1-7)–MAS axis functionality. Eur J Pharmacol 2015; 764:173-188. [DOI: 10.1016/j.ejphar.2015.07.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Revised: 06/30/2015] [Accepted: 07/01/2015] [Indexed: 11/15/2022]
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30
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Zhu L, Carretero OA, Xu J, Harding P, Ramadurai N, Gu X, Peterson E, Yang XP. Activation of angiotensin II type 2 receptor suppresses TNF-α-induced ICAM-1 via NF-кB: possible role of ACE2. Am J Physiol Heart Circ Physiol 2015; 309:H827-34. [PMID: 26163449 DOI: 10.1152/ajpheart.00814.2014] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 07/09/2015] [Indexed: 11/22/2022]
Abstract
ANG II type 2 receptor (AT2) and ANG I-converting enzyme 2 (ACE2) are important components of the renin-ANG system. Activation of AT2 and ACE2 reportedly counteracts proinflammatory effects of ANG II. However, the possible interaction between AT2 and ACE2 has never been established. We hypothesized that activation of AT2 increases ACE2 activity, thereby preventing TNF-α-stimulated ICAM-1 expression via inhibition of NF-κB signaling. Human coronary artery endothelial cells were pretreated with AT2 antagonist PD123319 (PD) or ACE2 inhibitor DX600 and then stimulated with TNF-α in the presence or absence of AT2 agonist CGP42112 (CGP). We found that AT2 agonist CGP increased both ACE2 protein expression and activity. This effect was blunted by AT2 antagonist PD. ICAM-1 expression was very low in untreated cells but greatly increased by TNF-α. Activation of AT2 with agonist CGP or with ANG II under concomitant AT1 antagonist reduced TNF-α-induced ICAM-1 expression, which was reversed by AT2 antagonist PD or ACE2 inhibitor DX600 or knockdown of ACE2 with small interfering RNA. AT2 activation also suppressed TNF-α-stimulated phosphorylation of inhibitory κB (p-IκB) and NF-κB activity. Inhibition of ACE2 reversed the inhibitory effect of AT2 on TNF-α-stimulated p-IκB and NF-κB activity. Our findings suggest that stimulation of AT2 reduces TNF-α-stimulated ICAM-1 expression, which is partly through ACE2-mediated inhibition of NF-κB signaling.
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Affiliation(s)
- Liping Zhu
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and
| | - Oscar A Carretero
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and
| | - Jiang Xu
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and
| | - Pamela Harding
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and
| | - Nithya Ramadurai
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and
| | - Xiaosong Gu
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and
| | - Edward Peterson
- Department of Public Health Science, Henry Ford Hospital, Detroit, Michigan
| | - Xiao-Ping Yang
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and
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31
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Demirtaş T, Utkan T, Karson A, Yazır Y, Bayramgürler D, Gacar N. The link between unpredictable chronic mild stress model for depression and vascular inflammation? Inflammation 2015; 37:1432-8. [PMID: 24614944 DOI: 10.1007/s10753-014-9867-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Inflammation has been suggested to be associated with stress-induced depression and cardiovascular dysfunction. Tumor necrosis factor alpha (TNF-α) is a major cytokine in the activation of neuroendocrine, immune, and behavioral responses. In this study, we investigated the effects of infliximab (a TNF-α inhibitor) on endothelium-dependent vascular reactivity, systemic blood pressure, and endothelial nitric oxide synthase (eNOS) immunoreactivity in the unpredictable chronic mild stress (UCMS) model of depression in rats. There was no significant change between all groups in the systemic blood pressure. In UCMS, endothelium-dependent relaxation of the smooth muscle in response to carbachol was significantly decreased with 50 % maximal response (E max) and pD2 values compared with the controls. Infliximab was able to reverse this UCMS effect. Relaxation in response to the nitric oxide (NO) donor sodium nitroprusside and papaverine and KCl-induced contractile responses was similar between groups. In UCMS, decreased expression of eNOS was detected. Moreover, there was no significant change in UCMS + infliximab group with respect to control rats. Our results suggest that tumor necrosis factor-alpha (TNF-α) could be a major mediator of vascular dysfunction associated with UCMS, leading to decreased expression of eNOS.
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MESH Headings
- Animals
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology
- Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/therapeutic use
- Aorta, Thoracic/drug effects
- Aorta, Thoracic/metabolism
- Aorta, Thoracic/pathology
- Chronic Disease
- Depression/metabolism
- Depression/pathology
- Disease Models, Animal
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/pathology
- Inflammation/drug therapy
- Inflammation/metabolism
- Inflammation/pathology
- Infliximab
- Male
- Organ Culture Techniques
- Rats
- Rats, Wistar
- Stress, Psychological/metabolism
- Stress, Psychological/pathology
- Vasodilation/drug effects
- Vasodilation/physiology
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Affiliation(s)
- Tuğçe Demirtaş
- Department of Pharmacology, Medical Faculty, Kocaeli University, Medical Faculty, 41380, Kocaeli, Turkey,
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Takao T, Horino T, Matsumoto R, Shimamura Y, Ogata K, Inoue K, Taniguchi Y, Taguchi T, Terada Y. Possible roles of tumor necrosis factor-α and angiotensin II type 1 receptor on high glucose-induced damage in renal proximal tubular cells. Ren Fail 2014; 37:160-4. [PMID: 25222109 DOI: 10.3109/0886022x.2014.959434] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Recent studies have identified that high glucose-induced renal tubular cell damage. We previously demonstrated that high glucose treatment induced oxidative stress in human renal proximal tubular epithelial cells (RPTECs), and angiotensin II type 1 (AT1) receptor blockers reduce high glucose-induced oxidative stress in RPTEC possibly via blockade of intracellular as well as extracellular AT1 receptor. However, exact roles of tumor necrosis factor (TNF)-α and AT1 receptor on high glucose-induced renal tubular function remain unclear. N-acetyl-beta-glucosaminidase (NAG), concentrations of TNF-α/angiotensin II and p22(phox) protein levels after high glucose treatment with or without AT1 receptor blocker or thalidomide, an inhibitor of TNF-α protein synthesis, were measured in immortalized human renal proximal tubular epithelial cells (HK2 cells). AT1 receptor knockdown was performed with AT1 receptor small interfering RNA (siRNA). High glucose treatment (30 mM) significantly increased NAG release, TNF-α/angiotensin II concentrations in cell media and p22(phox) protein levels compared with those in regular glucose medium (5.6 mM). Candesartan, an AT1R blocker, showed a significant reduction on high glucose-induced NAG release, TNF-α concentrations and p22(phox) protein levels in HK2 cells. In addition, significant decreases of NAG release, TNF-α concentrations and p22(phox) protein levels in HK2 cells were observed in high glucose-treated group with thalidomide. AT1R knockdown with siRNA markedly reversed high glucose, angiotensin II or TNF-α-induced p22(phox) protein levels in HK2 cells. TNF-α may be involved in high glucose-induced renal tubular damage in HK2 cells possibly via AT1 receptor signaling.
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Affiliation(s)
- Toshihiro Takao
- Department of Health Care Medicine, Kawasaki Medical School , Kurashiki , Japan and
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33
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Ham SA, Lee H, Hwang JS, Kang ES, Yoo T, Paek KS, Do JT, Park C, Oh JW, Kim JH, Han CW, Seo HG. Activation of Peroxisome Proliferator-Activated Receptor δ Inhibits Angiotensin II-Induced Activation of Matrix Metalloproteinase-2 in Vascular Smooth Muscle Cells. J Vasc Res 2014; 51:221-30. [DOI: 10.1159/000365250] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 06/07/2014] [Indexed: 11/19/2022] Open
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Inhibition of MMP-2 expression with siRNA increases baseline cardiomyocyte contractility and protects against simulated ischemic reperfusion injury. BIOMED RESEARCH INTERNATIONAL 2014; 2014:810371. [PMID: 25147815 PMCID: PMC4131446 DOI: 10.1155/2014/810371] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Accepted: 06/25/2014] [Indexed: 11/17/2022]
Abstract
Matrix metalloproteinases (MMPs) significantly contribute to ischemia reperfusion (I/R) injury, namely, by the degradation of contractile proteins. However, due to the experimental models adopted and lack of isoform specificity of MMP inhibitors, the cellular source and identity of the MMP(s) involved in I/R injury remain to be elucidated. Using isolated adult rat cardiomyocytes, subjected to chemically induced I/R-like injury, we show that specific inhibition of MMP-2 expression and activity using MMP-2 siRNA significantly protected cardiomyocyte contractility from I/R-like injury. This was also associated with increased expression of myosin light chains 1 and 2 (MLC1/2) in comparison to scramble siRNA transfection. Moreover, the positive effect of MMP-2 siRNA transfection on cardiomyocyte contractility and MLC1/2 expression levels was also observed under control conditions, suggesting an important additional role for MMP-2 in physiological sarcomeric protein turnover. This study clearly demonstrates that intracellular expression of MMP-2 plays a significant role in sarcomeric protein turnover, such as MLC1 and MLC2, under aerobic (physiological) conditions. In addition, this study identifies intracellular/autocrine, cardiomyocyte-produced MMP-2, rather than paracrine/extracellular, as responsible for the degradation of MLC1/2 and consequent contractile dysfunction in cardiomyocytes subjected to I/R injury.
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Gao TC, Cho JY, Feng LY, Chanmuang S, Park SY, Ham KS, Auh CK, Pai TK. Mineral-rich solar sea salt generates less oxidative stress in rats than mineral-deficient salt. Food Sci Biotechnol 2014. [DOI: 10.1007/s10068-014-0128-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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36
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Kopaliani I, Martin M, Zatschler B, Bortlik K, Müller B, Deussen A. Cell-specific and endothelium-dependent regulations of matrix metalloproteinase-2 in rat aorta. Basic Res Cardiol 2014; 109:419. [PMID: 24907869 DOI: 10.1007/s00395-014-0419-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 05/12/2014] [Accepted: 05/26/2014] [Indexed: 01/04/2023]
Abstract
Chronic activation of angiotensin II (ANGII) and matrix metalloproteinase-2 (MMP-2) during hypertension contributes to increased aortic stiffness. We studied signalling mechanisms employed by ANGII in the regulation of latent (pro-) and active forms of MMP-2 in rat aortic endothelial and smooth muscle cells, along with isolated rat aorta. Using western blotting, we demonstrate that ANGII (1 µmol/L) significantly (P < 0.01) increases pro-MMP-2 protein expression after 8 h not only in endothelial and smooth muscle cells, but also in isolated rat aorta. We demonstrate that ANGII acts via AT1 receptor-activated cell-specific pathways. In endothelial cells, the JNK1/c-jun pathway is activated, whereas in smooth muscle cells, the JAK2/STAT3 pathway. Activation of JAK2/STAT3 pathway in response to ANGII was EGF receptor-dependent. Results obtained in cell culture are in agreement with the results obtained in isolated aorta. However, active MMP-2 was not found under cell culture conditions, whereas in isolated aorta, active MMP-2 was significantly (P < 0.05) increased after stimulation with ANGII, as detected by gelatine zymography. This increase of MMP-2 activity was not inhibited by blocking the pathways we identified to control pro-MMP-2 protein expression, but was abolished in the absence of endothelium. Our findings demonstrate that ANGII regulates pro-MMP-2 protein expression via cell-specific pathways in rat aorta. The endothelium may play an essential role in the activation of pro-MMP-2. These results may lead to new strategies for inhibiting MMP-2 expression and activity in distinct cell types of the aortic wall.
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Affiliation(s)
- Irakli Kopaliani
- Medical Faculty Carl Gustav Carus, Department of Physiology, TU Dresden, Fetscherstr. 74, Dresden, Germany
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Pires PW, Girgla SS, McClain JL, Kaminski NE, van Rooijen N, Dorrance AM. Improvement in middle cerebral artery structure and endothelial function in stroke-prone spontaneously hypertensive rats after macrophage depletion. Microcirculation 2014; 20:650-61. [PMID: 23647512 DOI: 10.1111/micc.12064] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Accepted: 04/30/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Inflammation is involved in the pathogenesis of hypertension. Hypertensive animals have an increased number of perivascular macrophages in cerebral arteries. Macrophages might be involved in remodeling of the cerebral vasculature. We hypothesized that peripheral macrophage depletion would improve MCA structure and function in hypertensive rats. METHODS For macrophage depletion, six-week-old stroke-prone spontaneously hypertensive rats (SHRSP) were treated with CLOD, 10 mL/kg every three or four days, i.p., or vehicle (PBS lipo). MCA structure and function were analyzed by pressure and wire myography. RESULTS Blood pressure was not affected by CLOD. The number of perivascular CD163-positive cells per microscopic field was reduced in the brain of SHRSP+CLOD. CLOD treatment caused an improvement in endothelium-dependent dilation after intralumenal perfusion of ADP and incubation with Ach. Inhibition of NO production blunted the Ach response, and endothelium-independent dilation was not altered. At an intralumenal pressure of 80 mmHg, MCA from SHRSP+CLOD showed increased lumen diameter, decreased wall thickness, and wall-to-lumen ratio. Cross-sectional area of pial arterioles from SHRSP+CLOD was higher than PBS lipo. CONCLUSIONS These results suggest that macrophage depletion attenuates MCA remodeling and improves MCA endothelial function in SHRSP.
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Affiliation(s)
- Paulo W Pires
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA
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Serum Levels of the Adipokine Zinc- α 2-glycoprotein Are Decreased in Patients with Hypertension. ISRN ENDOCRINOLOGY 2014; 2014:374090. [PMID: 24665369 PMCID: PMC3934454 DOI: 10.1155/2014/374090] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 12/22/2013] [Indexed: 01/28/2023]
Abstract
Objective. Zinc-α2-glycoprotein (ZAG) has recently been proposed as a new adipokine involved in body weight regulation. The purpose of this study is to investigate serum levels of ZAG in patients with hypertension and its association with related characteristics. Methods. 32 hypertension patients and 42 normal controls were recruited and the relationship between serum ZAG, total and high molecular weight (HMW) adiponectin, and tumor necrosis factor-α (TNFα) determined by enzyme-linked immunosorbent assay (ELISA) and metabolic-related parameters was investigated. Results. Serum ZAG concentrations were significantly lowered in patients with hypertension compared with healthy controls (61.4 ± 32 versus 78.3 ± 42 μg/mL, P < 0.05). The further statistical analysis demonstrated that serum ZAG levels were negatively correlated with waist-to-hip ratio (WHR) (r = −0.241, P < 0.05) and alanine aminotransferase (ALT) (r = −0.243, P < 0.05). Additionally, serum HMW adiponectin significantly decreased, while TNFα greatly increased in hypertension patients as compared with healthy controls (2.32 ± 0.41 versus 5.24 ± 1.02 μg/mL, 3.30 ± 1.56 versus 2.34 ± 0.99 pg/mL, P < 0.05). Conclusions. Serum ZAG levels are significantly lowered in hypertension patients and negatively correlated with obesity-related item WHR, suggesting ZAG is a factor associated with hypertension.
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Wang Z, Ren Z, Hu Z, Hu X, Zhang H, Wu H, Zhang M. Angiotensin-II induces phosphorylation of ERK1/2 and promotes aortic adventitial fibroblasts differentiating into myofibroblasts during aortic dissection formation. J Mol Histol 2013; 45:401-12. [DOI: 10.1007/s10735-013-9558-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 11/26/2013] [Indexed: 10/25/2022]
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Majumder K, Chakrabarti S, Morton JS, Panahi S, Kaufman S, Davidge ST, Wu J. Egg-derived tri-peptide IRW exerts antihypertensive effects in spontaneously hypertensive rats. PLoS One 2013; 8:e82829. [PMID: 24312436 PMCID: PMC3843735 DOI: 10.1371/journal.pone.0082829] [Citation(s) in RCA: 101] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 11/07/2013] [Indexed: 02/07/2023] Open
Abstract
Background There is a growing interest in using functional food components as therapy for cardiovascular diseases such as hypertension. We have previously characterized a tri-peptide IRW (Ile-Arg-Trp) from egg white protein ovotransferrin; this peptide showed anti-inflammatory, anti-oxidant and angiotensin converting enzyme (ACE) inhibitor properties invitro. Given the pathogenic roles played by angiotensin, oxidative stress and inflammation in the spontaneously hypertensive rat (SHR), we tested the therapeutic potential of IRW in this well-established model of hypertension. Methods and Results 16–17 week old male SHRs were orally administered IRW at either a low dose (3 mg/Kg BW) or a high dose (15 mg/Kg BW) daily for 18 days. Blood pressure (BP) and heart rate were measured by telemetry. Animals were sacrificed at the end of the treatment for vascular function studies and measuring markers of inflammation. IRW treatment attenuated mean BP by ~10 mmHg and ~40 mmHg at the low- and high-dose groups respectively compared to untreated SHRs. Heart rate was not affected. Reduction in BP was accompanied by the restoration of diurnal variations in BP, preservation of nitric oxide dependent vasorelaxation, as well as reduction of plasma angiotensin II, other inflammatory markers and tissue fibrosis. Conclusion Our results demonstrate anti-hypertensive effects of IRW invivo likely mediated through ACE inhibition, endothelial nitric oxide synthase and anti-inflammatory properties.
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Affiliation(s)
- Kaustav Majumder
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Subhadeep Chakrabarti
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Jude S. Morton
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Sareh Panahi
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Susan Kaufman
- Women and Children’s Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Sandra T. Davidge
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada
- Women and Children’s Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Jianping Wu
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
- Women and Children’s Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
- * E-mail:
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Qi J, Zhang DM, Suo YP, Song XA, Yu XJ, Elks C, Lin YX, Xu YY, Zang WJ, Zhu Z, Kang YM. Renin-angiotensin system modulates neurotransmitters in the paraventricular nucleus and contributes to angiotensin II-induced hypertensive response. Cardiovasc Toxicol 2013; 13:48-54. [PMID: 22971929 DOI: 10.1007/s12012-012-9184-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Angiotensin II (ANG II)-induced inflammatory and oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether renin-angiotensin system (RAS) activation in the hypothalamic paraventricular nucleus (PVN) contributes to the ANG II-induced hypertensive response via interaction with neurotransmitters in the PVN. Rats underwent subcutaneous infusion of ANG II or saline for 4 weeks. These rats were treated for 4 weeks through bilateral PVN infusion with either vehicle or losartan (LOS), an angiotensin II type 1 receptor (AT1-R) antagonist, via osmotic minipump. ANG II infusion resulted in higher levels of glutamate, norepinephrine (NE), AT1-R and pro-inflammatory cytokines (PIC), and lower level of gamma-aminobutyric acid (GABA) in the PVN. Rats receiving ANG II also had higher levels of mean arterial pressure, plasma PIC, NE and aldosterone than control animals. PVN treatment with LOS attenuated these ANG II-induced hypertensive responses. In conclusion, these findings suggest that the RAS activation in the PVN contributes to the ANG II-induced hypertensive response via interaction with PIC and neurotransmitters (glutamate, NE and GABA) in the PVN.
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Affiliation(s)
- Jie Qi
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China
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Silveira KD, Coelho FM, Vieira AT, Barroso LC, Queiroz-Junior CM, Costa VV, Sousa LFC, Oliveira ML, Bader M, Silva TA, Santos RAS, Silva ACSE, Teixeira MM. Mechanisms of the anti-inflammatory actions of the angiotensin type 1 receptor antagonist losartan in experimental models of arthritis. Peptides 2013; 46:53-63. [PMID: 23727291 DOI: 10.1016/j.peptides.2013.05.012] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Revised: 05/14/2013] [Accepted: 05/14/2013] [Indexed: 12/28/2022]
Abstract
Angiotensin (Ang) II and its AT1 receptors have been implicated in the pathogenesis of rheumatoid arthritis. Activation of the counter-regulatory Ang-(1-7)-Mas receptor axis may contribute to some of the effects of AT₁ receptor blockers (ARBs). In this study, we have used losartan, an ARB, to investigate the role of and the mechanisms by which AT₁ receptors participated in two experimental models of arthritis: antigen-induced arthritis (AIA) in mice and adjuvant-induced arthritis (AdIA) in rats. Treatment with losartan decreased neutrophil recruitment, hypernociception and the production of TNF-α, IL-1β and chemokine (C-X-C motif) ligand 1 in mice subjected to AIA. Histopathological analysis showed significant reduction of tissue injury and inflammation and decreased proteoglycan loss. In addition to decreasing cytokine production, losartan directly reduced leukocyte rolling and adhesion. Anti-inflammatory effects of losartan were not associated to Mas receptor activation and/or Ang-(1-7) production. Anti-inflammatory effects were reproduced in rats subjected to AdIA. This study shows that ARBs have potent anti-inflammatory effects in animal models of arthritis. Mechanistically, reduction of leukocyte accumulation and of joint damage was associated with local inhibition of cytokine production and direct inhibition of leukocyte-endothelium interactions. The anti-inflammatory actions of losartan were accompanied by functional improvement of the joint, as seen by reduced joint hypernociception. These findings support the use of ARBs for the treatment of human arthritis and provide potential mechanisms for the anti-inflammatory actions of these compounds.
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MESH Headings
- Angiotensin I/biosynthesis
- Angiotensin II Type 1 Receptor Blockers/pharmacology
- Animals
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology
- Arthritis, Experimental/drug therapy
- Arthritis, Rheumatoid/drug therapy
- Cell Adhesion/drug effects
- Chemokine CXCL1/biosynthesis
- Disease Models, Animal
- Female
- Hyperalgesia/drug therapy
- Inflammation/drug therapy
- Interleukin-1beta/biosynthesis
- Leukocyte Rolling/drug effects
- Losartan/pharmacology
- Male
- Mice
- Mice, Inbred C57BL
- Neutrophil Infiltration/drug effects
- Peptide Fragments/biosynthesis
- Proto-Oncogene Mas
- Proto-Oncogene Proteins/metabolism
- Rats
- Rats, Sprague-Dawley
- Receptor, Angiotensin, Type 1/drug effects
- Receptor, Angiotensin, Type 1/metabolism
- Receptors, G-Protein-Coupled/metabolism
- Tumor Necrosis Factor-alpha/biosynthesis
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Affiliation(s)
- Kátia D Silveira
- Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Brazil
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Inhibition of TNF in the brain reverses alterations in RAS components and attenuates angiotensin II-induced hypertension. PLoS One 2013; 8:e63847. [PMID: 23691105 PMCID: PMC3655013 DOI: 10.1371/journal.pone.0063847] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 04/05/2013] [Indexed: 02/07/2023] Open
Abstract
Dysfunction of brain renin-angiotensin system (RAS) components is implicated in the development of hypertension. We previously showed that angiotensin (Ang) II-induced hypertension is mediated by increased production of proinflammatory cytokines (PIC), including tumor necrosis factor (TNF), in brain cardiovascular regulatory centers such as the paraventricular nucleus (PVN). Presently, we tested the hypothesis that central TNF blockade prevents dysregulation of brain RAS components and attenuates Ang II-induced hypertension. Male Sprague-Dawley rats were implanted with radio-telemetry transmitters to measure mean arterial pressure (MAP) and subjected to intracerebroventricular (i.c.v.) infusion of etanercept (10 µg/kg/day) with/without concurrent subcutaneous 4-week Ang II (200 ng/kg/min) infusion. Chronic Ang II infusion resulted in a significant increase in MAP and cardiac hypertrophy, which was attenuated by inhibition of brain TNF with etanercept. Etanercept treatment also attenuated Ang II-induced increases in PIC and decreases in IL-10 expression in the PVN. Additionally, Ang II infusion increased expression of pro-hypertensive RAS components (ACE and AT1R), while decreasing anti-hypertensive RAS components (ACE2, Mas, and AT2 receptors), within the PVN. I.c.v. etanercept treatment reversed these changes. Ang II-infusion was associated with increased oxidative stress as indicated by increased NAD(P)H oxidase activity and super oxide production in the PVN, which was prevented by inhibition of TNF. Moreover, brain targeted TNF blockade significantly reduced Ang II-induced NOX-2 and NOX-4 mRNA and protein expression in the PVN. These findings suggest that chronic TNF blockade in the brain protects rats against Ang II-dependent hypertension and cardiac hypertrophy by restoring the balance between pro- and anti-hypertensive RAS axes and inhibiting PIC and oxidative stress genes and proteins in the PVN.
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Inflammation and hypertension: are there regional differences? Int J Hypertens 2013; 2013:492094. [PMID: 23573414 PMCID: PMC3618944 DOI: 10.1155/2013/492094] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 02/19/2013] [Indexed: 12/16/2022] Open
Abstract
Hypertension is a chronic disease with global prevalence and incidence rapidly increasing in low and medium income countries. The surveillance of cardiovascular risk factors, such as hypertension, is a global health priority in order to estimate the burden and trends, to appropriately direct resources, and to measure the effect of interventions. We propose here that the adoption of Western lifestyles in low and middle incomes countries has dramatically increased the prevalence of abdominal obesity, which is the main source of proinflammatory cytokines, and that the vascular systemic inflammation produced by adipose tissue contributes to the development of hypertension. The concentration of proinflammatory cytokines is higher in the Latin American population than that reported in developed countries, suggesting a higher susceptibility to develop systemic low-degree inflammation at a given level of abdominal obesity. These particularities are important to be considered when planning resources for health care programs. Moreover, studying these singularities may provide a better understanding of the causes of the burden of cardiovascular risk factors and the remarkable variability in the prevalence of these medical conditions within and between countries.
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Proteasome inhibition decreases inflammation in human endothelial cells exposed to lipopolysaccharide. J Cardiovasc Pharmacol 2013; 60:381-9. [PMID: 22820895 DOI: 10.1097/fjc.0b013e3182657eec] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND The proteasome degrades ubiquitinated proteins and is the major pathway for intracellular protein degradation. The role of the proteasome in endothelial dysfunction observed in septic shock remains unknown. We stimulated primary cultures of human umbilical vein endothelial cells with lipopolysaccharide (LPS) and investigated effects on the proteasome. We hypothesized that proteasome inhibition would decrease endothelial cell activation, oxidative stress, and alter the proteome. METHODS Endothelial cells were exposed to LPS (100 ng/mL) for 6 hours with or without lactacystin (5 mM), a proteasome inhibitor. Proteasome content and ubiquitinated proteins were measured by enzyme-linked immunosorbent assay and immunoblot, respectively. Markers of cellular activation, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, were measured by immunoblot and immunoassay. Superoxide anion production was determined by dihydroethidium assay, and nitrotyrosine (a marker of peroxynitrite) was visualized by immunofluoresence. The endothelial cell proteome was analyzed by 2D gel electrophoresis. RESULTS LPS stimulation of endothelial cells significantly increased proteasome content, whereas the total levels of ubquitinated proteins decreased. This suggests that LPS activates the proteasome system in endothelial cells. LPS increased total content and cell surface expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, whereas proteasome inhibition ameliorated these increases. LPS increased both superoxide anion production and nitrotyrosine staining. Proteasome inhibition decreased both markers of cellular oxidative stress. Proteomic analysis identified two novel proteins upregulated by LPS and normalized with proteasome inhibition as follows: guanine nucleotide binding protein-1 and heterogeneous ribonucleoprotein K transcript variant. CONCLUSIONS These results suggest that inhibition of the proteasome diminishes a number of markers of cellular stress induced by LPS. The proteasome may be a promising therapeutic target in clinical situations of severe pro-inflammatory stress.
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Majumder K, Chakrabarti S, Davidge S, Wu J. Structure and activity study of egg protein ovotransferrin derived peptides (IRW and IQW) on endothelial inflammatory response and oxidative stress. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2013; 61:2120-9. [PMID: 23317476 PMCID: PMC3592331 DOI: 10.1021/jf3046076] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Egg protein ovotransferrin derived peptides (IRW and IQW) can attenuate tumor necrosis factor (TNF) induced inflammatory responses and oxidative stress in endothelial cells. The present study investigates the structural requirements and molecular mechanisms underlying these events. Whereas IRW significantly inhibited TNF-induced up-regulation of intercellular cell adhesion molecule-I (ICAM-1) and vascular cell adhesion molecule-I (VCAM-1), IQW could inhibit only the up-regulation of ICAM-1. The anti-inflammatory effects of these peptides appeared to be mediated by the nuclear factor-κB (NF-κB) pathway, which was differentially regulated by IRW and IQW. Both IRW and IQW exhibited antioxidant effects as shown by reduction of TNF-induced superoxide generation. The structural integrity of these peptides was essential for their activities, because dipeptides or the combination of constituent amino acids did not exhibit the same effect. This study demonstrated the significance of the structural integrity of these two tripeptides in attenuating endothelial inflammation and oxidative stress, indicating their potential as nutraceuticals.
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Affiliation(s)
- Kaustav Majumder
- Department of Agricultural
Food and Nutritional Science, Faculty of Agricultural
Life and Environmental Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Subhadeep Chakrabarti
- Departments of Obstetrics
and Gynecology and Physiology, Women and Children’s
Health Research Institute, Cardiovascular Research Centre and the
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Sandra
T. Davidge
- Departments of Obstetrics
and Gynecology and Physiology, Women and Children’s
Health Research Institute, Cardiovascular Research Centre and the
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Jianping Wu
- Department of Agricultural
Food and Nutritional Science, Faculty of Agricultural
Life and Environmental Sciences, University of Alberta, Edmonton, Alberta, Canada
- Postal address: 4-10 Ag/For Centre,
Edmonton, AB, Canada T6G 2P5. Phone: (780) 492-6885. Fax (780) 492-4265. E-mail:
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Piastowska-Ciesielska AW, Domińska K, Nowakowska M, Gajewska M, Gajos-Michniewicz A, Ochędalski T. Angiotensin modulates human mammary epithelial cell motility. J Renin Angiotensin Aldosterone Syst 2013; 15:419-29. [PMID: 23390187 DOI: 10.1177/1470320313475904] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Angiotensin II is an effector peptide showing multiple physiological effects, such as regulation of vascular tone, tissue growth and remodelling. Postlactational involution of mammary gland involves changes such as high matrix metalloproteinase activity and release of bioactive fragments of fibronectin and laminin, which may be directly regulated by angiotensin II. The aim of the present study was to evaluate the influence of angiotensin II on proliferation, viability and motility of normal human mammary epithelial cells (184A1 cell line) and to determine the role of angiotensin II receptors in these processes. MATERIALS AND METHODS Real-time reverse transcription-PCR, western blot and gelatin zymography were used to study the effect of angiotensin II on the expression of angiotensin receptors and matrix metalloproteinases in 184A1 cells. WST-1, AlamarBlue and BrdU assays were used as indicators of cell viability and proliferation after angiotensin II stimulation. Boyden chamber assays and monolayer wound migration assay were used to evaluate in vitro the changes in cell adhesion, migration and invasion. RESULTS Angiotensin II increased motility of the 184A1 cells and the ability of wound closure. Modifications in cell-substrate adhesion systems and increased secretion and activity of matrix metalloproteinases were also observed. The effect of angiotensin II was abolished by blocking angiotensin type 1 receptor with specific inhibitors candesartan and losartan. CONCLUSIONS The results indicate that angiotensin II modulates cell behaviour via AT1-R and stimulates secretion of MMP-2 by human mammary epithelial cells.
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Affiliation(s)
| | - Kamila Domińska
- Department of Comparative Endocrinology, Faculty of Biomedical Sciences and Postgraduate Training, Medical University of Lodz, Poland
| | - Magdalena Nowakowska
- Department of Molecular Carcinogenesis, Faculty of Biomedical Sciences and Postgraduate Training, Medical University of Lodz, Poland
| | - Małgorzata Gajewska
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences - SGGW, Poland
| | - Anna Gajos-Michniewicz
- Department of Comparative Endocrinology, Faculty of Biomedical Sciences and Postgraduate Training, Medical University of Lodz, Poland
| | - Tomasz Ochędalski
- Department of Comparative Endocrinology, Faculty of Biomedical Sciences and Postgraduate Training, Medical University of Lodz, Poland
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Refaat R, Salama M, Abdel Meguid E, El Sarha A, Gowayed M. Evaluation of the effect of losartan and methotrexate combined therapy in adjuvant-induced arthritis in rats. Eur J Pharmacol 2013; 698:421-8. [DOI: 10.1016/j.ejphar.2012.10.024] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Revised: 10/15/2012] [Accepted: 10/23/2012] [Indexed: 12/20/2022]
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G-protein coupled receptor 30 (GPR30): a novel regulator of endothelial inflammation. PLoS One 2012; 7:e52357. [PMID: 23285008 PMCID: PMC3527521 DOI: 10.1371/journal.pone.0052357] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 11/13/2012] [Indexed: 12/25/2022] Open
Abstract
Estrogen, the female sex hormone, is known to exert anti-inflammatory and anti-atherogenic effects. Traditionally, estrogen effects were believed to be largely mediated through the classical estrogen receptors (ERs). However, there is increasing evidence that G-protein coupled receptor 30 (GPR30), a novel estrogen receptor, can mediate many estrogenic effects on the vasculature. Despite this, the localization and functional significance of GPR30 in the human vascular endothelium remains poorly understood. Given this background, we examined the subcellular location and potential anti-inflammatory roles of GPR30 using human umbilical vein endothelial cells as a model system. Inflammatory changes were induced by treatment with tumor necrosis factor (TNF), a pro-inflammatory cytokine involved in atherogenesis and many other inflammatory conditions. We found that GPR30 was located predominantly in the endothelial cell nuclei. Treatment with the selective GPR30 agonist G-1 partially attenuated the TNF induced upregulation of pro-inflammatory proteins such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). This effect was completely abolished by the selective GPR30 antagonist G-15, suggesting that it was indeed mediated in a GPR30 dependent manner. Interestingly, estrogen alone had no effects on TNF-treated endothelium. Concomitant activation of the classical ERs blocked the anti-inflammatory effects of G-1, indicating opposing effects of GPR30 and the classical ERs. Our findings demonstrate that endothelial GPR30 is a novel regulator of the inflammatory response which could be a potential therapeutic target against atherosclerosis and other inflammatory diseases.
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Chakrabarti S, Davidge ST. Estradiol modulates tumor necrosis factor-induced endothelial inflammation: role of tumor necrosis factor receptor 2. J Vasc Res 2012; 50:21-34. [PMID: 23095497 DOI: 10.1159/000342736] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2012] [Accepted: 08/13/2012] [Indexed: 11/19/2022] Open
Abstract
The sex hormone estradiol (E(2)) appears to mediate both anti-atherogenic and pro-inflammatory effects in premenopausal women, suggesting a complex immunomodulatory role. Tumor necrosis factor (TNF) is a key pro-inflammatory cytokine involved in the pathogenesis of atherosclerosis and other inflammatory diseases. Alterations at the TNF receptors (TNFRs) and their downstream signaling/transcriptional pathways can affect inflammatory responses. Given this background, we hypothesized that chronic E(2) exposure would alter endothelial inflammatory response involving modulation at the levels of TNFRs and signaling pathways. HUVECs were used as the model system. Pre-treatment with E(2) did not significantly alter TNF-induced upregulation of pro-inflammatory molecules ICAM-1 (3-6 times) and VCAM-1 (5-7 times). However, pharmacological inhibition of transcriptional pathways suggested a partial shift from NF-ĸB (from 97 to 64%) towards the JNK/AP-1 pathway in ICAM-1 upregulation on E(2) treatment. In contrast, VCAM-1 expression remained NF-ĸB dependent in both control (∼96%) and E(2) treated (∼85%) cells. The pro-inflammatory TNF effects were mediated by TNFR1. Interestingly, E(2) pre-treatment increased TNFR2 levels in these cells. Concomitant TNFR2 activation (but not TNFR1 activation alone) led to the shift towards JNK/AP-1-mediated ICAM-1 upregulation in E(2)-treated cells, suggesting the effects of chronic E(2) to be dependent on TNFR2 signaling.
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Affiliation(s)
- Subhadeep Chakrabarti
- Departments of Obstetrics and Gynecology and Physiology, Women and Children's Health Research Institute, Cardiovascular Research Center and Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alta., Canada
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