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Richard A, Bocquet A, Belin de Chantemèle E, Retailleau K, Toutain B, Mongue-Din H, Guihot AL, Fassot C, Fromes Y, Henrion D, Loufrani L. Reduced microvascular flow-mediated dilation in Syrian hamsters lacking δ-sarcoglycan is caused by increased oxidative stress. Am J Physiol Heart Circ Physiol 2025; 328:H75-H83. [PMID: 39485294 DOI: 10.1152/ajpheart.00569.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 10/10/2024] [Accepted: 10/28/2024] [Indexed: 11/03/2024]
Abstract
δ-Sarcoglycan mutation reduces mechanotransduction and induces dilated cardiomyopathy with aging. We hypothesized that in young hamsters with δ-sarcoglycan mutation, which do not show cardiomyopathy, flow mechanotransduction might be affected in resistance arteries as the control of local blood flow. Flow-mediated dilation (FMD) was measured in isolated mesenteric resistance arteries, using 3-mo-old hamsters carrying a mutation in the δ-sarcoglycan gene (CH-147) and their control littermates. The FMD was significantly reduced in the CHF-147 group. Nevertheless, passive arterial diameter, vascular structure, and endothelium-independent dilation to sodium nitroprusside were not modified. Contraction induced by KCl was not modified, whereas contraction due to phenylephrine was increased. The basal nitric oxide production and total endothelial nitric oxide synthase (eNOS) expression levels were not altered. Nevertheless, eNOS phosphorylation, focal adhesion kinases, and RhoA expression were reduced in CH-147. In contrast, p47phox, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase, and reactive oxygen species (ROS) levels were higher in the endothelium of CHF-147 hamsters. Reducing ROS levels using the superoxide dismutase analog Tempol significantly restored the flow-mediated dilation (FMD) levels in CHF-147 hamsters. However, treatment with the COX-2 inhibitor NS-398 showed a nonsignificant improvement in FMD.NEW & NOTEWORTHY This study suggests that the sarcoglycan complex is selectively involved in flow-mediated dilation, thus highlighting its role in endothelial responsiveness to shear stress and amplifying tissue damage in myopathy.
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Affiliation(s)
- Alexis Richard
- MitoVasc, Carme, SFR ICAT, CNRS 6015, Inserm 1083, University of Angers, Angers, France
| | - Arnaud Bocquet
- MitoVasc, Carme, SFR ICAT, CNRS 6015, Inserm 1083, University of Angers, Angers, France
| | - Eric Belin de Chantemèle
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
- Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
| | - Kevin Retailleau
- MitoVasc, Carme, SFR ICAT, CNRS 6015, Inserm 1083, University of Angers, Angers, France
| | - Bertrand Toutain
- MitoVasc, Carme, SFR ICAT, CNRS 6015, Inserm 1083, University of Angers, Angers, France
| | - Héloïse Mongue-Din
- Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
| | - Anne-Laure Guihot
- MitoVasc, Carme, SFR ICAT, CNRS 6015, Inserm 1083, University of Angers, Angers, France
| | - Céline Fassot
- MitoVasc, Carme, SFR ICAT, CNRS 6015, Inserm 1083, University of Angers, Angers, France
| | - Yves Fromes
- Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
| | - Daniel Henrion
- MitoVasc, Carme, SFR ICAT, CNRS 6015, Inserm 1083, University of Angers, Angers, France
| | - Laurent Loufrani
- MitoVasc, Carme, SFR ICAT, CNRS 6015, Inserm 1083, University of Angers, Angers, France
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Puertas-Umbert L, Puig N, Camacho M, Dantas AP, Marín R, Martí-Fàbregas J, Jiménez-Xarrié E, Benitez S, Camps-Renom P, Jiménez-Altayó F. Serum from Stroke Patients with High-Grade Carotid Stenosis Promotes Cyclooxygenase-Dependent Endothelial Dysfunction in Non-ischemic Mice Carotid Arteries. Transl Stroke Res 2024; 15:140-152. [PMID: 36536168 PMCID: PMC10796474 DOI: 10.1007/s12975-022-01117-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/15/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022]
Abstract
Atherosclerosis is responsible for 20% of ischemic strokes, and severe carotid stenosis is associated with a higher incidence of first-ever and recurrent strokes. The release of pro-inflammatory mediators into the blood in severe atherosclerosis may aggravate endothelial dysfunction after stroke contributing to impair disease outcomes. We hypothesize that environments of severe carotid atherosclerotic disease worsen endothelial dysfunction in stroke linked to enhanced risk of further cerebrovascular events. We mounted nonischemic common carotid arteries from 2- to 4-month-old male Oncins France 1 mice in tissue baths for isometric contraction force measurements and exposed them to serum from men with a recent ischemic stroke and different degrees of carotid stenosis: low- or moderate-grade stenosis (LMGS; < 70%) and high-grade stenosis (HGS; ≥ 70%). The results show that serum from stroke patients induced an impairment of acetylcholine relaxations in mice carotid arteries indicative of endothelium dysfunction. This effect was more pronounced after incubation with serum from patients with a recurrent stroke or vascular death within 1 year of follow-up. When patients were stratified according to the degree of stenosis, serum from HGS patients induced more pronounced carotid artery endothelial dysfunction, an effect that was associated with enhanced circulating levels of IL-1β. Mechanistically, endothelial dysfunction was prevented by both nonselective and selective COX blockade. Altogether, the present findings add knowledge on the understanding of the mechanisms involved in the increased risk of stroke in atherosclerosis and suggest that targeting COX in the carotid artery wall may represent a potential novel therapeutic strategy for secondary stroke prevention.
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Affiliation(s)
- Lídia Puertas-Umbert
- Department of Pharmacology, Therapeutics and Toxicology, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Neuroscience Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Institut d'Investigació Biomèdica Sant Pau (IIB, SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Núria Puig
- Institut d'Investigació Biomèdica Sant Pau (IIB, SANT PAU), Barcelona, Spain
- Department of Molecular Biology and Biochemistry, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Mercedes Camacho
- Institut d'Investigació Biomèdica Sant Pau (IIB, SANT PAU), Barcelona, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Ana Paula Dantas
- Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Cardiovascular Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Rebeca Marín
- Department of Neurology, IIB SANT PAU, Hospital de La Santa Creu i Sant Pau, Barcelona, Spain
| | - Joan Martí-Fàbregas
- Department of Neurology, IIB SANT PAU, Hospital de La Santa Creu i Sant Pau, Barcelona, Spain
| | - Elena Jiménez-Xarrié
- Department of Neurology, IIB SANT PAU, Hospital de La Santa Creu i Sant Pau, Barcelona, Spain
| | - Sonia Benitez
- Institut d'Investigació Biomèdica Sant Pau (IIB, SANT PAU), Barcelona, Spain
- CIBER of Diabetes and Related Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Pol Camps-Renom
- Department of Neurology, IIB SANT PAU, Hospital de La Santa Creu i Sant Pau, Barcelona, Spain
| | - Francesc Jiménez-Altayó
- Department of Pharmacology, Therapeutics and Toxicology, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
- Neuroscience Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
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Akide Ndunge OB, Kilian N, Salman MM. Cerebral Malaria and Neuronal Implications of Plasmodium Falciparum Infection: From Mechanisms to Advanced Models. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2202944. [PMID: 36300890 PMCID: PMC9798991 DOI: 10.1002/advs.202202944] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 09/22/2022] [Indexed: 06/01/2023]
Abstract
Reorganization of host red blood cells by the malaria parasite Plasmodium falciparum enables their sequestration via attachment to the microvasculature. This artificially increases the dwelling time of the infected red blood cells within inner organs such as the brain, which can lead to cerebral malaria. Cerebral malaria is the deadliest complication patients infected with P. falciparum can experience and still remains a major public health concern despite effective antimalarial therapies. Here, the current understanding of the effect of P. falciparum cytoadherence and their secreted proteins on structural features of the human blood-brain barrier and their involvement in the pathogenesis of cerebral malaria are highlighted. Advanced 2D and 3D in vitro models are further assessed to study this devastating interaction between parasite and host. A better understanding of the molecular mechanisms leading to neuronal and cognitive deficits in cerebral malaria will be pivotal in devising new strategies to treat and prevent blood-brain barrier dysfunction and subsequent neurological damage in patients with cerebral malaria.
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Affiliation(s)
- Oscar Bate Akide Ndunge
- Department of Internal MedicineSection of Infectious DiseasesYale University School of Medicine300 Cedar StreetNew HavenCT06510USA
| | - Nicole Kilian
- Centre for Infectious Diseases, ParasitologyHeidelberg University HospitalIm Neuenheimer Feld 32469120HeidelbergGermany
| | - Mootaz M. Salman
- Department of PhysiologyAnatomy and GeneticsUniversity of OxfordOxfordOX1 3QUUK
- Kavli Institute for NanoScience DiscoveryUniversity of OxfordOxfordUK
- Oxford Parkinson's Disease CentreUniversity of OxfordOxfordUK
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Araujo P, Espe M, Lucena E, Yang Y, Holen E. Differential production of prostaglandins and prostacyclins by liver and head kidney cells from Atlantic salmon challenged with arachidonic and eicosapentaenoic acids. FISH AND SHELLFISH IMMUNOLOGY REPORTS 2021; 2:100015. [DOI: 10.1016/j.fsirep.2021.100015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/26/2021] [Accepted: 06/28/2021] [Indexed: 10/20/2022] Open
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Raees A, Bakhamis A, Mohamed-Ali V, Bashah M, Al-Jaber M, Abraham D, Clapp LH, Orie NN. Altered cyclooxygenase-1 and enhanced thromboxane receptor activities underlie attenuated endothelial dilatory capacity of omental arteries in obesity. Life Sci 2019; 239:117039. [PMID: 31704447 DOI: 10.1016/j.lfs.2019.117039] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/29/2019] [Accepted: 10/31/2019] [Indexed: 01/05/2023]
Abstract
AIMS Obesity is a risk factor for endothelial dysfunction, the severity of which is likely to vary depending on extent and impact of adiposity on the vasculature. This study investigates the roles of cyclooxygenase isoforms and thromboxane receptor activities in the differential endothelial dilatory capacities of arteries derived from omental and subcutaneous adipose tissues in obesity. MAIN METHODS Small arteries were isolated from omental and subcutaneous adipose tissues obtained from consented morbidly obese patients (n = 65, BMI 45 ± 6 kg m-2 [Mean ± SD]) undergoing bariatric surgery. Relaxation to acetylcholine was studied by wire myography in the absence or presence of indomethacin (10 μM, cyclooxygenase inhibitor), FR122047 (1 μM, cyclooxygenase-1 inhibitor), Celecoxib (4 μM, cyclooxygenase-2 inhibitor), Nω-Nitro-L-arginine methyl ester (L-NAME, 100 μM, nitric oxide synthase inhibitor) or combination of apamin (0.5 μM) and charybdotoxin (0.1 μM) that together inhibit endothelium-derived hyperpolarizing factor (EDHF). Contractions to U46619 (thromboxane A2 mimetic) were also studied. KEY FINDINGS Acetylcholine relaxation was significantly attenuated in omental compared with subcutaneous arteries from same patients (p < 0.01). Indomethacin (p < 0.01) and FR122047 (p < 0.001) but not Celecoxib significantly improved the omental arteriolar relaxation. Cyclooxygenase-1 mRNA and U46619 contractions were both increased in omental compared with subcutaneous arteries (p < 0.05). L-NAME comparably inhibited acetylcholine relaxation in both arteries, while apamin+charybdotoxin were less effective in omental compared with subcutaneous arteries. SIGNIFICANCE The results show that the depot-specific reduction in endothelial dilatory capacity of omental compared with subcutaneous arteries in obesity is in large part due to altered cyclooxygenase-1 and enhanced thromboxane receptor activities, which cause EDHF deficiency.
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Affiliation(s)
- Asmaa Raees
- Qatar Analytics and BioResearch Lab, Anti-Doping Lab Qatar, Qatar
| | - Aysha Bakhamis
- Qatar Analytics and BioResearch Lab, Anti-Doping Lab Qatar, Qatar
| | | | - Moataz Bashah
- Metabolic and Bariatric Surgery Department, Hamad Medical Corporation, Doha, Qatar
| | - Mashael Al-Jaber
- Qatar Analytics and BioResearch Lab, Anti-Doping Lab Qatar, Qatar
| | - David Abraham
- Centre for Rheumatology and Connective Tissue Diseases, Division of Medicine, University College London, UK
| | - Lucie H Clapp
- Institute of Cardiovascular Sciences, University College London, UK
| | - Nelson N Orie
- Qatar Analytics and BioResearch Lab, Anti-Doping Lab Qatar, Qatar.
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Marone G, Galdiero MR, Pecoraro A, Pucino V, Criscuolo G, Triassi M, Varricchi G. Prostaglandin D 2 receptor antagonists in allergic disorders: safety, efficacy, and future perspectives. Expert Opin Investig Drugs 2018; 28:73-84. [PMID: 30513028 DOI: 10.1080/13543784.2019.1555237] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Prostaglandin D2 (PGD2) is a major cyclooxygenase mediator that is synthesized by activated human mast cells and other immune cells. The biological effects of PGD2 are mediated by D-prostanoid (DP1), DP2 (CRTH2) and thromboxane prostanoid (TP) receptors that are expressed on several immune and non-immune cells involved in allergic inflammation. PGD2 exerts various proinflammatory effects relevant to the pathophysiology of allergic disorders. Several selective, orally active, DP2 receptor antagonists and a small number of DP1 receptor antagonists are being developed for the treatment of allergic disorders. AREAS COVERED The role of DP2 and DP1 receptor antagonists in the treatment of asthma and allergic rhinitis. EXPERT OPINION Head-to-head studies that compare DP1 antagonists with the standard treatment for allergic rhinitis are necessary to verify the role of these novel drugs as mono- or combination therapies. Further clinical trials are necessary to verify whether DP2 antagonists as monotherapies or, more likely, as add-on therapies, will be effective for the treatment of different phenotypes of adult and childhood asthma. Long-term studies are necessary to evaluate the safety of targeted anti-PGD2 treatments.
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Affiliation(s)
- Giancarlo Marone
- a Department of Public Health , University of Naples Federico II , Naples , Italy.,b Monaldi Hospital Pharmacy , Naples , Italy
| | - Maria Rosaria Galdiero
- c Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI) , University of Naples Federico II , Naples , Italy.,d WAO Center of Excellence , Naples , Italy
| | - Antonio Pecoraro
- c Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI) , University of Naples Federico II , Naples , Italy.,d WAO Center of Excellence , Naples , Italy
| | - Valentina Pucino
- e William Harvey Research Institute, Barts and The London School of Medicine &Dentistry , Queen Mary University of London , London , UK
| | - Gjada Criscuolo
- c Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI) , University of Naples Federico II , Naples , Italy.,d WAO Center of Excellence , Naples , Italy
| | - Maria Triassi
- a Department of Public Health , University of Naples Federico II , Naples , Italy
| | - Gilda Varricchi
- c Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI) , University of Naples Federico II , Naples , Italy.,d WAO Center of Excellence , Naples , Italy
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Peinhaupt M, Sturm EM, Heinemann A. Prostaglandins and Their Receptors in Eosinophil Function and As Therapeutic Targets. Front Med (Lausanne) 2017; 4:104. [PMID: 28770200 PMCID: PMC5515835 DOI: 10.3389/fmed.2017.00104] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 06/27/2017] [Indexed: 02/06/2023] Open
Abstract
Of the known prostanoid receptors, human eosinophils express the prostaglandin D2 (PGD2) receptors DP1 [also D-type prostanoid (DP)] and DP2 (also chemoattractant receptor homologous molecule, expressed on Th2 cells), the prostaglandin E2 receptors EP2 and EP4, and the prostacyclin (PGI2) receptor IP. Prostanoids can bind to either one or multiple receptors, characteristically have a short half-life in vivo, and are quickly degraded into metabolites with altered affinity and specificity for a given receptor subtype. Prostanoid receptors signal mainly through G proteins and naturally activate signal transduction pathways according to the G protein subtype that they preferentially interact with. This can lead to the activation of sometimes opposing signaling pathways. In addition, prostanoid signaling is often cell-type specific and also the combination of expressed receptors can influence the outcome of the prostanoid impulse. Accordingly, it is assumed that eosinophils and their (patho-)physiological functions are governed by a sensitive prostanoid signaling network. In this review, we specifically focus on the functions of PGD2, PGE2, and PGI2 and their receptors on eosinophils. We discuss their significance in allergic and non-allergic diseases and summarize potential targets for drug intervention.
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Affiliation(s)
- Miriam Peinhaupt
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Eva M Sturm
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Akos Heinemann
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
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Barthelmes J, Nägele MP, Ludovici V, Ruschitzka F, Sudano I, Flammer AJ. Endothelial dysfunction in cardiovascular disease and Flammer syndrome-similarities and differences. EPMA J 2017; 8:99-109. [PMID: 28824736 DOI: 10.1007/s13167-017-0099-1] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 05/21/2017] [Indexed: 12/25/2022]
Abstract
The endothelium has increasingly been recognized as a smart barrier and a key regulator of blood flow in micro- and macrovascular beds. Endothelial dysfunction marks a stage of atherosclerosis and is an important prognostic marker for cardiovascular disease. Yet, some people who tend to be slim and physically active and with rather low blood pressure show a propensity to respond to certain stimuli such as emotional stress with endothelial-mediated vascular dysregulation (Flammer syndrome). This leads to characteristic vascular symptoms such as cold hands but also a risk for vascular-mediated diseases such as normal-tension glaucoma. It is the aim of this review to delineate the differences between Flammer syndrome and its "counterpart" endothelial dysfunction in the context of cardiovascular diseases.
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Affiliation(s)
- Jens Barthelmes
- University Hospital Zurich, University Heart Center, Raemistrasse 100, 8091 Zurich, Switzerland
| | - Matthias P Nägele
- University Hospital Zurich, University Heart Center, Raemistrasse 100, 8091 Zurich, Switzerland
| | - Valeria Ludovici
- University Hospital Zurich, University Heart Center, Raemistrasse 100, 8091 Zurich, Switzerland
| | - Frank Ruschitzka
- University Hospital Zurich, University Heart Center, Raemistrasse 100, 8091 Zurich, Switzerland
| | - Isabella Sudano
- University Hospital Zurich, University Heart Center, Raemistrasse 100, 8091 Zurich, Switzerland
| | - Andreas J Flammer
- University Hospital Zurich, University Heart Center, Raemistrasse 100, 8091 Zurich, Switzerland
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Vanhoutte PM, Shimokawa H, Feletou M, Tang EHC. Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta Physiol (Oxf) 2017; 219:22-96. [PMID: 26706498 DOI: 10.1111/apha.12646] [Citation(s) in RCA: 629] [Impact Index Per Article: 78.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Revised: 10/27/2015] [Accepted: 12/17/2015] [Indexed: 02/06/2023]
Abstract
The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best-characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDH-mediated responses). As regards the latter, hydrogen peroxide (H2 O2 ) now appears to play a dominant role. Endothelium-dependent relaxations involve both pertussis toxin-sensitive Gi (e.g. responses to α2 -adrenergic agonists, serotonin, and thrombin) and pertussis toxin-insensitive Gq (e.g. adenosine diphosphate and bradykinin) coupling proteins. New stimulators (e.g. insulin, adiponectin) of the release of EDRFs have emerged. In recent years, evidence has also accumulated, confirming that the release of NO by the endothelial cell can chronically be upregulated (e.g. by oestrogens, exercise and dietary factors) and downregulated (e.g. oxidative stress, smoking, pollution and oxidized low-density lipoproteins) and that it is reduced with ageing and in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and EDH, in particular those due to H2 O2 ), endothelial cells also can evoke contraction of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factors. Recent evidence confirms that most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells and that prostacyclin plays a key role in such responses. Endothelium-dependent contractions are exacerbated when the production of nitric oxide is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive and diabetic patients. In addition, recent data confirm that the release of endothelin-1 can contribute to endothelial dysfunction and that the peptide appears to be an important contributor to vascular dysfunction. Finally, it has become clear that nitric oxide itself, under certain conditions (e.g. hypoxia), can cause biased activation of soluble guanylyl cyclase leading to the production of cyclic inosine monophosphate (cIMP) rather than cGMP and hence causes contraction rather than relaxation of the underlying vascular smooth muscle.
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Affiliation(s)
- P. M. Vanhoutte
- State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy; Li Ka Shing Faculty of Medicine; The University of Hong Kong; Hong Kong City Hong Kong
| | - H. Shimokawa
- Department of Cardiovascular Medicine; Tohoku University; Sendai Japan
| | - M. Feletou
- Department of Cardiovascular Research; Institut de Recherches Servier; Suresnes France
| | - E. H. C. Tang
- State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy; Li Ka Shing Faculty of Medicine; The University of Hong Kong; Hong Kong City Hong Kong
- School of Biomedical Sciences; Li Ka Shing Faculty of Medicine; The University of Hong Kong; Hong Kong City Hong Kong
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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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Toniolo A, Buccellati C, Trenti A, Trevisi L, Carnevali S, Sala A, Bolego C. Antiinflammatory and antioxidant effects of H2O2 generated by natural sources in Il1β-treated human endothelial cells. Prostaglandins Other Lipid Mediat 2015; 121:190-8. [PMID: 26391839 DOI: 10.1016/j.prostaglandins.2015.09.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 08/07/2015] [Accepted: 09/16/2015] [Indexed: 10/23/2022]
Abstract
Specific reactive oxygen species (ROS) from different sources, might lead to different and even opposite, cellular effects. We studied the production of specific ROS resulting from the exposure of human umbilical veins endothelial cells (HUVEC) to H2O2 derived from the natural antioxidant epigallocathechin gallate (EGCG) or from the exposure to IL-1β using a fluorogenic probe and flow cytometry, and evaluated by western blot analysis and immunocytochemistry the associated expression of transcription factors sensitive to both inflammatory and oxidative stress, such as NF-κB and Nrf2, and some downstream activated genes such as cyclooxygenase-2 (COX-2) and hemeoxygenase 1 (HO-1). The results obtained showed that exogenously-generated H2O2 induce anti-inflammatory and antioxidant effects in HUVECs counteracting the pro-inflammatory and pro-oxidant effect of IL-1β related to the production of superoxide anions. The underlying mechanisms resulting from the extracellular production of H2O2, include (1) Nrf2 nuclear translocation and the enhanced expression of antioxidant enzymes such as HO-1, and (2) the previously unreported inhibition of NF-κB and COX-2 expression. Overall, these findings provide evidence that the production of specific reactive oxygen species finely tunes endothelial cell function and might be relevant for the reappraisal of the effects of exogenous antioxidants in the context of cardiovascular diseases.
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Affiliation(s)
- Alice Toniolo
- Department of Pharmaceuticaland Pharmacological Sciences, University of Padova, Italy
| | - Carola Buccellati
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy
| | - Annalisa Trenti
- Department of Pharmaceuticaland Pharmacological Sciences, University of Padova, Italy
| | - Lucia Trevisi
- Department of Pharmaceuticaland Pharmacological Sciences, University of Padova, Italy
| | - Silvia Carnevali
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy
| | - Angelo Sala
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy; Institute of Biomedicine and Molecular Immunology, National Research Council, Palermo, Italy.
| | - Chiara Bolego
- Department of Pharmaceuticaland Pharmacological Sciences, University of Padova, Italy
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Solà-Villà D, Dilmé JF, Rodríguez C, Soto B, Vila L, Escudero JR, Martínez-González J, Camacho M. Expression and Cellular Localization of 15-Hydroxy-Prostaglandin-Dehydrogenase in Abdominal Aortic Aneurysm. PLoS One 2015; 10:e0136201. [PMID: 26287481 PMCID: PMC4545606 DOI: 10.1371/journal.pone.0136201] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 07/30/2015] [Indexed: 01/07/2023] Open
Abstract
PGE2 has been implicated in abdominal aortic aneurysm (AAA) associated hypervascularization. PGE2-metabolism involves 15-hydroxyprostaglandin-dehydrogenase (15-PGDH) the expression of which in AAA is unknown. The aim of this study was to examine the expression and cell distribution of 15-PGDH in AAA. Here, we show that 15-PGDH mRNA levels were significantly higher in aorta samples from patients undergoing AAA repair than in those from healthy multiorgan donors. Consequently, the ratio of metabolized PGE2 secreted by aortic samples was significantly higher in AAA. AAA production of total PGE2 and PGE2 metabolites correlated positively with PGI2 production, while the percentage of metabolized PGE2 correlated negatively with the total amount of PGE2 and with PGI2. Transcript levels of 15-PGDH were statistically associated with leukocyte markers but did not correlate with microvascular endothelial cell markers. Immunohistochemistry revealed 15-PGDH in the areas of leukocyte infiltration in AAA samples, mainly associated with CD45-positive cells, but not in normal aorta samples. We provide new data concerning 15-PGDH expression in human AAA, showing that 15-PGDH is upregulated in AAA and mainly expressed in infiltrating leukocytes. Our data suggest that microvasculature was not involved in PGE2 catabolism, reinforcing the potential role of microvasculature derived PGE2 in AAA-associated hypervascularization.
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Affiliation(s)
- David Solà-Villà
- Autonomous University of Barcelona, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
| | - Jaime-Félix Dilmé
- Angiology, Vascular Biology and Inflammation Laboratory, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
- Vascular Surgery Department, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
| | - Cristina Rodríguez
- Cardiovascular Research Center (CSIC-ICCC), Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
| | - Begoña Soto
- Angiology, Vascular Biology and Inflammation Laboratory, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
- Vascular Surgery Department, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
| | - Luis Vila
- Angiology, Vascular Biology and Inflammation Laboratory, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
| | - José-Román Escudero
- Angiology, Vascular Biology and Inflammation Laboratory, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
- Vascular Surgery Department, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
| | - José Martínez-González
- Cardiovascular Research Center (CSIC-ICCC), Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
| | - Mercedes Camacho
- Angiology, Vascular Biology and Inflammation Laboratory, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
- * E-mail:
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Di Francesco L, Dovizio M, Trenti A, Marcantoni E, Moore A, O'Gaora P, McCarthy C, Tacconelli S, Bruno A, Alberti S, Gizzo S, Nardelli GB, Orso G, Belton O, Trevisi L, Dixon DA, Patrignani P. Dysregulated post-transcriptional control of COX-2 gene expression in gestational diabetic endothelial cells. Br J Pharmacol 2015; 172:4575-4587. [PMID: 26140661 DOI: 10.1111/bph.13241] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 06/02/2015] [Accepted: 06/25/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND PURPOSE Hyperglycaemic memory describes the progression of diabetic complications during subsequent periods of improved glycaemia. We addressed the hypothesis that transient hyperglycaemia causes aberrant COX-2 expression in HUVEC in response to IL-1β through the induction of long-lasting epigenetic changes involving microRNA-16 (miR-16), a post-transcriptional modulator of COX-2 expression. EXPERIMENTAL APPROACH Studies were performed on HUVEC collected from women with gestational diabetes mellitus (GDM) (dHUVEC) and normal women (nHUVEC). KEY RESULTS In dHUVEC treated with IL-1β, the expression of COX-2 mRNA and protein was enhanced and generation of prostanoids increased (the most abundant was the promitogenic PGF2α ). COX-2 mRNA was more stable in dHUVEC and this was associated with miR-16 down-regulation and c-Myc induction (a suppressor of miR expression). dHUVEC showed increased proliferation in response to IL-1β, which was prevented by a COX-2 inhibitor and PGF2α receptor antagonist. Comparable changes in COX-2 mRNA, miR-16 and c-Myc detected in dHUVEC were produced in nHUVEC exposed to transient high glucose and then stimulated with IL-1β under physiological glucose levels; superoxide anion production was enhanced under these experimental conditions. CONCLUSIONS AND IMPLICATIONS Our results describe a possible mechanism operating in GDM that links the enhanced superoxide anion production and epigenetic changes, associated with hyperglycaemic memory, to endothelial dysfunction through dysregulated post-transcriptional control of COX-2 gene expression in response to inflammatory stimuli. The association of conventional therapy for glycaemic control with agents affecting inflammatory responses and oxidative stress might lead to a more effective prevention of the complications associated with GDM.
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Affiliation(s)
- Luigia Di Francesco
- Department of Neuroscience Imaging and Clinical Sciences, Center of Excellence on Aging (CeSI), G. d'Annunzio University, Chieti, Italy
| | - Melania Dovizio
- Department of Neuroscience Imaging and Clinical Sciences, Center of Excellence on Aging (CeSI), G. d'Annunzio University, Chieti, Italy
| | - Annalisa Trenti
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
| | - Emanuela Marcantoni
- Department of Neuroscience Imaging and Clinical Sciences, Center of Excellence on Aging (CeSI), G. d'Annunzio University, Chieti, Italy
| | - Ashleigh Moore
- Department of Cancer Biology, University of Kansas Cancer Center, Kansas City, KS, USA
| | - Peadar O'Gaora
- School of Biomolecular and Biomedical Science, Conway Institute, UCD, Dublin, Ireland
| | - Cathal McCarthy
- School of Biomolecular and Biomedical Science, Conway Institute, UCD, Dublin, Ireland
| | - Stefania Tacconelli
- Department of Neuroscience Imaging and Clinical Sciences, Center of Excellence on Aging (CeSI), G. d'Annunzio University, Chieti, Italy
| | - Annalisa Bruno
- Department of Neuroscience Imaging and Clinical Sciences, Center of Excellence on Aging (CeSI), G. d'Annunzio University, Chieti, Italy
| | - Sara Alberti
- Department of Neuroscience Imaging and Clinical Sciences, Center of Excellence on Aging (CeSI), G. d'Annunzio University, Chieti, Italy
| | - Salvatore Gizzo
- Department of Women's and Children's Health, University of Padua, Padua, Italy
| | | | - Genny Orso
- E. MEDEA Scientific Institute, Conegliano, Treviso, Italy
| | - Orina Belton
- School of Biomolecular and Biomedical Science, Conway Institute, UCD, Dublin, Ireland
| | - Lucia Trevisi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
| | - Dan A Dixon
- Department of Cancer Biology, University of Kansas Cancer Center, Kansas City, KS, USA
| | - Paola Patrignani
- Department of Neuroscience Imaging and Clinical Sciences, Center of Excellence on Aging (CeSI), G. d'Annunzio University, Chieti, Italy
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Cao J, Tsenovoy PL, Thompson EA, Falck JR, Touchon R, Sodhi K, Rezzani R, Shapiro JI, Abraham NG. Agonists of epoxyeicosatrienoic acids reduce infarct size and ameliorate cardiac dysfunction via activation of HO-1 and Wnt1 canonical pathway. Prostaglandins Other Lipid Mediat 2015; 116-117:76-86. [PMID: 25677507 PMCID: PMC5553685 DOI: 10.1016/j.prostaglandins.2015.01.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 01/15/2015] [Accepted: 01/16/2015] [Indexed: 12/27/2022]
Abstract
Myocardial infarction (MI) is complicated by ventricular fibrosis and associated diastolic and systolic failure. Emerging studies implicate Wnt1 signaling in the formation of new blood vessels. Epoxyeicosatrienoic acids (EETs)-mediated up-regulation of heme oxygenase-1 (HO-1) protects against the detrimental consequences of MI in several animal models, however, the mechanism(s) by which this occurs remains unclear. The aim of this study was to examine these mechanisms in the LAD ligation animal model of post infarcted heart failure. Specifically, we sought to clarify the mechanistic basis of the interactions of the Wnt1 canonical pathway, HO-1 and associated angiogenesis. Human microvascular endothelial cells (HMECs) were exposed to anoxia and treated with the EET agonist, NUDSA, in the presence and absence of tin mesoporphyrin (SnMP). Increased capillary density, and Wnt1 and HO-1 expression occurred in cells treated with NUDSA. Anoxic HMECs treated with NUDSA and Wnt1 siRNA, exhibited decreased in the expression of β-catenin and the Wnt1 target gene, PPARδ (p<0.05 vs. NUDSA). Furthermore, blocking the Wnt 1 antagonist, Dickkopf 1, by siRNA increased β-catenin and PPARδ expression, and this effect was further enhanced by the concurrent administration of NUDSA. In in vivo experiments, C57B16 mice were divided into 4 groups: sham, mice with MI via LAD ligation and mice with MI treated with NUDSA, with and without SnMP. Increased fractional area change (FAC) and myocardial angiogenesis were observed in mice treated with NUDSA (p<0.05 vs. MI). Increased expression of HO-1, Wnt1, β-catenin, adiponectin, and phospho-endothelial nitric oxide synthetase (p-eNOS), and a decrease in the glycosylated subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, gp91(phox) expression occurred in cardiac tissue of mice treated with NUDSA (p<0.05 vs. MI). SnMP reversed these effects. This novel study demonstrates that increasing the canonical Wnt1 signaling cascade with the subsequent increase in HO-1, adiponectin and angiogenesis ameliorates fibrosis and cardiac dysfunction in a mouse model of MI and supports the hypothesis that HO-1 is an integral component of the EETs-adiponectin axis and is central for the control of resistance to fibrosis and vascular dysfunction and in part determine how they influence the cellular/vascular homeostasis and provides insight into the mechanisms involved in vascular dysfunction as well as potential targets for the treatment of CVD.
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Affiliation(s)
- Jian Cao
- Chinese PLA General Hospital, Beijing 100853, China
| | | | - Ellen A Thompson
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States
| | - John R Falck
- University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States
| | - Robert Touchon
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States
| | - Komal Sodhi
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States
| | - Rita Rezzani
- New York Medical College, Valhalla, NY, United States
| | - Joseph I Shapiro
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States
| | - Nader G Abraham
- New York Medical College, Valhalla, NY, United States; Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States.
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15
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Camacho M, Piñeiro Z, Alcolea S, García J, Balart J, Terra X, Avilés-Jurado FX, Soler M, Quer M, León X, Vila L. Prostacyclin-synthase expression in head and neck carcinoma patients and its prognostic value in the response to radiotherapy. J Pathol 2014; 235:125-35. [DOI: 10.1002/path.4453] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 09/04/2014] [Accepted: 09/23/2014] [Indexed: 01/09/2023]
Affiliation(s)
- Mercedes Camacho
- Laboratory of Angiology, Vascular Biology and Inflammation; Institute of Biomedical Research (IIB Sant Pau) and Universitat Autònoma de Barcelona; Barcelona Spain
| | - Zenaida Piñeiro
- Laboratory of Angiology, Vascular Biology and Inflammation; Institute of Biomedical Research (IIB Sant Pau) and Universitat Autònoma de Barcelona; Barcelona Spain
- Otorhinolaryngology Department; Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona; Barcelona Spain
| | - Sonia Alcolea
- Laboratory of Angiology, Vascular Biology and Inflammation; Institute of Biomedical Research (IIB Sant Pau) and Universitat Autònoma de Barcelona; Barcelona Spain
| | - Jacinto García
- Otorhinolaryngology Department; Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona; Barcelona Spain
| | - Josep Balart
- Radiation Oncology Department; Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona; Barcelona Spain
| | - Ximena Terra
- Otorhinolaryngology Department; Hospital Universitari de Tarragona Joan XXIII, ISPV, Universitat Rovira i Virgili; Tarragona Spain
| | - Francesc-Xavier Avilés-Jurado
- Otorhinolaryngology Department; Hospital Universitari de Tarragona Joan XXIII, ISPV, Universitat Rovira i Virgili; Tarragona Spain
| | - Marta Soler
- Scientific and Technical Services Platform of the Institute of Biomedical Research (II-B Sant Pau); Barcelona Spain
| | - Miquel Quer
- Otorhinolaryngology Department; Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona; Barcelona Spain
| | - Xavier León
- Otorhinolaryngology Department; Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona; Barcelona Spain
| | - Luis Vila
- Laboratory of Angiology, Vascular Biology and Inflammation; Institute of Biomedical Research (IIB Sant Pau) and Universitat Autònoma de Barcelona; Barcelona Spain
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16
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Active smoking increases microsomal PGE2-synthase-1/PGE-receptor-4 axis in human abdominal aortic aneurysms. Mediators Inflamm 2014; 2014:316150. [PMID: 24876670 PMCID: PMC4021751 DOI: 10.1155/2014/316150] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Accepted: 04/10/2014] [Indexed: 01/19/2023] Open
Abstract
Background. The cyclooxygenase- (COX-) 2/microsomal PGE-synthase- (mPGES-) 1/PGE-receptor- (EP-) 4 axis could play a key role in the physiopathology of abdominal aortic aneurysm (AAA) in humans. In this study, we investigated the influence of cardiovascular risk factors on the expression of the PGE2 pathway in human AAA. Methods. Aortic (n = 89) and plasma (n = 79) samples from patients who underwent AAA repair were collected. Patients were grouped according to risk factors. COX-isoenzymes, mPGES-1, EPs, α-actin, and CD45 and CD68 transcripts levels were quantified by QRT-PCR and plasma PGE2 metabolites by EIA. Results. Current smoking (CS) patients compared to no-CS had significantly higher local levels of mPGES-1 (P = 0.009), EP-4 (P = 0.007), and PGE2 metabolites plasma levels (P = 0.008). In the multiple linear regression analysis, these parameters remained significantly enhanced in CS after adding confounding factors. Results from association studies with cell type markers suggested that the increased mPGES-1/EP-4 levels were mainly associated with microvascular endothelial cells. Conclusions. This study shows that elements of the PGE2 pathway, which play an important role in AAA development, are increased in CS. These results provide insight into the relevance of tobacco smoking in AAA development and reinforce the potential of mPGES-1 and EP-4 as targets for therapy in AAA patients.
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17
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Camacho M, Dilmé J, Solà-Villà D, Rodríguez C, Bellmunt S, Siguero L, Alcolea S, Romero JM, Escudero JR, Martínez-González J, Vila L. Microvascular COX-2/mPGES-1/EP-4 axis in human abdominal aortic aneurysm. J Lipid Res 2013; 54:3506-15. [PMID: 24133193 DOI: 10.1194/jlr.m042481] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
We investigated the prostaglandin (PG)E2 pathway in human abdominal aortic aneurysm (AAA) and its relationship with hypervascularization. We analyzed samples from patients undergoing AAA repair in comparison with those from healthy multiorgan donors. Patients were stratified according to maximum aortic diameter: low diameter (LD) (<55 mm), moderate diameter (MD) (55-69.9 mm), and high diameter (HD) (≥70 mm). AAA was characterized by abundant microvessels in the media and adventitia with perivascular infiltration of CD45-positive cells. Like endothelial cell markers, cyclooxygenase (COX)-2 and the microsomal isoform of prostaglandin E synthase (mPGES-1) transcripts were increased in AAA (4.4- and 1.4-fold, respectively). Both enzymes were localized in vascular cells and leukocytes, with maximal expression in the LD group, whereas leukocyte markers display a maximum in the MD group, suggesting that the upregulation of COX-2/mPGES-1 precedes maximal leukocyte infiltration. Plasma and in vitro tissue secreted levels of PGE2 metabolites were higher in AAA than in controls (plasma-controls, 19.9 ± 2.2; plasma-AAA, 38.8 ± 5.5 pg/ml; secretion-normal aorta, 16.5 ± 6.4; secretion-AAA, 72.9 ± 6.4 pg/mg; mean ± SEM). E-prostanoid receptor (EP)-2 and EP-4 were overexpressed in AAA, EP-4 being the only EP substantially expressed and colocalized with mPGES-1 in the microvasculature. Additionally, EP-4 mediated PGE2-induced angiogenesis in vitro. We provide new data concerning mPGES-1 expression in human AAA. Our findings suggest the potential relevance of the COX-2/mPGES-1/EP-4 axis in the AAA-associated hypervascularization.
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Affiliation(s)
- Mercedes Camacho
- Angiology, Vascular Biology, and Inflammation Laboratory, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
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18
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Gomez I, Foudi N, Longrois D, Norel X. The role of prostaglandin E2 in human vascular inflammation. Prostaglandins Leukot Essent Fatty Acids 2013; 89:55-63. [PMID: 23756023 DOI: 10.1016/j.plefa.2013.04.004] [Citation(s) in RCA: 116] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Revised: 04/04/2013] [Accepted: 04/05/2013] [Indexed: 10/26/2022]
Abstract
Prostaglandins (PG) are the product of a cascade of enzymes such as cyclooxygenases and PG synthases. Among PG, PGE2 is produced by 3 isoforms of PGE synthase (PGES) and through activation of its cognate receptors (EP1-4), this PG is involved in the pathophysiology of vascular diseases. Some anti-inflammatory drugs (e.g. glucocorticoids, nonsteroidal anti-inflammatory drugs) interfere with its metabolism or effects. Vascular cells can initiate many of the responses associated with inflammation. In human vascular tissue, PGE2 is involved in many physiological processes, such as increasing vascular permeability, cell proliferation, cell migration and control of vascular smooth muscle tone. PGE2 has been shown to contribute to the pathogenesis of atherosclerosis, abdominal aortic aneurysm but also in physiologic/adaptive processes such as angiogenesis. Understanding the roles of PGE2 and its cognate receptors in vascular diseases could help to identify diagnostic and prognostic biomarkers. In addition, from these recent studies new promising therapeutic approaches like mPGES-1 inhibition and/or EP4-antagonism should be investigated.
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Affiliation(s)
- I Gomez
- INSERM, U698, Paris F-75018, France; University Paris Nord, UMR-S698, Paris F-75018, France
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19
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Toniolo A, Buccellati C, Pinna C, Gaion RM, Sala A, Bolego C. Cyclooxygenase-1 and prostacyclin production by endothelial cells in the presence of mild oxidative stress. PLoS One 2013; 8:e56683. [PMID: 23441213 PMCID: PMC3575487 DOI: 10.1371/journal.pone.0056683] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 01/14/2013] [Indexed: 11/19/2022] Open
Abstract
This study aimed at evaluating the relative contribution of endothelial cyclooxygenase-1 and -2 (COX-1 and COX-2) to prostacyclin (PGI2) production in the presence of mild oxidative stress resulting from autooxidation of polyphenols such as (-)-epigallocatechin 3-gallate (EGCG), using both endothelial cells in culture and isolated blood vessels. EGCG treatment resulted in an increase in hydrogen peroxide formation in human umbilical vein endothelial cells. In the presence of exogenous arachidonic acid and EGCG, PGI2 production was preferentially inhibited by a selective COX-1 inhibitor. This effect of selective inhibition was also substantially reversed by catalase. In addition, EGCG caused vasorelaxation of rat aortic ring only partially abolished by a nitric oxide synthase inhibitor. Concomitant treatment with a selective COX-1 inhibitor completely prevented the vasorelaxation as well as the increase in PGI2 accumulation in the perfusate observed in EGCG-treated aortic rings, while a selective COX-2 inhibitor was completely uneffective. Our data strongly support the notions that H2O2 generation affects endothelial PGI2 production, making COX-1, and not COX-2, the main source of endothelial PGI2 under altered oxidative tone conditions. These results might be relevant to the reappraisal of the impact of COX inhibitors on vascular PGI2 production in patients undergoing significant oxidative stress.
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Affiliation(s)
- Alice Toniolo
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Carola Buccellati
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milano, Italy
| | - Christian Pinna
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milano, Italy
| | - Rosa Maria Gaion
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Angelo Sala
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milano, Italy
- IBIM, Consiglio Nazionale delle Ricerche, Palermo, Italy
- * E-mail:
| | - Chiara Bolego
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
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20
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Zhao L, Wu Y, Xu Z, Wang H, Zhao Z, Li Y, Yang P, Wei X. Involvement of COX-2/PGE2 signalling in hypoxia-induced angiogenic response in endothelial cells. J Cell Mol Med 2012; 16:1840-55. [PMID: 22050691 PMCID: PMC3822696 DOI: 10.1111/j.1582-4934.2011.01479.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
To evaluate the impact of hypoxia on the angiogenic capability of endothelial cells (ECs), and further investigate whether the cyclooxygenase-2 (COX-2)/prostaglandin E(2) (PGE(2)) signalling is involved in the angiogenic response of ECs to hypoxia. We explored the impact of various periods (1, 3, 6, 12, 24 hrs) of hypoxia (2% O(2)) on human umbilical vein endothelial cells (HUVECs) in vitro. We observed cell viability, migration, tube formation, analysed COX-2, vascular endothelial growth factor (VEGF), AQP1 mRNA transcription, protein expression and measured PGE(2), VEGF protein concentration in cell supernatants. Then we treated HUVECs with COX-2 selective inhibitor NS398, EP1/2 combined antagonist AH6809 and exogenous PGE(2) to investigate the role of COX-2/PGE(2) signalling in the angiogenic response of ECs to hypoxia. The results demonstrated that short-term hypoxic treatment enhanced HUVECs proliferation, migration, tube formation, significantly up-regulated COX-2, VEGF, AQP1 mRNA level, protein expression and promoted PGE(2) , VEGF release. The pharmacological inhibition study revealed that exposure of HUVEC to NS398 and AH6809 under hypoxia impaired the biological responses of ECs to hypoxia. Exogenous PGE(2) augments the effects of hypoxia on HUVECs, and partially reversed the inhibitory effects of NS398 on HUVECs proliferation and angiogenic capability. Short-term hypoxic treatment enhanced angiogenic capability of ECs, and COX-2/PGE(2) signalling may play a critical role in the biological response of ECs to hypoxia.
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Affiliation(s)
- Lixing Zhao
- State Key Laboratory of Oral Diseases, Department of Orthodontics, West China College of Stomatology, Sichuan University, Chengdu, China
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21
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Basei FL, Cabrini DA, Figueiredo CP, Forner S, Hara DB, Nascimento AFZ, Ceravolo GS, Carvalho MHC, Bader M, Medeiros R, Calixto JB. Endothelium dependent expression and underlying mechanisms of des-Arg⁹-bradykinin-induced B₁R-mediated vasoconstriction in rat portal vein. Peptides 2012; 37:216-24. [PMID: 22868213 DOI: 10.1016/j.peptides.2012.07.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2012] [Revised: 07/23/2012] [Accepted: 07/24/2012] [Indexed: 10/28/2022]
Abstract
Endothelial dysfunction has been implicated in portal vein obstruction, a condition responsible for major complications in chronic portal hypertension. Increased vascular tone due to disruption of endothelial function has been associated with an imbalance in the equilibrium between endothelium-derived relaxing and contracting factors. Herein, we assessed underlying mechanisms by which expression of bradykinin B(1) receptor (B(1)R) is induced in the endothelium and how its stimulation triggers vasoconstriction in the rat portal vein. Prolonged in vitro incubation of portal vein resulted in time- and endothelium-dependent expression of B(1)R and cyclooxygenase-2 (COX-2). Inhibition of protein kinase C (PKC) or phosphatidylinositol 3-kinase (PI3K) significantly reduced expression of B(1)R through the regulation of transcription factors, activator protein-1 (AP-1) and cAMP response element-binding protein (CREB). Moreover, pharmacological studies showed that B(1)R-mediated portal vein contraction was reduced by COX-2, but not COX-1, inhibitors. Notably, activation of endothelial B(1)R increased phospholipase A(2)/COX-2-derived thromboxane A(2) (TXA(2)) levels, which in turn mediated portal vein contraction through binding to TXA(2) receptors expressed in vascular smooth muscle cells. These results provide novel molecular mechanisms involved in the regulation of B(1)R expression and identify a critical role for the endothelial B(1)R in the modulation of portal vein vascular tone. Our study suggests a potential role for B(1)R antagonists as therapeutic tools for diseases where portal hypertension may be involved.
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Affiliation(s)
- Fernanda L Basei
- Departamento de Farmacologia, Universidade Federal de Santa Catarina, Santa Catarina, Brazil
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22
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Philipose S, Konya V, Lazarevic M, Pasterk LM, Marsche G, Frank S, Peskar BA, Heinemann A, Schuligoi R. Laropiprant attenuates EP3 and TP prostanoid receptor-mediated thrombus formation. PLoS One 2012; 7:e40222. [PMID: 22870195 PMCID: PMC3411562 DOI: 10.1371/journal.pone.0040222] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Accepted: 06/02/2012] [Indexed: 11/24/2022] Open
Abstract
The use of the lipid lowering agent niacin is hampered by a frequent flush response which is largely mediated by prostaglandin (PG) D2. Therefore, concomitant administration of the D-type prostanoid (DP) receptor antagonist laropiprant has been proposed to be a useful approach in preventing niacin-induced flush. However, antagonizing PGD2, which is a potent inhibitor of platelet aggregation, might pose the risk of atherothrombotic events in cardiovascular disease. In fact, we found that in vitro treatment of platelets with laropiprant prevented the inhibitory effects of PGD2 on platelet function, i.e. platelet aggregation, Ca2+ flux, P-selectin expression, activation of glycoprotein IIb/IIIa and thrombus formation. In contrast, laropiprant did not prevent the inhibitory effects of acetylsalicylic acid or niacin on thrombus formation. At higher concentrations, laropiprant by itself attenuated platelet activation induced by thromboxane (TP) and E-type prostanoid (EP)-3 receptor stimulation, as demonstrated in assays of platelet aggregation, Ca2+ flux, P-selectin expression, and activation of glycoprotein IIb/IIIa. Inhibition of platelet function exerted by EP4 or I-type prostanoid (IP) receptors was not affected by laropiprant. These in vitro data suggest that niacin/laropiprant for the treatment of dyslipidemias might have a beneficial profile with respect to platelet function and thrombotic events in vascular disease.
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Affiliation(s)
- Sonia Philipose
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Viktoria Konya
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Mirjana Lazarevic
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Lisa M. Pasterk
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Gunther Marsche
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Sasa Frank
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Bernhard A. Peskar
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Akos Heinemann
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
- * E-mail:
| | - Rufina Schuligoi
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
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23
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Sun LT, Friedrich E, Heuslein JL, Pferdehirt RE, Dangelo NM, Natesan S, Christy RJ, Washburn NR. Reduction of burn progression with topical delivery of (antitumor necrosis factor-α)-hyaluronic acid conjugates. Wound Repair Regen 2012; 20:563-72. [PMID: 22712482 DOI: 10.1111/j.1524-475x.2012.00813.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Accepted: 02/29/2012] [Indexed: 02/01/2023]
Abstract
In this study, we explored whether topical application of antibodies targeting tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) conjugated to hyaluronic acid (HA) could reduce the extension of necrosis by modulating inflammation locally in a partial-thickness rat burn model. Partial-thickness to deep partial-thickness burn injuries present significant challenges in healing, as these burns often progress following the initial thermal insult, resulting in necrotic expansion and increased likelihood of secondary complications. Necrotic expansion is driven by a microenvironment with elevated levels of pro-inflammatory mediators, and local neutralization of these using antibody conjugates could reduce burn progression. Trichrome-stained tissue sections indicated the least necrotic tissue in (anti-TNF-α)-HA-treated sites, while (anti-IL-6)-HA-treated sites displayed similar outcomes to saline controls. This was confirmed by vimentin immunostaining, which demonstrated that HA treatment alone reduced burn progression by nearly 30%, but (anti-TNF-α)-HA reduced it by approximately 70%. At all time points, (anti-TNF-α)-HA-treated sites showed reduced tissue levels of IL-1β compared to controls, suggesting inhibition of a downstream mediator of inflammation. Decreased macrophage infiltration in (anti-TNF-α)-HA-treated sites compared to controls was elucidated by immunohistochemical staining of macrophages, suggesting a reduction in overall inflammation in all time points. These results suggest that local targeting of TNF-α may be an effective strategy for preventing progression of partial-thickness burns.
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Affiliation(s)
- Liang Tso Sun
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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24
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PGH1, the precursor for the anti-inflammatory prostaglandins of the 1-series, is a potent activator of the pro-inflammatory receptor CRTH2/DP2. PLoS One 2012; 7:e33329. [PMID: 22442685 PMCID: PMC3307725 DOI: 10.1371/journal.pone.0033329] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Accepted: 02/07/2012] [Indexed: 12/19/2022] Open
Abstract
Prostaglandin H1 (PGH1) is the cyclo-oxygenase metabolite of dihomo-γ-linolenic acid (DGLA) and the precursor for the 1-series of prostaglandins which are often viewed as “anti-inflammatory”. Herein we present evidence that PGH1 is a potent activator of the pro-inflammatory PGD2 receptor CRTH2, an attractive therapeutic target to treat allergic diseases such as asthma and atopic dermatitis. Non-invasive, real time dynamic mass redistribution analysis of living human CRTH2 transfectants and Ca2+ flux studies reveal that PGH1 activates CRTH2 as PGH2, PGD2 or PGD1 do. The PGH1 precursor DGLA and the other PGH1 metabolites did not display such effect. PGH1 specifically internalizes CRTH2 in stable CRTH2 transfectants as assessed by antibody feeding assays. Physiological relevance of CRTH2 ligation by PGH1 is demonstrated in several primary human hematopoietic lineages, which endogenously express CRTH2: PGH1 mediates migration of and Ca2+ flux in Th2 lymphocytes, shape change of eosinophils, and their adhesion to human pulmonary microvascular endothelial cells under physiological flow conditions. All these effects are abrogated in the presence of the CRTH2 specific antagonist TM30089. Together, our results identify PGH1 as an important lipid intermediate and novel CRTH2 agonist which may trigger CRTH2 activation in vivo in the absence of functional prostaglandin D synthase.
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25
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Prostanoids in tumor angiogenesis: therapeutic intervention beyond COX-2. Trends Mol Med 2012; 18:233-43. [PMID: 22425675 DOI: 10.1016/j.molmed.2012.02.002] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Revised: 02/10/2012] [Accepted: 02/14/2012] [Indexed: 02/06/2023]
Abstract
Prostanoids regulate angiogenesis in carcinoma and chronic inflammatory disease progression. Although prostanoid biosynthetic enzymes and signaling have been extensively analyzed in inflammation, little is known about how prostanoids mediate tumor-induced angiogenesis. Targeted cyclooxygenase (COX)-2 inhibition in tumor, stromal and endothelial cells is an attractive antiangiogenic strategy; however, the associated cardiovascular side effects have led to the development of a new generation of nonsteroidal anti-inflammatory drugs (NSAIDs) acting downstream of COX. These agents target terminal prostanoid synthases and prostanoid receptors, which may also include several peroxisome proliferator-activated receptors (PPARs). Here, we discuss the role of prostanoids as modulators of tumor angiogenesis and how prostanoid metabolism reflects complex cell-cell crosstalk that determines tumor growth. Finally, we discuss the potential of new NSAIDs for the treatment of angiogenesis-dependent tumor development.
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26
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Tian XY, Wong WT, Leung FP, Zhang Y, Wang YX, Lee HK, Ng CF, Chen ZY, Yao X, Au CL, Lau CW, Vanhoutte PM, Cooke JP, Huang Y. Oxidative stress-dependent cyclooxygenase-2-derived prostaglandin f(2α) impairs endothelial function in renovascular hypertensive rats. Antioxid Redox Signal 2012; 16:363-73. [PMID: 21951274 PMCID: PMC3584508 DOI: 10.1089/ars.2010.3874] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
UNLABELLED Abstract Aims: The role of endothelium-derived contracting factors (EDCFs) in regulating renovascular function is yet to be elucidated in renovascular hypertension (RH). The current study investigated whether oxidative stress-dependent cyclooxygenase (COX)-2-derived prostaglandin F(2α) (PGF(2α)) impairs endothelial function in renal arteries of renovascular hypertensive rats (RHR). RESULTS Renal hypertension was induced in rats by renal artery stenosis of both kidneys using the 2-kidney 2-clip model. Acute treatment with reactive oxygen species (ROS) scavengers, COX-2 inhibitors, and thromboxane-prostanoid receptor antagonists, but not COX-1 inhibitors, improved endothelium-dependent relaxations and eliminated endothelium-dependent contractions in RHR renal arteries. Five weeks of treatment with celecoxib or tempol reduced blood pressure, increased renal blood flow, and restored endothelial function in RHRs. Increased ROS production in RHR arteries was inhibited by ROS scavengers, but unaffected by COX-2 inhibitors; whereas increased PGF(2α) release was reduced by both ROS scavengers and COX-2 inhibitors. ROS also induced COX-2-dependent contraction in RHR renal arteries, which was accompanied by the release of COX-2-derived PGF(2α). Further, chronic tempol treatment reduced COX-2 and BMP4 upregulation, p38MAPK phosphorylation, and the nitrotyrosine level in RHR renal arteries. CONCLUSION These findings demonstrate the functional importance of oxidative stress, which serves as an initiator of increased COX-2 activity, and that COX-2-derived PGF(2α) plays an important role in mediating endothelial dysfunction in RH. INNOVATION The current study, thus, suggests that drugs targeting oxidative stress-dependent COX-2-derived PGF(2α) may be useful in the prevention and management of RH. Antioxid. Redox Signal. 16, 363-373.
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Affiliation(s)
- Xiao Yu Tian
- Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong SAR, China
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27
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Aging-shifted prostaglandin profile in endothelium as a factor in cardiovascular disorders. J Aging Res 2012; 2012:121390. [PMID: 22500225 PMCID: PMC3303603 DOI: 10.1155/2012/121390] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2011] [Revised: 10/10/2011] [Accepted: 10/28/2011] [Indexed: 12/31/2022] Open
Abstract
Age-associated endothelium dysfunction is a major risk factor for the development of cardiovascular diseases. Endothelium-synthesized prostaglandins and thromboxane are local hormones, which mediate vasodilation and vasoconstriction and critically maintain vascular homeostasis. Accumulating evidence indicates that the age-related changes in endothelial eicosanoids contribute to decline in endothelium function and are associated with pathological dysfunction. In this review we summarize currently available information on aging-shifted prostaglandin profiles in endothelium and how these shifts are associated with cardiovascular disorders, providing one molecular mechanism of age-associated endothelium dysfunction and cardiovascular diseases.
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28
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Alcolea S, Antón R, Camacho M, Soler M, Alfranca A, Avilés-Jurado FX, Redondo JM, Quer M, León X, Vila L. Interaction between head and neck squamous cell carcinoma cells and fibroblasts in the biosynthesis of PGE2. J Lipid Res 2012; 53:630-42. [PMID: 22308510 DOI: 10.1194/jlr.m019695] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Prostaglandin (PG)E(2) is relevant in tumor biology, and interactions between tumor and stroma cells dramatically influence tumor progression. We tested the hypothesis that cross-talk between head and neck squamous cell carcinoma (HNSCC) cells and fibroblasts could substantially enhance PGE(2) biosynthesis. We observed an enhanced production of PGE(2) in cocultures of HNSCC cell lines and fibroblasts, which was consistent with an upregulation of COX-2 and microsomal PGE-synthase-1 (mPGES-1) in fibroblasts. In cultured endothelial cells, medium from fibroblasts treated with tumor cell-conditioned medium induced in vitro angiogenesis, and in tumor cell induced migration and proliferation, these effects were sensitive to PGs inhibition. Proteomic analysis shows that tumor cells released IL-1, and tumor cell-induced COX-2 and mPGES-1 were suppressed by the IL-1-receptor antagonist. IL-1α levels were higher than those of IL-1β in the tumor cell-conditioning medium and in the secretion from samples obtained from 20 patients with HNSCC. Fractionation of tumor cell-conditioning media indicated that tumor cells secreted mature and unprocessed forms of IL-1. Our results support the concept that tumor-associated fibroblasts are a relevant source of PGE(2) in the tumor mass. Because mPGES-1 seems to be essential for a substantial biosynthesis of PGE(2), these findings also strengthen the concept that mPGES-1 may be \a target for therapeutic intervention in patients with HNSCC.
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Affiliation(s)
- Sonia Alcolea
- Laboratory of Angiology, Vascular Biology and Inflammation, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
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29
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Tanabe Y, Saito-Tanji M, Morikawa Y, Kamataki A, Sawai T, Nakayama K. Role of Secretory Phospholipase A2 in Rhythmic Contraction of Pulmonary Arteries of Rats With Monocrotaline-Induced Pulmonary Arterial Hypertension. J Pharmacol Sci 2012; 119:271-81. [DOI: 10.1254/jphs.12024fp] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
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30
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Zayat AS, Conaghan PG, Sharif M, Freeston JE, Wenham C, Hensor EMA, Emery P, Wakefield RJ. Do non-steroidal anti-inflammatory drugs have a significant effect on detection and grading of ultrasound-detected synovitis in patients with rheumatoid arthritis? Results from a randomised study. Ann Rheum Dis 2011; 70:1746-51. [PMID: 21803749 DOI: 10.1136/annrheumdis-2011-200017] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVES To determine whether non-steroidal anti-inflammatory drugs (NSAIDs) have a significant effect on ultrasonographic (US) grey scale (GS) and power Doppler (PD) assessment of synovitis in rheumatoid arthritis (RA). METHODS Patients with RA taking NSAIDs were randomised to either stopping (for a minimum of 5 drug half-lives) or continuing the drug. All patients had a clinical assessment and US examination of both hands and wrists before and after stopping/continuing the NSAID. Changes at follow-up were compared between groups using Mann-Whitney U tests. RESULTS A total of 58 patients with RA were recruited. All the clinical assessment parameters (including disease activity, pain, general state of health and physician global visual analogue score and tender and swollen joints count) showed an increase in the group who stopped their NSAID treatment. The total GS and PD score showed median (first to third quartiles) increase of 9.5 (5.75 to 19.0) and 4.0 (2.0 to 6.0) per patient, respectively, in the patients who stopped their NSAID in comparison with 1.0 (-1.0 to 2.25) and 0.0 (-2.0 to 3.0), respectively, in the patients who continued their NSAID (p<0.001). There was an increase in the number of joints scoring >0 for GS and PD in the patients who stopped the NSAID. The inter- and intrareader agreement was good to excellent for the US examination. CONCLUSION NSAID usage may mask the GS and PD signal and result in lower scoring despite continuing disease activity. Consideration should be given to the NSAID effect in designing clinical studies which use US to assess response to therapeutic.
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Affiliation(s)
- Ahmed S Zayat
- Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, LS7 4SA, UK.
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31
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Tanabe Y, Saito M, Morikawa Y, Kamataki A, Sawai T, Hirose M, Nakayama K. Inhibition of untransformed prostaglandin H(2) production and stretch-induced contraction of rabbit pulmonary arteries by indoxam, a selective secretory phospholipase A(2) inhibitor. J Pharmacol Sci 2011; 115:525-31. [PMID: 21422723 DOI: 10.1254/jphs.10247sc] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
Involvement of secretory phospholipase A(2) (sPLA(2)) in the stretch-induced production of untransformed prostaglandin H(2) (PGH(2)) in the endothelium of rabbit pulmonary arteries was investigated. The stretch-induced contraction was significantly inhibited by indoxam, a selective inhibitor for sPLA(2), and NS-398, a selective inhibitor for cyclooxygenase-2 (COX-2). Indoxam inhibited the RGD-sensitive-integrin-independent production of untransformed PGH(2), but did not affect the RGD-sensitive-integrin-dependent production of thromboxane A(2) (TXA(2)). These results suggest that the stretch-induced contraction and untransformed PGH(2) production was mediated by sPLA(2)-COX-2 pathway, making it a new possible target for pharmacological intervention of pulmonary artery contractility.
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Affiliation(s)
- Yoshiyuki Tanabe
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Iwate Medical University, Japan.
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32
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Camacho M, Rodríguez C, Guadall A, Alcolea S, Orriols M, Escudero JR, Martínez-González J, Vila L. Hypoxia upregulates PGI-synthase and increases PGI₂ release in human vascular cells exposed to inflammatory stimuli. J Lipid Res 2011; 52:720-31. [PMID: 21296955 DOI: 10.1194/jlr.m011007] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Hypoxia affects vascular function and cell metabolism, survival, growth, and motility; these processes are partially regulated by prostanoids. We analyzed the effect of hypoxia and inflammation on key enzymes involved in prostanoid biosynthesis in human vascular cells. In human vascular smooth muscle cells (VSMC), hypoxia and interleukin (IL)-1β synergistically increased prostaglandin (PG)I₂ but not PGE₂ release, thereby increasing the PGI₂/PGE₂ ratio. Concomitantly, these stimuli upregulated cyclooxygenase-2 (COX-2) expression (mRNA and protein) and COX activity. Interestingly, hypoxia enhanced PGI-synthase (PGIS) expression and activity in VSMC and human endothelial cells. Hypoxia did not significantly modify the inducible microsomal-PGE-synthase (mPGES)-1. Hypoxia-inducible factor (HIF)-1α-silencing abrogated hypoxia-induced PGIS upregulation. PGIS transcriptional activity was enhanced by hypoxia; however, the minimal PGIS promoter responsive to hypoxia (-131 bp) did not contain any putative hypoxia response element (HRE), suggesting that HIF-1 does not directly drive PGIS transcription. Serial deletion and site-directed mutagenesis studies suggested several transcription factors participate cooperatively. Plasma levels of the stable metabolite of PGI₂ and PGIS expression in several tissues were also upregulated in mice exposed to hypoxia. These data suggest that PGIS upregulation is part of the adaptive response of vascular cells to hypoxic stress and could play a role in counteracting the deleterious effect of inflammatory stimuli.
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Affiliation(s)
- Mercedes Camacho
- Angiology, Vascular Biology, and Inflammation Laboratory, Institute of Biomedical Research (IIB-Sant Pau), Barcelona, Spain
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Casós K, Siguero L, Fernández-Figueras MT, León X, Sardá MP, Vila L, Camacho M. Tumor cells induce COX-2 and mPGES-1 expression in microvascular endothelial cells mainly by means of IL-1 receptor activation. Microvasc Res 2011; 81:261-8. [PMID: 21277871 DOI: 10.1016/j.mvr.2011.01.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2010] [Revised: 01/18/2011] [Accepted: 01/18/2011] [Indexed: 01/13/2023]
Abstract
Prostaglandin (PG) E(2) plays a key role in immune response, tumor progression and metastasis. We previously showed that macrovessel-derived endothelial cells do not produce PGE(2) enzymatically because they do not express the inducible microsomal PGE-synthase-1 (mPGES-1). Nevertheless, differences between macro- and micro-vessel-derived endothelial cells regarding arachidonic acid (AAc) metabolism profile have been reported. The present work was conducted to evaluate the expression of PGE(2)-pathway-related enzymes in human microvascular endothelial cells (HMVEC) in culture and to test the hypothesis that the tumor cell-HMVEC cross talk could increase mPGES-1 expression in HMVEC. We treated HMVEC in culture with human recombinant IL-1β. IL-1β induced PGE(2) release and COX-2 and mPGES-1 expression in terms of mRNA and protein, determined by real-time PCR and immunoblotting, respectively. HMVEC constitutively expressed mPGES-2 and cytosolic PGES (cPGES) and the IL-1β treatment did not modify their expression. PGE(2) synthesized by HMVEC from exogenous AAc was linked to mPGES-1 expression. Immunohistochemistry analysis confirmed mPGES-1 expression in microvessels in vivo. COX-2 and mPGES-1 were also induced in HMVEC by the conditioned medium from two squamous head and neck carcinoma cell lines. Conditioned medium from tumor cell cultures contained several cytokines including the IL-1β and IL-1α. Tumor cell-induced COX-2 and mPGES-1 in HMVEC was strongly inhibited by the IL-1-receptor antagonist, indicating the important implication of IL-1 in this effect. HMVEC could therefore contribute directly to PGE(2) formed in the tumor. Our findings support the concept that mPGES-1 could be a target for therapeutic intervention in patients with cancer.
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Affiliation(s)
- Kelly Casós
- Laboratory of Angiology, Vascular Biology and Inflammation, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain
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Wong MSK, Vanhoutte PM. COX-mediated endothelium-dependent contractions: from the past to recent discoveries. Acta Pharmacol Sin 2010; 31:1095-102. [PMID: 20711228 DOI: 10.1038/aps.2010.127] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Endothelial cells release various substances to control the tone of the underlying vascular smooth muscle. Nitric oxide (NO) is the best defined endothelium-derived relaxing factor (EDRF). Endothelial cells can also increase vascular tone by releasing endothelium-derived contracting factors (EDCF). The over-production of EDCF contributes to the endothelial dysfunctions which accompanies various vascular diseases. The present review summarizes and discusses the mechanisms leading to the release of EDCFs derived from the metabolism of arachidonic acid. This release can be triggered by agonists such as acetylcholine, adenosine nucleotides or by stretch. All these stimuli are able to induce calcium influx into the endothelial cells, an effect which can be mimicked by calcium ionophores. The augmentation in intracellular calcium ion concentration initiates the release of EDCF. Downstream processes include activation of phospholipase A(2) (PLA(2)), cyclooxygenases (COX) and the production of reactive oxygen species (ROS) and vasoconstrictor prostanoids (endoperoxides, prostacyclin, thromboxane A(2) and other prostaglandins) which subsequently diffuse to, and activate thromboxane-prostanoid (TP) receptors on the vascular smooth muscle cells leading to contraction.
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35
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Riederer M, Ojala PJ, Hrzenjak A, Graier WF, Malli R, Tritscher M, Hermansson M, Watzer B, Schweer H, Desoye G, Heinemann A, Frank S. Acyl chain-dependent effect of lysophosphatidylcholine on endothelial prostacyclin production. J Lipid Res 2010; 51:2957-66. [PMID: 20610733 DOI: 10.1194/jlr.m006536] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Previously we identified palmitoyl-lysophosphatidylcholine (16:0 LPC), linoleoyl-LPC (18:2 LPC), arachidonoyl-LPC (20:4 LPC), and oleoyl-LPC (18:1 LPC) as the most prominent LPC species generated by the action of endothelial lipase (EL) on high-density lipoprotein. In the present study, the impact of those LPC on prostacyclin (PGI(2)) production was examined in vitro in primary human aortic endothelial cells (HAEC) and in vivo in mice. Although 18:2 LPC was inactive, 16:0, 18:1, and 20:4 LPC induced PGI(2) production in HAEC by 1.4-, 3-, and 8.3-fold, respectively. LPC-elicited 6-keto PGF1α formation depended on both cyclooxygenase (COX)-1 and COX-2 and on the activity of cytosolic phospholipase type IVA (cPLA2). The LPC-induced, cPLA2-dependent (14)C-arachidonic acid (AA) release was increased 4.5-fold with 16:0, 2-fold with 18:1, and 2.7-fold with 20:4 LPC, respectively, and related to the ability of LPC to increase cytosolic Ca(2+) concentration. In vivo, LPC increased 6-keto PGF(1α) concentration in mouse plasma with a similar order of potency as found in HAEC. Our results indicate that the tested LPC species are capable of eliciting production of PGI(2), whereby the efficacy and the relative contribution of underlying mechanisms are strongly related to acyl-chain length and degree of saturation.
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Affiliation(s)
- Monika Riederer
- Institute of Molecular Biology and Biochemistry, University of Helsinki, Helsinki, Finland
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36
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Félétou M, Huang Y, Vanhoutte PM. Vasoconstrictor prostanoids. Pflugers Arch 2010; 459:941-50. [PMID: 20333529 DOI: 10.1007/s00424-010-0812-6] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2009] [Revised: 02/15/2010] [Accepted: 02/18/2010] [Indexed: 01/20/2023]
Abstract
In cardiovascular diseases and during aging, endothelial dysfunction is due in part to the release of endothelium-derived contracting factors that counteract the vasodilator effect of the nitric oxide. Endothelium-dependent contractions involve the activation of endothelial cyclooxygenases and the release of various prostanoids, which activate thromboxane prostanoid (TP) receptors of the underlying vascular smooth muscle. The stimulation of TP receptors elicits not only the contraction and the proliferation of vascular smooth muscle cells but also diverse physiological/pathophysiological reactions, including platelet aggregation and activation of endothelial inflammatory responses. TP receptor antagonists curtail endothelial dysfunction in diseases such as hypertension and diabetes, are potent antithrombotic agents, and prevent vascular inflammation.
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37
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Vila L, Martinez-Perez A, Camacho M, Buil A, Alcolea S, Pujol-Moix N, Soler M, Antón R, Souto JC, Fontcuberta J, Soria JM. Heritability of thromboxane A2 and prostaglandin E2 biosynthetic machinery in a Spanish population. Arterioscler Thromb Vasc Biol 2009; 30:128-34. [PMID: 19850905 DOI: 10.1161/atvbaha.109.193219] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Prostanoids play a critical role in clinical areas such as inflammation, thrombosis, immune response, and cancer. Although some studies suggest that there are genes that determine variability of some prostanoid-related phenotypes, the genetic influence on these traits has not been evaluated. METHODS AND RESULTS The relative contributions of genetic and environmental influences to the prostanoid biosynthetic pathway-related phenotypes, cyclooxygenase isoenzymes, microsomal-PGE-synthase-1 and TxA-synthase expression, and thromboxane-A(2) and prostaglandin-E(2) production by stimulated whole blood, were assessed in a sample of 308 individuals in 15 extended families. The effects of measured covariates (such as sex, age, and smoking), genes, and environmental variables shared by members of a household were quantified. Heritabilities ranging from 0.406 to 0.634 for enzyme expression and from 0.283 to 0. 751 for prostanoid production were found. CONCLUSIONS These results demonstrate clearly the importance of genetic factors in determining variation in phenotypes that are components of the prostanoid biosynthetic pathways. The presence of such strong genetic effects suggest that it will be possible to localize previously unknown genes that influence quantitative variation in these phenotypes, some of which affect multiple aspects of cell biology, with important clinical implications.
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Affiliation(s)
- Luis Vila
- H.S. Creu i S. Pau, S. Antonio M Claret 167, 08025-Barcelona, Spain.
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38
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Shen X, Wan C, Ramaswamy G, Mavalli M, Wang Y, Duvall CL, Deng LF, Guldberg RE, Eberhardt A, Clemens TL, Gilbert SR. Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice. J Orthop Res 2009; 27:1298-305. [PMID: 19338032 PMCID: PMC3767389 DOI: 10.1002/jor.20886] [Citation(s) in RCA: 160] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Skeletal trauma and impaired skeletal healing is commonly associated with diminished vascularity. Hypoxia inducible factor alpha (HIF-1) is a key transcription factor responsible for activating angiogenic factors during development and tissue repair. Small molecule inhibitors of the prolyl hydroxylase enzyme (PHD), the key enzyme responsible for degrading HIF-1, have been shown to activate HIF-1, and are effective in inducing angiogenesis. Here we examined the effects of several commercially available PHD inhibitors on bone marrow mesenchymal stromal cells (MSCs) in vitro and in a stabilized fracture model in vivo. Three PHD inhibitors [Desferrioxamine (DFO), L-mimosine (L-mim), and Dimethyloxalylglycine (DMOG)] effectively activated a HIF-1 target reporter, induced expression of vascular endothelial growth factor (VEGF) mRNA in vitro, and increased capillary sprouting in a functional angiogenesis assay. DFO and DMOG were applied by direct injection at the fracture site in a stabilized murine femur fracture model. PHD inhibition increased the vascularity at 14 days and increased callus size as assessed by microCT at 28 days. These results suggest that HIF activation is a viable approach to increase vascularity and bone formation following skeletal trauma.
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Affiliation(s)
- Xing Shen
- Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Jiao Tong University, School of Medicine, Shanghai, People’s Republic of China,Department of Surgery, Division of Orthopedic Surgery, University of Alabama at Birmingham, 1600 7th Avenue South, ACC Suite 316, Birmingham, Alabama
| | - Chao Wan
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35233
| | - Girish Ramaswamy
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, Alabama
| | - Mahendra Mavalli
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35233
| | - Ying Wang
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35233
| | - Craig L. Duvall
- Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia
| | - Lian Fu Deng
- Department of Surgery, Division of Orthopedic Surgery, University of Alabama at Birmingham, 1600 7th Avenue South, ACC Suite 316, Birmingham, Alabama
| | - Robert E. Guldberg
- Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia
| | - Alan Eberhardt
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, Alabama
| | - Thomas L. Clemens
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35233
| | - Shawn R. Gilbert
- Department of Surgery, Division of Orthopedic Surgery, University of Alabama at Birmingham, 1600 7th Avenue South, ACC Suite 316, Birmingham, Alabama
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Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol 2009; 157:527-36. [PMID: 19630832 PMCID: PMC2707964 DOI: 10.1111/j.1476-5381.2009.00240.x] [Citation(s) in RCA: 185] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2008] [Revised: 01/20/2009] [Accepted: 02/05/2009] [Indexed: 12/14/2022] Open
Abstract
The endothelium is a crucial regulator of vascular physiology, producing in healthy conditions several substances with a potent antiatherosclerotic properties. Accordingly, the presence of endothelial dysfunction is associated with subclinical atherosclerosis and with an increased future risk of cardiovascular events. A large body of evidence supports the fundamental role of nitric oxide (NO) as the main endothelium-derived relaxing factor. However, in the presence of pathological conditions, such as hypertension, endothelial cells, in response to a number of agents and physical stimuli, become also a source of endothelium-derived contracting factors (EDCFs), including endothelins and angiotensin II and particularly cyclooxygenase-derived prostanoids and superoxide anions. These latter were at first identified as responsible for impaired endothelium-dependent vasodilation in patients with essential hypertension. However, cyclooxygenase-dependent EDCFs production is characteristic of the aging process, and essential hypertension seems to only anticipate the phenomenon. It is worth noting that both in aging and hypertension EDCF production is associated with a parallel decrease in NO availability, suggesting that this substance could be oxygen free radicals themselves. Accordingly, in hypertension both indomethacin, a cyclooxygenase inhibitor, and vitamin C, an antioxidant, increase the vasodilation to acetylcholine by restoring NO availability. In conclusion, hypertension is characterized by a decline in endothelial function, associated with a progressive decrease in NO bioavailability and increase in the production of EDCF. The mechanisms that regulate the balance between NO and EDCF, and the processes transforming the endothelium from a protective organ to a source of vasoconstrictor, proaggregatory and promitogenic mediators remain to be determined.
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Affiliation(s)
- Daniele Versari
- Department of Internal Medicine, University of Pisa, Pisa, Italy
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40
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Abstract
The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO). The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDHF-mediated responses). Endothelium-dependent relaxations involve both pertussis toxin-sensitive G(i) (e.g. responses to serotonin and thrombin) and pertussis toxin-insensitive G(q) (e.g. adenosine diphosphate and bradykinin) coupling proteins. The release of NO by the endothelial cell can be up-regulated (e.g. by oestrogens, exercise and dietary factors) and down-regulated (e.g. oxidative stress, smoking and oxidized low-density lipoproteins). It is reduced in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively loose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and causing endothelium-dependent hyperpolarizations), endothelial cells also can evoke contraction (constriction) of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factor (EDCF). Most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells. EDCF-mediated responses are exacerbated when the production of NO is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive patients.
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Affiliation(s)
- P M Vanhoutte
- Department of Pharmacology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
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41
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Tamura K, Hashimoto K, Suzuki K, Yoshie M, Kutsukake M, Sakurai T. Insulin-like growth factor binding protein-7 (IGFBP7) blocks vascular endothelial cell growth factor (VEGF)-induced angiogenesis in human vascular endothelial cells. Eur J Pharmacol 2009; 610:61-7. [PMID: 19374835 DOI: 10.1016/j.ejphar.2009.01.045] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2008] [Revised: 01/07/2009] [Accepted: 01/27/2009] [Indexed: 11/29/2022]
Abstract
Insulin-like growth factor binding protein-7 (IGFBP7) and vascular endothelial growth factor (VEGF) are expressed in vascular endothelial cells in several tumor types. In this study, we examined the effect of IGFBP7 on VEGF-induced tube formation in cultured human umbilical vein endothelial cells (HUVECs) and its potential action in the modulation of VEGF signaling in vascular cells. IGFBP7 treatment suppressed VEGF-induced tube formation, proliferation, and the phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) 1/2 in HUVECs. IGFBP7 attenuated VEGF-enhanced cyclooxygenase (COX)-2 and VEGF mRNA expression, and prostaglandin E(2) secretion. Knocking down endogenous IGFBP7 enhanced COX-2 and VEGF mRNA expression. A significant increase in IGFBP7-induced caspases was not observed in the presence of VEGF. These findings indicate that IGFBP7 can modulate the stimulatory effect of VEGF on angiogenesis by interfering with VEGF expression as well as VEGF signaling and not by inducing apoptosis.
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Affiliation(s)
- Kazuhiro Tamura
- Department of Endocrine Pharmacology, Tokyo University of Pharmacy & Life Sciences, Horinouchi 1432-1, Hachioji, Tokyo, 192-0392, Japan.
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Félétou M, Verbeuren TJ, Vanhoutte PM. Endothelium-dependent contractions in SHR: a tale of prostanoid TP and IP receptors. Br J Pharmacol 2009; 156:563-74. [PMID: 19154435 DOI: 10.1111/j.1476-5381.2008.00060.x] [Citation(s) in RCA: 124] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
In the aorta of spontaneously hypertensive rats (SHR), the endothelial dysfunction is due to the release of endothelium-derived contracting factors (EDCFs) that counteract the vasodilator effect of nitric oxide, with no or minor alteration of its production. The endothelium-dependent contractions elicited by acetylcholine (ACh) involve an increase in endothelial [Ca(2+)](i), the production of reactive oxygen species, the activation of endothelial cyclooxygenase-1, the diffusion of EDCF and the subsequent stimulation of smooth muscle cell TP receptors. The EDCFs released by ACh have been identified as PGH(2) and paradoxically prostacyclin. Prostacyclin generally acts as an endothelium-derived vasodilator, which, by stimulating IP receptors, produces hyperpolarization and relaxation of the smooth muscle and inhibits platelet aggregation. In the aorta of SHR and Wistar-Kyoto rats, prostacyclin is the principal metabolite of arachidonic acid released by ACh. However, in SHR aorta, prostacyclin does not produce relaxations but activates the TP receptors on vascular smooth muscle cells and produces contraction. The IP receptor is not functional in the aortic smooth muscle cells of SHR as early as 12 weeks of age, but its activity is not reduced in platelets. Therefore, prostacyclin in the rule protects the vascular wall, but in the SHR aorta it can contribute to endothelial dysfunction. Whether or not prostacyclin plays a detrimental role as an EDCF in other animal models or in human remains to be demonstrated. Nevertheless, because EDCFs converge to activate TP receptors, selective antagonists of this receptor, by preventing endothelium-dependent contractions, curtail the endothelial dysfunction in diseases such as hypertension and diabetes.
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Affiliation(s)
- Michel Félétou
- Department of Angiology, Institut de Recherches Servier, Suresnes, France.
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Foudi N, Louedec L, Cachina T, Brink C, Norel X. Selective cyclooxygenase-2 inhibition directly increases human vascular reactivity to norepinephrine during acute inflammation. Cardiovasc Res 2008; 81:269-77. [DOI: 10.1093/cvr/cvn287] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Yang K, Bai H, Ouyang Q, Lai L, Tang C. Finding multiple target optimal intervention in disease-related molecular network. Mol Syst Biol 2008; 4:228. [PMID: 18985027 PMCID: PMC2673713 DOI: 10.1038/msb.2008.60] [Citation(s) in RCA: 135] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2008] [Accepted: 09/14/2008] [Indexed: 11/09/2022] Open
Abstract
Drugs against multiple targets may overcome the many limitations of single targets and achieve a more effective and safer control of the disease. Numerous high-throughput experiments have been performed in this emerging field. However, systematic identification of multiple drug targets and their best intervention requires knowledge of the underlying disease network and calls for innovative computational methods that exploit the network structure and dynamics. Here, we develop a robust computational algorithm for finding multiple target optimal intervention (MTOI) solutions in a disease network. MTOI identifies potential drug targets and suggests optimal combinations of the target intervention that best restore the network to a normal state, which can be customer designed. We applied MTOI to an inflammation-related network. The well-known side effects of the traditional non-steriodal anti-inflammatory drugs and the recently recalled Vioxx were correctly accounted for in our network model. A number of promising MTOI solutions were found to be both effective and safer.
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Affiliation(s)
- Kun Yang
- Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
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Bolego C, Buccellati C, Prada A, Gaion RM, Folco G, Sala A. Critical role of COX-1 in prostacyclin production by human endothelial cells under modification of hydroperoxide tone. FASEB J 2008; 23:605-12. [PMID: 18838483 DOI: 10.1096/fj.08-106591] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We aimed at evaluating the relative contribution of cyclooxygenase (COX) -1 and COX-2 to the synthesis of prostacyclin in endothelial cells under static conditions in the presence or absence of exogenous arachidonic acid and/or altered intracellular redox balance. Selective inhibitors of either COX-1 (SC560 and FR122047) or COX-2 (SC236) concentration dependently (1-300 nM) reduced basal and interleukin (IL) -1beta-induced prostacyclin production in human umbilical vein endothelial cells by 70% or more; compound selectivity was confirmed using a whole-blood assay (IC(50) COX-1/COX-2: 13 nM/930 nM for SC-560; 9 microM/457 nM for SC-236). The observed concomitant formation of isoprostane appeared to be associated with COX enzyme activity, while formation of COX-1/COX-2 heterodimers was detected by immunoprecipitation. In the presence of arachidonic acid and 12-hydroperoxy-eicosatetraenoic acid, either exogenous or provided by platelet activation, or after glutathione depletion, COX-1 inhibition but not COX-2 inhibition concentration dependently decreased prostacyclin production. Both isoforms appear to contribute to basal prostacyclin production by endothelial cells, with COX-2 providing the hydroperoxide tone required for COX-1 activity. Conversely, in the case of intracellular glutathione depletion or enhanced availability of arachidonic acid and hydroperoxides, selective COX-2 inhibition did not significantly affect the production of endothelial prostacyclin. These findings contribute to a better understanding of the effects of cyclooxygenase inhibitors on prostacyclin production.
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Affiliation(s)
- Chiara Bolego
- Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy
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Abstract
Endothelial cells can induce contractions of the underlying vascular smooth muscle by generating vasoconstrictor prostanoids (endothelium-dependent contracting factor; EDCF). The endothelial COX-1 isoform of cyclooxygenase appears to play the dominant role in the phenomenon. Its activation requires an increase in intracellular Ca(2+) concentration. The production of EDCF is inhibited acutely and chronically by nitric oxide (NO), and possibly by endothelium-dependent hyperpolarizing factor (EDHF). The main prostanoids involved in endothelium-dependent contractions appear to be endoperoxides (PGH(2)) and prostacyclin, which activate thromboxane-prostanoid (TP) receptors of the vascular smooth muscle cells. Oxygen-derived free radicals can facilitate the production and/or the action of EDCF. Endothelium-dependent contractions are exacerbated by ageing, obesity, hypertension and diabetes, and thus are likely to contribute to the endothelial dysfunction observed in older people and in essential hypertensive patients.
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Affiliation(s)
- Paul M Vanhoutte
- Department of Pharmacology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.
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Camacho M, Rodríguez C, Salazar J, Martínez-González J, Ribalta J, Escudero JR, Masana L, Vila L. Retinoic acid induces PGI synthase expression in human endothelial cells. J Lipid Res 2008; 49:1707-14. [DOI: 10.1194/jlr.m700559-jlr200] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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48
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Prostaglandin E(2)-loaded microspheres as strategy to inhibit phagocytosis and modulate inflammatory mediators release. Eur J Pharm Biopharm 2008; 70:784-90. [PMID: 18640269 DOI: 10.1016/j.ejpb.2008.06.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2007] [Revised: 03/29/2008] [Accepted: 06/19/2008] [Indexed: 11/22/2022]
Abstract
PGE(2), an arachidonic acid metabolite produced by various type of cells regulates a broad range of physiological activities in the endocrine, cardiovascular, gastrointestinal, and immune systems, and is involved in maintaining the local homeostasis. In the immune system, PGE(2) is mainly produced by APCs and it can suppress the Th1-mediated immune responses. The aim of this study was to develop PGE(2)-loaded biodegradable MS that prolong and sustain the in vivo release of this mediator. An o/w emulsion solvent extraction-evaporation method was chosen to prepare the MS. We determined their diameters, evaluated the in vitro release of PGE(2), using enzyme immunoassay and MS uptake by peritoneal macrophages. To assess the preservation of biological activities of this mediator, we determined the effect of PGE(2) released from MS on LPS-induced TNF-alpha release by murine peritoneal macrophages. We also analyzed the effect of encapsulated PGE(2) on inflammatory mediators release from HUVECs. Finally, we studied the effect of PGE(2) released from biodegradable MS in sepsis animal model. The use of this formulation can provide an alternative strategy for treating infections, by modulating or inhibiting inflammatory responses, especially when they constitute an exacerbated profile.
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Hirao A, Kondo K, Takeuchi K, Inui N, Umemura K, Ohashi K, Watanabe H. Cyclooxygenase-dependent vasoconstricting factor(s) in remodelled rat femoral arteries. Cardiovasc Res 2008; 79:161-8. [DOI: 10.1093/cvr/cvn111] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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50
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Tan X, Essengue S, Talreja J, Reese J, Stechschulte DJ, Dileepan KN. Histamine directly and synergistically with lipopolysaccharide stimulates cyclooxygenase-2 expression and prostaglandin I(2) and E(2) production in human coronary artery endothelial cells. THE JOURNAL OF IMMUNOLOGY 2008; 179:7899-906. [PMID: 18025237 DOI: 10.4049/jimmunol.179.11.7899] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Although histamine plays an essential role in inflammation, its influence on cyclooxygenases (COX) and prostanoid homeostasis is not well understood. In this study, we investigated the effects of histamine on the expression of COX-1 and COX-2 and determined their contribution to the production of PGE(2), prostacyclin (PGI(2)), and thromboxane A(2) in human coronary artery endothelial cells (HCAEC). Incubation of HCAEC monolayers with histamine resulted in marked increases in the expression of COX-2 and production of PGI(2) and PGE(2) with no significant change in the expression of COX-1. Histamine-induced increases in PGI(2) and PGE(2) production were due to increased expression and function of COX-2 because gene silencing by small interfering RNA or inhibition of the catalytic activity by a COX-2 inhibitor blocked prostanoid production. The effects of histamine on COX-2 expression and prostanoid production were mediated through H(1) receptors. In addition to the direct effect, histamine was found to amplify LPS-stimulated COX-2 expression and PGE(2) and PGI(2) production. In contrast, histamine did not stimulate thromboxane A(2) production in resting or LPS-activated HCAEC. Histamine-induced increases in the production of PGE(2) and PGI(2) were associated with increased expression of mRNA encoding PGE(2) and PGI(2) synthases. The physiological role of histamine on the regulation of COX-2 expression in the vasculature is indicated by the findings that the expression of COX-2 mRNA, but not COX-1 mRNA, was markedly reduced in the aortic tissues of histidine decarboxylase null mice. Thus, histamine plays an important role in the regulation of COX-2 expression and prostanoid homeostasis in vascular endothelium.
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Affiliation(s)
- Xiaoyu Tan
- Division of Allergy, Clinical Immunology, and Rheumatology, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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