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2. Estrogen Receptor and Vascular Aging

Author

Davezac, Morgane, Buscato, Melissa, Zahreddine, Rana, Lacolley, Patrick, Henrion, Daniel, Lenfant, Francoise, Arnal, Jean-Francois, and Fontaine, Coralie

Subjects
endothelium, vascular aging, Geriatrics, estradiol, RC952-954.6, menopause, General Medicine, atherosclerosis, estrogen receptor
Abstract

Cardiovascular diseases remain an age-related pathology in both men and women. These pathologies are 3-fold more frequent in men than in women before menopause, although this difference progressively decreases after menopause. The vasculoprotective role of estrogens are well established before menopause, but the consequences of their abrupt decline on the cardiovascular risk at menopause remain debated. In this review, we will attempt to summarize the main clinical and experimental studies reporting the protective effects of estrogens against cardiovascular diseases, with a particular focus on atherosclerosis, and the impact of aging and estrogen deprivation on their endothelial actions. The arterial actions of estrogens, but also part of that of androgens through their aromatization into estrogens, are mediated by the estrogen receptor (ER)α and ERβ. ERs belong to the nuclear receptor family and act by transcriptional regulation in the nucleus, but also exert non-genomic/extranuclear actions. Beside the decline of estrogens at menopause, abnormalities in the expression and/or function of ERs in the tissues, and particularly in arteries, could contribute to the failure of classic estrogens to protect arteries during aging. Finally, we will discuss how recent insights in the mechanisms of action of ERα could contribute to optimize the hormonal treatment of the menopause.

Published
2021

3. Concept of Extremes in Vascular Aging

Author

Laurent, Stephane, Boutouyrie, Pierre, Cunha, Pedro Guimarães, Lacolley, Patrick, Nilsson, Peter, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Minho [Braga], Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Skane University Hospital [Malmo], Lund University [Lund], and LACOLLEY, Patrick

Subjects
Aged, 80 and over, Male, Sweden, Aging, Biomedical Research, Arteriosclerosis, [SDV]Life Sciences [q-bio], Age Factors, Middle Aged, Risk Assessment, Survival Analysis, [SDV] Life Sciences [q-bio], Vascular Stiffness, Cardiovascular Diseases, Disease Progression, Prevalence, Humans, Female, Age of Onset, ComputingMilieux_MISCELLANEOUS, Aged
Abstract

International audience; No abstract available

Published
2019

4. Implication of Free Fatty Acids in Thrombin Generation and Fibrinolysis in Vascular Inflammation in Zucker Rats and Evolution with Aging

Author

Lagrange, Jérémy, Didelot, Mélusine, Mohamadi, Amel, Walton, Lucy A., Bloemen, Saartje, de Laat, Bas, Louis, Huguette, Thornton, Simon N., Derby, Brian, Sherratt, Michael J., Fève, Bruno, Challande, Pascal, Akhtar, Riaz, Cruickshank, J. Kennedy, Lacolley, Patrick, Regnault, Véronique, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, Johannes Gutenberg - Universität Mainz (JGU), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), University of Manchester [Manchester], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Jean Le Rond d'Alembert (DALEMBERT), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Liverpool, King‘s College London, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), University of Salford, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and REGNAULT, Véronique

Subjects
Thrombin generation, obesity, MATRIX METALLOPROTEINASES, Physiology, [SDV]Life Sciences [q-bio], SMOOTH-MUSCLE-CELLS, ENDOTHELIAL FUNCTION, blood coagulation test, fatty acids, Physiology (medical), WHOLE-BLOOD, Obesity, Fatty acids, Blood coagulation test, ComputingMilieux_MISCELLANEOUS, IN-VIVO, METABOLIC SYNDROME, GENE-EXPRESSION, Original Research, FACTOR-VIII, Vascular aging, [SDV] Life Sciences [q-bio], vascular aging, thrombin generation, PLATELET-AGGREGATION, ARTERIAL STIFFNESS
Abstract

International audience; Background: The metabolic syndrome (MetS) and aging are associated with modifications in blood coagulation factors, vascular inflammation, and increased risk of thrombosis. Objectives: Our aim was to determine concomitant changes in thrombin generation in the blood compartment and at the surface of vascular smooth muscle cells (VSMCs) and its interplay with adipokines, free fatty acids (FFA), and metalloproteinases (MMPs) in obese Zucker rats that share features of the human MetS. Methods: Obese and age-matched lean Zucker rats were compared at 25 and 80 weeks of age. Thrombin generation was assessed by calibrated automated thrombography (CAT). Results: Endogenous thrombin potential (ETP) was increased in obese rats independent of platelets and age. Clot half-lysis time was delayed with obesity and age. Interleukin (IL)-1β and IL-13 were increased with obesity and age respectively. Addition of exogenous fibrinogen, leptin, linoleic, or palmitic acid increased thrombin generation in plasma whereas adiponectin had an opposite effect. ETP was increased at the surface of VSMCs from obese rats and addition of exogenous palmitic acid further enhanced ETP values. Gelatinase activity was increased in aorta at both ages in obese rats and MMP-2 activity was increased in VSMCs from obese rats. Conclusions: Our study demonstrated in MetS an early prothrombotic phenotype of the blood compartment reinforced by procoagulant properties of dedifferentiated and inflammatory VSMCs. Mechanisms involved (1) increased fibrinogen and impaired fibrinolysis and (2) increased saturated fatty acids responsible for additive procoagulant effects. Whether specifically targeting this hypercoagulability using direct thrombin inhibitors would improve outcome in MetS is worth investigating.

Published
2017

5. Selective Involvement of Serum Response Factor in Pressure-Induced Myogenic Tone in Resistance Arteries

Author

Retailleau, Kevin, Toutain, Bertrand, Galmiche, Guillaume, Fassot, Celine, Sharif-Naeini, Reza, Kauffenstein, Gilles, Mericskay, Mathias, Duprat, Fabrice, Li, Linda, Mérot, Jean, Lardeux, Aurelie, Pizard, Anne, Baudrie, Véronique, Jeunemaitre, Xavier, Feil, Robert, Göthert, Joachim, Lacolley, Patrick, Henrion, Daniel, Li, Zhenlin, Loufrani, Laurent, Grimaud, L., Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), UMR915, Nutrition et athérome, Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [AP-HP Hôpital Européen Georges Pompidou, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Eberhard Karls Universität Tübingen, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Biologie Neurovasculaire et Mitochondriale Intégrée, Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Physiologie de la Nutrition et du Comportement Alimentaire ( PNCA ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Défaillance Cardiovasculaire Aiguë et Chronique ( DCAC ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Universitätsklinikum Essen [Universität Duisburg-Essen] ( Uniklinik Essen ), Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Serum Response Factor, MESH : RNA, Messenger, Vasodilator Agents, MESH: Vascular Resistance, MESH : Actins, MESH : Blotting, Western, Filamin, Mechanotransduction, Cellular, Muscle, Smooth, Vascular, MESH : Mechanotransduction, Cellular, Mice, Contractile Proteins, 0302 clinical medicine, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Myosin-Light-Chain Kinase, MESH : Patch-Clamp Techniques, MESH : p38 Mitogen-Activated Protein Kinases, 0303 health sciences, Microscopy, Confocal, MESH : Vasoconstrictor Agents, MESH : Gene Expression Regulation, Electrical impedance myography, MESH : Reverse Transcriptase Polymerase Chain Reaction, Arteries, MESH : Vascular Resistance, MESH : Arterial Pressure, MESH: Serum Response Factor, MESH: Vasoconstriction, MESH : Tail, MESH : Vasoconstriction, Cardiology and Cardiovascular Medicine, Tail, medicine.medical_specialty, Blotting, Western, MESH: Myography, MESH: Actins, MESH : Vasodilator Agents, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Serum response factor, MESH: Membrane Potentials, MESH: Blotting, Western, MESH: Contractile Proteins, RNA, Messenger, MESH : Microscopy, Confocal, Myosin-Light-Chain Kinase, MESH: Arteries, Phenylephrine, Dose-Response Relationship, Drug, MESH: Mechanotransduction, Cellular, MESH : Muscle, Smooth, Vascular, MESH : Protein Kinase Inhibitors, MESH: Vasodilator Agents, Endocrinology, Vasoconstriction, Vascular Resistance, Patch-Clamp Techniques, Time Factors, Contraction (grammar), Medizin, MESH : Dose-Response Relationship, Drug, 030204 cardiovascular system & hematology, MESH : Filamins, p38 Mitogen-Activated Protein Kinases, MESH: Mice, Knockout, Membrane Potentials, MESH: Dose-Response Relationship, Drug, MESH : Vasodilation, MESH : Calcium Signaling, MESH: Reverse Transcriptase Polymerase Chain Reaction, Vasoconstrictor Agents, MESH : Membrane Potentials, MESH: Microscopy, Confocal, MESH : Contractile Proteins, MESH: Filamins, Mice, Knockout, MESH : Myography, Reverse Transcriptase Polymerase Chain Reaction, MESH: Real-Time Polymerase Chain Reaction, Microfilament Proteins, MESH: Tail, MESH: Muscle, Smooth, Vascular, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Gene Expression Regulation, MESH: Myosin Light Chains, Vasodilation, MESH : Time Factors, medicine.drug, Myosin Light Chains, Myosin light-chain kinase, MESH : Microfilament Proteins, Filamins, MESH : Male, MESH: Arterial Pressure, MESH : Myosin Light Chains, MESH : Real-Time Polymerase Chain Reaction, Biology, Real-Time Polymerase Chain Reaction, MESH : Myosin-Light-Chain Kinase, MESH: Calcium Signaling, MESH: Vasodilation, MESH: Microfilament Proteins, MESH: Vasoconstrictor Agents, Internal medicine, MESH : Mice, MESH: Patch-Clamp Techniques, medicine, Animals, Arterial Pressure, Calcium Signaling, Patch clamp, Protein Kinase Inhibitors, MESH: Mice, Actin, MESH: RNA, Messenger, 030304 developmental biology, MESH: Time Factors, Myography, Actins, MESH : Arteries, MESH: Male, MESH: p38 Mitogen-Activated Protein Kinases, Gene Expression Regulation, MESH : Mice, Knockout, MESH : Serum Response Factor, MESH : Animals
Abstract

Objective— In resistance arteries, diameter adjustment in response to pressure changes depends on the vascular cytoskeleton integrity. Serum response factor (SRF) is a dispensable transcription factor for cellular growth, but its role remains unknown in resistance arteries. We hypothesized that SRF is required for appropriate microvascular contraction. Methods and Results— We used mice in which SRF was specifically deleted in smooth muscle or endothelial cells, and their control. Myogenic tone and pharmacological contraction was determined in resistance arteries. mRNA and protein expression were assessed by quantitative real-time PCR (qRT-PCR) and Western blot. Actin polymerization was determined by confocal microscopy. Stress-activated channel activity was measured by patch clamp. Myogenic tone developing in response to pressure was dramatically decreased by SRF deletion (5.9±2.3%) compared with control (16.3±3.2%). This defect was accompanied by decreases in actin polymerization, filamin A, myosin light chain kinase and myosin light chain expression level, and stress-activated channel activity and sensitivity in response to pressure. Contractions induced by phenylephrine or U46619 were not modified, despite a higher sensitivity to p38 blockade; this highlights a compensatory pathway, allowing normal receptor-dependent contraction. Conclusion— This study shows for the first time that SRF has a major part to play in the control of local blood flow via its central role in pressure-induced myogenic tone in resistance arteries.

Published
2013

6. International consensus on the prevention of venous and arterial thrombotic events in patients with inflammatory bowel disease

Author

Olivera, Pablo A, Zuily, Stephane, Kotze, Paulo G, Regnault, Veronique, Al Awadhi, Sameer, Bossuyt, Peter, Gearry, Richard B, Ghosh, Subrata, Kobayashi, Taku, Lacolley, Patrick, Louis, Edouard, Magro, Fernando, Ng, Siew C, Papa, Alfredo, Raine, Tim, Teixeira, Fabio V, Rubin, David T, Danese, Silvio, and Peyrin-Biroulet, Laurent

Subjects
Hospitalization, Fibrinolytic Agents, Risk Factors, International Cooperation, Anti-Inflammatory Agents, Patient Acuity, Humans, Thrombosis, Inflammatory Bowel Diseases, Risk Assessment, digestive system diseases, 3. Good health
Abstract

Patients with inflammatory bowel disease (IBD) are at increased risk of thrombotic events. Therapies for IBD have the potential to modulate this risk. The aims of this Evidence-Based Guideline were to summarize available evidence and to provide practical recommendations regarding epidemiological aspects, prevention and drug-related risks of venous and arterial thrombotic events in patients with IBD. A virtual meeting took place in May 2020 involving 14 international IBD experts and 3 thrombosis experts from 12 countries. Proposed statements were voted upon in an anonymous manner. Agreement was defined as at least 75% of participants voting as 'fully agree' or 'mostly agree' with each statement. For each statement, the level of evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) grading system. Consensus was reached for 19 statements. Patients with IBD harbour an increased risk of venous and arterial thrombotic events. Thromboprophylaxis is indicated during hospitalization of any cause in patients with IBD. Disease activity is a modifiable risk factor in patients with IBD, and physicians should aim to achieve deep remission to reduce the risk. Exposure to steroids should be limited. Antitumour necrosis factor agents might be associated with a reduced risk of thrombotic events.

7. International consensus on the prevention of venous and arterial thrombotic events in patients with inflammatory bowel disease

Author

Olivera, Pablo A, Zuily, Stephane, Kotze, Paulo G, Regnault, Veronique, Al Awadhi, Sameer, Bossuyt, Peter, Gearry, Richard B, Ghosh, Subrata, Kobayashi, Taku, Lacolley, Patrick, Louis, Edouard, Magro, Fernando, Ng, Siew C, Papa, Alfredo, Raine, Tim, Teixeira, Fabio V, Rubin, David T, Danese, Silvio, and Peyrin-Biroulet, Laurent

Subjects
digestive system diseases, 3. Good health
Abstract

Patients with inflammatory bowel disease (IBD) are at increased risk of thrombotic events. Therapies for IBD have the potential to modulate this risk. The aims of this Evidence-Based Guideline were to summarize available evidence and to provide practical recommendations regarding epidemiological aspects, prevention and drug-related risks of venous and arterial thrombotic events in patients with IBD. A virtual meeting took place in May 2020 involving 14 international IBD experts and 3 thrombosis experts from 12 countries. Proposed statements were voted upon in an anonymous manner. Agreement was defined as at least 75% of participants voting as 'fully agree' or 'mostly agree' with each statement. For each statement, the level of evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) grading system. Consensus was reached for 19 statements. Patients with IBD harbour an increased risk of venous and arterial thrombotic events. Thromboprophylaxis is indicated during hospitalization of any cause in patients with IBD. Disease activity is a modifiable risk factor in patients with IBD, and physicians should aim to achieve deep remission to reduce the risk. Exposure to steroids should be limited. Antitumour necrosis factor agents might be associated with a reduced risk of thrombotic events.

8. Potassium channel openers increase aortic elastic fiber formation and reverse the genetically determined elastin deficit in the BN rat

Author

Slove, Séverin, Lannoy, Morgane, Behmoaras, Jacques, Pezet, Mylène, Sloboda, Natacha, Lacolley, Patrick, Escoubet, Brigitte, Buján, Julia, Jacob, Marie-Paule, Bujan, J., Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Université Paris Diderot - Paris 7 (UPD7), Centre d'Explorations Fonctionnelles Intégré (CEFI), Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Physiologie [Bichat-Claude Bernard], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Departments of Medicine and Medical Specialities, Universidad de Alcalá - University of Alcalá (UAH), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]

Subjects
Male, Vasodilator Agents, MESH: Pinacidil, MESH: Minoxidil, MESH: Diazoxide, Blood Pressure, MESH: Elastic Tissue, 030204 cardiovascular system & hematology, Muscle, Smooth, Vascular, chemistry.chemical_compound, 0302 clinical medicine, Rats, Inbred BN, Glyburide, MESH: Animals, 0303 health sciences, biology, Pinacidil, MESH: Myocytes, Smooth Muscle, MESH: Aorta, MESH: Muscle, Smooth, Vascular, MESH: Potassium Channels, MESH: Blood Pressure, potassium channels, Potassium channel, 3. Good health, MESH: Rats, Inbred BN, medicine.anatomical_structure, Minoxidil, Potassium channel opener, Elastic fiber, medicine.drug, medicine.medical_specialty, MESH: Rats, Myocytes, Smooth Muscle, MESH: Elastin, elastin, elastic tissue, MESH: Glyburide, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Internal Medicine, medicine, Diazoxide, Animals, Antihypertensive Agents, 030304 developmental biology, MESH: Antihypertensive Agents, business.industry, Potassium channel blocker, MESH: Male, Surgery, MESH: Vasodilator Agents, rats, aorta, Endocrinology, chemistry, biology.protein, business, Elastin
Abstract

International audience; Hypertension is a cardiovascular disorder that appears in more than half of the patients with Williams-Beuren syndrome, hemizygous for the elastin gene among 26 to 28 other genes. It was shown that the antihypertensive drug minoxidil, an ATP-dependent potassium channel opener, enhances elastic fiber formation; however, no wide clinical application was developed because of its adverse side effects. The Brown Norway rat was used here as an arterial elastin-deficient model. We tested 3 different potassium channel openers, minoxidil, diazoxide, and pinacidil, and 1 potassium channel blocker, glibenclamide, on cultured smooth muscle cells from Brown Norway rat aorta. All tested potassium channel openers increased mRNAs encoding proteins and enzymes involved in elastic fiber formation, whereas glibenclamide had the opposite effect. The higher steady-state level of tropoelastin mRNA in minoxidil-treated cells was attributable to an increase in both transcription and mRNA stability. Treatment of Brown Norway rats for 10 weeks with minoxidil or diazoxide increased elastic fiber content and decreased cell number in the aortic media, without changing collagen content. The minoxidil-induced cardiac hypertrophy was reduced when animals simultaneously received irbesartan, an angiotensin II-receptor antagonist. This side effect of minoxidil was not observed in diazoxide-treated animals. In conclusion, diazoxide, causing less undesirable side effects than minoxidil, or coadministration of minoxidil and irbesartan, increases elastic fiber content, decreases cell number in the aorta and, thus, could be suitable for treating vascular pathologies characterized by diminished arterial elastin content and simultaneous hypertension.

9. Cell senescence: basic mechanisms and the need for computational networks in vascular ageing

Author

Véronique Regnault, Florence Pinet, Pascal Challande, Zhenlin Li, Patrick Lacolley, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Sorbonne Université (SU), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Jean Le Rond d'Alembert (DALEMBERT), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and LACOLLEY, Patrick

Subjects
Proteomics, Senescence, Physiology, [SDV]Life Sciences [q-bio], Cell, Cell Cycle Proteins, 030204 cardiovascular system & hematology, Biology, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), medicine, Animals, Humans, Gene Regulatory Networks, Protein Interaction Maps, Vascular Diseases, Epigenetics, Senolytic, Cellular Senescence, Cell Proliferation, 030304 developmental biology, 0303 health sciences, Systems Biology, Computational Biology, Cell Cycle Checkpoints, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Signalling, Gene Expression Regulation, Blood Vessels, Cardiology and Cardiovascular Medicine, Cell aging, Neuroscience, Algorithms, Function (biology), Biological network, Signal Transduction
Abstract

This review seeks to provide an update of the mechanisms of vascular cell senescence, from newly identified molecules to arterial ageing phenotypes, and finally to present a computational approach to connect these selected proteins in biological networks. We will discuss current key signalling and gene expression pathways by which these focus proteins and networks drive normal and accelerated vascular ageing. We also review the possibility that senolytic drugs, designed to restore normal cell differentiation and function, could effectively treat multiple age-related vascular diseases. Finally, we discuss how cell senescence is both a cause and a consequence of vascular ageing because of the possible feedback controls between identified networks.

Published
2020

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