17 results on '"Audrey Ayer"'
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2. The Tryptophan/Kynurenine Pathway: A Novel Cross-Talk between Nutritional Obesity, Bariatric Surgery and Taste of Fat
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Claire Blanchard, Philippe Besnard, Jean-Paul Pais de Barros, Aurélie Dastugue, Jean-Charles Martin, Cindy Le Bourgot, Cédric Le May, Séverine Ledoux, Arnaud Bernard, Pascaline Delaby, Audrey Ayer, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), General and Digestive Surgery Department, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Lesieur Groupe Avril, Tereos Starch & Sweeteners [Aals], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du(2011), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer(2011), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Tereos, Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lucas, Nelly, and Laboratoires d'excellence - Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer - - Lipstic2011 - ANR-11-LABX-0021 - LABX - VALID
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0301 basic medicine ,Male ,Taste ,Kynurenine pathway ,medicine.medical_treatment ,chemistry.chemical_compound ,Mice ,Taste Disorders ,0302 clinical medicine ,TX341-641 ,Postoperative Period ,fatty taste ,Kynurenine ,Nutrition and Dietetics ,Tryptophan ,Taste Perception ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,Health ,Metabolome ,Female ,Signal Transduction ,kynurenine pathway ,Adult ,medicine.medical_specialty ,Sleeve gastrectomy ,diet-induced obesity ,bariatric surgery ,Article ,03 medical and health sciences ,Food Preferences ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Gastrectomy ,medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,Humans ,In patient ,Obesity ,tryptophan metabolism ,Nutrition. Foods and food supply ,business.industry ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,medicine.disease ,Dietary Fats ,Surgery ,[SDV.AEN] Life Sciences [q-bio]/Food and Nutrition ,030104 developmental biology ,chemistry ,business ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition ,030217 neurology & neurosurgery ,sleeve gastrectomy ,Food Science - Abstract
International audience; Diet-induced obesity (DIO) reduces the orosensory perception of lipids in rodents and in some humans. Although bariatric surgery partially corrects this alteration, underlying mechanisms remain poorly understood. To explore whether metabolic changes might explain this fat taste disturbance, plasma metabolome analyses, two-bottle choice tests and fungiform papillae (Fun) counting were performed in vertical sleeve gastrectomized (VSG) mice and sham-operated controls. An exploratory clinic study was also carried out in adult patients undergone a VSG. In mice, we found that (i) the VSG reduces both the plasma neurotoxic signature due to the tryptophan/kynurenine (Trp/Kyn) pathway overactivation and the failure of fat preference found in sham-operated DIO mice, (ii) the activity of Trp/Kyn pathway is negatively correlated to the density of Fun, and (iii) the pharmacological inhibition of the Kyn synthesis mimics in non-operated DIO mice the positive effects of VSG (i.e., decrease of Kyn synthesis, increase of Fun number, improvement of the fat taste perception). In humans, a reduction of the plasma Kyn level is only found in patients displaying a post-surgery improvement of their fat taste sensitivity. Altogether these data provide a plausible metabolic explanation to the degradation of the orosensory lipid perception observed in obesity.
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- 2021
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3. PCSK9 is not secreted from mature differentiated intestinal cells
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Melissa Touvron, Cédric Le May, Thibaud Sotin, Xavier Prieur, L. Arnaud, Annik Prat, Anna Roubtsova, Claire Blanchard, Nabil G. Seidah, Wieneke Dijk, Audrey Ayer, Moreau François, Bertrand Cariou, Laurianne Van Landeghem, Gilliane Chadeuf, Damien Garçon, Aurélie Thedrez, Mikaël Croyal, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Montréal (UdeM), Centre hospitalier universitaire de Nantes (CHU Nantes), North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC), Dijk, Wieneke, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches Cliniques de Montréal (IRCM), and Le May, Cedric
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[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,[SDV]Life Sciences [q-bio] ,3′DGE, 3′ digital gene expression ,Regulator ,030204 cardiovascular system & hematology ,Biochemistry ,Caco-2 cell ,PCSK9 ,Mice ,0302 clinical medicine ,Endocrinology ,Intestine, Small ,liver-specific knockout ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,portal blood ,Mice, Knockout ,[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,lipoprotein metabolism ,0303 health sciences ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,medicine.diagnostic_test ,Chemistry ,Cell Differentiation ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Cell biology ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,WB, Western blot ,Kexin ,Proprotein Convertase 9 ,Corrigendum ,Research Article ,DEGs, differentially expressed genes ,Mice, Transgenic ,QD415-436 ,Ussing chambers ,endoH, endoglycosidase H ,TICE, trans-intestinal cholesterol excretion ,03 medical and health sciences ,Western blot ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Animals ,Humans ,Secretion ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,PCSK9 LivKO, mouse model lacking PCSK9 specifically in hepatocytes ,intestine ,030304 developmental biology ,PPL, postprandial lipemia ,systemic blood ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Cell Biology ,Proprotein convertase ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Small intestine ,Mice, Inbred C57BL ,LDL receptor ,cholesterol metabolism ,Caco-2 Cells ,PCSK9, proprotein convertase subtilisin/kexin type 9 ,PNGase F, N-glycosidase F ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes lysosomal degradation of the LDL receptor and is a key regulator of cholesterol metabolism. After the liver, the small intestine is the second organ that highly expresses PCSK9. However, the small intestine's ability to secrete PCSK9 remains a matter of debate. While liver-specific PCSK9-deficient mice present no PCSK9 in systemic blood, human intestinal Caco-2 cells can actively secrete PCSK9. This raises the possibility for active intestinal secretion via the portal blood. Here, we aimed to determine whether enterocytes can secrete PCSK9 using in vitro, ex vivo, and in vivo approaches. We first observed that PCSK9 secretion from Caco-2 cells was biphasic and dependent on Caco-2 maturation status. Transcriptional analysis suggested that this transient reduction in PCSK9 secretion might be due to loss of SREBP2-mediated transcription of PCSK9. Consistently, PCSK9 secretion was not detected ex vivo in human or mouse intestinal biopsies mounted in Ussing chambers. Finally, direct comparison of systemic versus portal blood PCSK9 concentrations in WT or liver-specific PCSK9-deficient mice confirmed the inability of the small intestine to secrete PCSK9 into the portal compartment. Altogether, our data demonstrate that mature enterocytes do not secrete PCSK9 and reinforce the central role of the liver in the regulation of the concentration of circulating PCSK9 and consequently of cellular LDL receptors.
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- 2021
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4. Circulating Rather Than Intestinal PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Regulates Postprandial Lipemia in Mice
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Bertrand Cariou, François Moreau, Nabil G. Seidah, Annik Prat, Anna Roubtsova, Damien Garçon, Cédric Le May, Wieneke Dijk, L. Arnaud, Xavier Prieur, Audrey Ayer, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Le May, Cedric, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Université de Montréal (UdeM), and Centre hospitalier universitaire de Nantes (CHU Nantes)
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Male ,0301 basic medicine ,[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Endogeny ,030204 cardiovascular system & hematology ,0302 clinical medicine ,ComputingMilieux_MISCELLANEOUS ,Hypolipidemic Agents ,[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,Mice, Knockout ,PCSK9 Inhibitors ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,Postprandial Period ,Lipids ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,3. Good health ,Intestines ,Postprandial ,diabetes mellitus ,Kexin ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,mice ,Hyperlipidemias ,liver ,Antibodies, Monoclonal, Humanized ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,lipid ,Internal medicine ,Diabetes mellitus ,medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,Risk factor ,intestine ,business.industry ,PCSK9 ,Subtilisin ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Proprotein convertase ,medicine.disease ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,Receptors, LDL ,business - Abstract
Objective: Increased postprandial lipemia (PPL) is an independent risk factor for atherosclerotic cardiovascular diseases. PCSK9 (Proprotein convertase subtilisin kexin type 9) is an endogenous inhibitor of the LDLR (low-density lipoprotein receptor) pathway. We previously showed that PCSK9 inhibition in mice reduces PPL. However, the relative contribution of intracellular intestinal PCSK9 or liver-derived circulating PCSK9 to this effect is still unclear. Approach and Results: To address this issue, we generated the first intestine-specific Pcsk9 -deficient (i- Pcsk9 −/− ) mouse model. PPL was measured in i- Pcsk9 −/− as well as in wild-type and streptozotocin-induced diabetic mice following treatment with a PCSK9 monoclonal antibody (alirocumab). Blocking the circulating form of PCSK9 with alirocumab significantly reduced PPL, while overexpressing human PCSK9 in the liver of full Pcsk9 −/− mice had the opposite effect. Alirocumab regulated PPL in a LDLR-dependent manner as this effect was abolished in Ldlr −/− mice. In contrast, i- Pcsk9 −/− mice did not exhibit alterations in plasma lipid parameters nor in PPL. Finally, PPL was highly exacerbated by streptozotocin-induced diabetes mellitus in Pcsk9 +/+ but not in Pcsk9 −/− mice, an effect that was mimicked by the use of alirocumab in streptozotocin-treated Pcsk9 +/+ mice. Conclusions: Taken together, our data demonstrate that PPL is significantly altered by full but not intestinal PCSK9 deficiency. Treatment with a PCSK9 monoclonal antibody mimics the effect of PCSK9 deficiency on PPL suggesting that circulating PCSK9 rather than intestinal PCSK9 is a critical regulator of PPL. These data validate the clinical relevance of PCSK9 inhibitors to reduce PPL, especially in patients with type 2 diabetes mellitus.
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- 2020
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5. Roux-en-Y gastric bypass reduces plasma cholesterol in diet-induced obese mice by affecting trans-intestinal cholesterol excretion and intestinal cholesterol absorption
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Michel Krempf, Frédéric Borel, Claire Blanchard, Bertrand Cariou, C. Le May, Mikaël Croyal, Michel Neunlist, L. Toque, Audrey Aguesse, François Moreau, Xavier Prieur, L. Arnaud, Audrey Ayer, Damien Garçon, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Guillaume et René Laennec - Centre Hospitalier Universitaire de Nantes, U913, and Institut National de la Santé et de la Recherche Médicale (INSERM)
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Male ,0301 basic medicine ,medicine.medical_specialty ,Sleeve gastrectomy ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Gastric Bypass ,Mice, Obese ,Medicine (miscellaneous) ,Blood lipids ,Intestinal absorption ,Metabolic symdrome ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Weight loss ,Internal medicine ,medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,Obesity ,ComputingMilieux_MISCELLANEOUS ,2. Zero hunger ,Nutrition and Dietetics ,Cholesterol ,business.industry ,nutritional and metabolic diseases ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,medicine.disease ,Obesity, Morbid ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Cardiovascular diseases ,Intestinal Absorption ,chemistry ,Intestinal cholesterol absorption ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,business ,Fat metabolism ,Diet-induced obese ,Dyslipidemia - Abstract
International audience; OBJECTIVE: Bariatric surgery appears as the most efficient therapeutic alternative in morbidly obese patients. In addition to its efficiency to decrease body weight, it also improves metabolic complications associated to morbid obesity, including dyslipidemia. Although the cholesterol-lowering effect varies with the bariatric procedures, the underlying molecular mechanisms remain poorly defined. This study aims to assess the consequence of both restrictive (sleeve gastrectomy; SG) and malabsorptive (Roux-en-Y gastric bypass; RYGB) procedures on cholesterol metabolism in mice. SUBJECTS: Ten-week-old C57BL6/J males were fed with a high-fat diet for 8-14 weeks before sleeve or RYGB surgery. RESULTS: SG has a modest and transient effect on plasma cholesterol levels, linked to a reduction in food intake. In contrast, modified RYGB led to a sustained ≈35% reduction in plasma cholesterol concentrations with a drastic increase in fecal cholesterol output. Mechanistically, RYGB exerts a synergystic effect on cholesterol metabolism by inducing the trans-intestinal cholesterol efflux and reducing the intestinal cholesterol absorption. CONCLUSIONS: In mice, RYGB, but not sleeve, strongly favors plasma cholesterol elimination by concomitantly increasing trans-intestinal cholesterol excretion and by decreasing intestinal cholesterol absorption. Our models open new perspective for deciphering the hypocholesterolemic effects of bariatric procedures.
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- 2018
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6. The Sodium–Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Cardiomyopathy in a Diabetic Lipodystrophic Mouse Model
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Benoît Jagu, Jocelyne Magré, L. Dollet, Bertrand Cariou, Xavier Prieur, Xavier Marechal, David Montaigne, Michael Joubert, Cédric Le May, Audrey Ayer, Gilles Toumaniantz, Flavien Charpentier, Angela Tesse, Alain Manrique, Bart Staels, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)
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Blood Glucose ,Lipodystrophy ,Diabetic Cardiomyopathies ,[SDV]Life Sciences [q-bio] ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Glucose uptake ,Left ,Cardiomyopathy ,030204 cardiovascular system & hematology ,Seipin ,chemistry.chemical_compound ,Mice ,Ventricular Dysfunction, Left ,0302 clinical medicine ,Glucosides ,Diabetic cardiomyopathy ,GTP-Binding Protein gamma Subunits ,Ventricular Dysfunction ,Medicine ,Ventricular Function ,Dapagliflozin ,ComputingMilieux_MISCELLANEOUS ,Mice, Knockout ,Hypertrophic cardiomyopathy ,Heart ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,Heterotrimeric GTP-Binding Proteins ,Magnetic Resonance Imaging ,3. Good health ,Echocardiography ,Type 2 ,medicine.drug ,medicine.medical_specialty ,Knockout ,030209 endocrinology & metabolism ,03 medical and health sciences ,Sodium-Glucose Transporter 2 ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Fluorodeoxyglucose F18 ,Internal medicine ,Diabetes Mellitus ,Internal Medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,Hypoglycemic Agents ,Benzhydryl Compounds ,Sodium-Glucose Transporter 2 Inhibitors ,Pioglitazone ,Animal ,business.industry ,Insulin ,Myocardium ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Cardiomyopathy, Hypertrophic ,medicine.disease ,Disease Models, Animal ,Endocrinology ,chemistry ,Diabetes Mellitus, Type 2 ,Hypertrophic ,Hyperglycemia ,Positron-Emission Tomography ,Disease Models ,Thiazolidinediones ,Radiopharmaceuticals ,business - Abstract
International audience; Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for heart failure. T2DM is associated with altered cardiac energy metabolism, leading to ectopic lipid accumulation and glucose overload, the exact contribution of these two parameters remaining unclear. To provide new insight into the mechanism driving the development of diabetic cardiomyopathy, we studied a unique model of T2DM: lipodystrophic Bscl2(-/-) (seipin knockout [SKO]) mice. Echocardiography and cardiac magnetic resonance imaging revealed hypertrophic cardiomyopathy with left ventricular dysfunction in SKO mice, and these two abnormalities were strongly correlated with hyperglycemia. Surprisingly, neither intramyocardial lipid accumulation nor lipotoxic hallmarks were detected in SKO mice. [(18)F]Fludeoxyglucose positron emission tomography showed increased myocardial glucose uptake. Consistently, the O-GlcNAcylated protein levels were markedly increased in an SKO heart, suggesting a glucose overload. To test this hypothesis, we treated SKO mice with the hypoglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin and the insulin sensitizer pioglitazone. Both treatments reduced the O-GlcNAcylated protein levels in SKO mice, and dapagliflozin successfully prevented the development of hypertrophic cardiomyopathy. Our data demonstrate that glucotoxicity by itself can trigger cardiac dysfunction and that a glucose-lowering agent can correct it. This result will contribute to better understanding of the potential cardiovascular benefits of SGLT2 inhibitors.
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- 2017
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7. Techniques of Sleeve Gastrectomy and Modified Roux-en-Y Gastric Bypass in Mice
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Claire Blanchard, Xavier Prieur, François Moreau, Cédric Le May, Audrey Ayer, Frédéric Borel, Michel Neunlist, Bertrand Cariou, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Fonctionnement et conduite des systèmes de culture tropicaux et méditerranéens (UMR SYSTEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre International de Hautes Etudes Agronomiques Méditerranéennes - Institut Agronomique Méditerranéen de Montpellier (CIHEAM-IAMM), Centre International de Hautes Études Agronomiques Méditerranéennes (CIHEAM)-Centre International de Hautes Études Agronomiques Méditerranéennes (CIHEAM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre International de Hautes Etudes Agronomiques Méditerranéennes - Institut Agronomique Méditerranéen de Montpellier (CIHEAM-IAMM), and Centre International de Hautes Études Agronomiques Méditerranéennes (CIHEAM)-Centre International de Hautes Études Agronomiques Méditerranéennes (CIHEAM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)
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Male ,medicine.medical_specialty ,Sleeve gastrectomy ,General Chemical Engineering ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Gastric Bypass ,Bariatric Surgery ,030209 endocrinology & metabolism ,Type 2 diabetes ,General Biochemistry, Genetics and Molecular Biology ,Body Mass Index ,Mice ,03 medical and health sciences ,0302 clinical medicine ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Gastrectomy ,Weight loss ,Weight Loss ,medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,ComputingMilieux_MISCELLANEOUS ,2. Zero hunger ,General Immunology and Microbiology ,business.industry ,General Neuroscience ,Therapeutic effect ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,medicine.disease ,Roux-en-Y anastomosis ,Obesity ,Obesity, Morbid ,3. Good health ,Surgery ,Mice, Inbred C57BL ,Treatment Outcome ,030220 oncology & carcinogenesis ,Models, Animal ,Medicine ,Female ,Laparoscopy ,medicine.symptom ,business ,Body mass index ,Dyslipidemia - Abstract
International audience; Obesity is a major public health issue, with a prevalence of 4 to 28% for men and 6.2 to 36.5% for women in Europe (from 2003 to 2008). Morbid obesity is frequently associated with metabolic complications, such as type 2 diabetes, hypertension, and dyslipidemia, reducing life expectancy and quality. In the absence of any effective noninvasive treatments, bariatric surgery is a valuable therapeutic option for patients with morbid obesity (body mass index (BMI) \textgreater40 kg/m(2)), leading to long-term, sustained weight loss and improvements in metabolic complications. However, the underlying cellular and molecular mechanisms sustaining the beneficial effects of bariatric surgery are not yet fully understood. Due to the numerous genetically-modified strains available, the mouse model is the most convenient animal model to explore the molecular mechanisms behind the pleiotropic beneficial effects of bariatric surgeries. Here, we detailed the optimized healthcare methods and surgical protocols in mice for the two most widely-used bariatric surgeries: the sleeve gastrectomy and the modified Roux-en-Y gastric bypass. Deciphering the molecular mechanisms underlying the therapeutic effects of bariatric surgeries offers the promise of identifying new therapeutics targets.
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- 2017
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8. Sleeve Gastrectomy Alters Intestinal Permeability in Diet-Induced Obese Mice
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Damien Garçon, Bertrand Cariou, Julien Chevalier, Michel Neunlist, Jean-Paul Pais de Barros, Thomas Gautier, Cédric Le May, Claire Blanchard, L. Arnaud, Audrey Ayer, François Moreau, Clinique de chirurgie digestive et endocrinienne, IMAD, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Lipidomique [Dijon] (LAP), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), unité de recherche de l'institut du thorax UMR1087 UMR6291 ( ITX ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme Lipidomique [Dijon] ( LAP ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Nantes ( UN ), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM)
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0301 basic medicine ,Male ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,Mice, Obese ,Occludin ,Glucose homeostasis ,Jejunum ,Mice ,0302 clinical medicine ,Transcellular ,Intestinal Mucosa ,Sleeve gastrectomy ,ComputingMilieux_MISCELLANEOUS ,Adiposity ,Nutrition and Dietetics ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,medicine.anatomical_structure ,Adipose Tissue ,Liver ,Paracellular transport ,[ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,medicine.medical_specialty ,LPS ,030209 endocrinology & metabolism ,[SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery ,Intestinal permeability ,Diet, High-Fat ,Permeability ,03 medical and health sciences ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Gastrectomy ,Internal medicine ,medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,Obesity ,Inflammation ,business.industry ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,medicine.disease ,Surgery ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Insulin Resistance ,business ,Diet-induced obese - Abstract
IF 3.947; International audience; BACKGROUND: Increased lipopolysaccharide (LPS) translocation due to altered intestinal permeability has been suggested as a mechanism for obesity-associated insulin resistance. The goal of this study was to assess the effect of sleeve gastrectomy (SG) on intestinal barrier permeability in diet-induced obese mice.MATERIALS AND METHODS: Four weeks after surgery, the effects of SG on intestinal permeabilities were assessed ex vivo and in vivo in male C57Bl/6J mice fed a high-fat diet. Gene expression of tight junction proteins and inflammatory cytokines was measured in jejunum, colon, liver, and inguinal adipose tissue. Plasma LPS was quantified by HPLCMS/MS spectrometry.RESULTS: SG significantly reduced body weight and improved glucose homeostasis, as expected. SG decreased paracellular (p = 0.01) and transcellular permeability (p = 0.03) in the jejunum; and increased mRNA levels of the tight junction proteins Jam A (p = 0.02) and occludin (p = 0.01). In contrast in the distal colon, paracellular permeability tended to be increased (p = 0.07) while transcellular permeability was significantly induced (p = 0.03) after SG. In vivo, the paracellular permeability was significantly increased 3 weeks after SG (p = 0.02). Plasma LPS level were increased after SG (p = 0.03), as well as mRNA levels of adipose and hepatic inflammatory markers (p = 0.02).CONCLUSIONS: SG significantly modifies intestinal permeability in a differential manner between the proximal and distal intestine. These changes promote LPS translocation in plasma, induce a low-grade pro-inflammatory state in adipose tissue and liver, but do not impair the SG-induced glucose homeostasis improvement.
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- 2017
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9. FGF21 Improves the Adipocyte Dysfunction Related to Seipin Deficiency
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Audrey Ayer, Soazig Le Lay, Cédric Le May, Tamer Coskun, Xavier Prieur, Jocelyne Magré, L. Dollet, Quentin Venara, Ruth E. Gimeno, Bertrand Cariou, Clara Levrel, Andrew C. Adams, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)
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0301 basic medicine ,medicine.medical_specialty ,FGF21 ,Endocrinology, Diabetes and Metabolism ,[SDV]Life Sciences [q-bio] ,Adipocytes, White ,Blotting, Western ,White adipose tissue ,Biology ,Seipin ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,3T3-L1 Cells ,GTP-Binding Protein gamma Subunits ,Adipocyte ,Internal medicine ,Internal Medicine ,medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,Homeostasis ,Adiponectin secretion ,RNA, Messenger ,ComputingMilieux_MISCELLANEOUS ,Mice, Knockout ,Gene knockdown ,Adiponectin ,Adipose tissue loss ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,Heterotrimeric GTP-Binding Proteins ,3. Good health ,Fibroblast Growth Factors ,030104 developmental biology ,Endocrinology ,Adipose Tissue ,chemistry - Abstract
International audience; Fibroblast growth factor 21 (FGF21) was shown to improve metabolic homeostasis, at least partly by controlling white adipocyte profile and adiponectin secretion. Here, we studied its effect on adipocyte dysfunction in the context of Berardinelli-Seip congenital lipodystrophy (BSCL) linked to seipin deficiency. Bscl2(-/-) mice displayed a progressive adipose tissue loss with aging as evidenced by the altered profile of residual fat pads and the decrease in adiponectin plasma levels in 12- vs. 4-week-old animals. Aiming to prevent this impairment, we treated 6-week-old Bscl2(-/-) mice with an FGF21 analog (LY2405319) for a period of 28 days. FGF21 treatment increased adiponectin plasma levels and normalized insulin sensitivity in Bscl2(-/-) mice by improving the white adipose tissue gene expression pattern. To further decipher the molecular pathways altered by seipin deficiency in mature adipocytes, we developed a unique inducible seipin knockdown cell line (SKD). SKD showed chronic activation of the p38 MAPK pathway associated with apoptotic cell death. Interestingly, FGF21 treatment exerted an antistress effect on SKD cells, reducing p38 MAPK phosphorylation and limiting mature adipocyte loss. Our data demonstrate that FGF21 treatment improves the metabolic profile of Bscl2(-/-) lipodystrophic mice, partly by improving mature adipocyte maintenance through suppression of cellular stress via inhibition of p38 MAPK activity.
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- 2016
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10. Central Role of P2Y 6 UDP Receptor in Arteriolar Myogenic Tone
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Hannah Monyer, Brant E. Isakson, Bertrand Toutain, Jean-Marie Boeynaems, Fabrice Prunier, Marie Billaud, Laurent Loufrani, Vincent Procaccio, Bernard Robaye, Audrey Ayer, Sophie Tamareille, Linda Grimaud, Charlotte Roy, Daniel Henrion, Gilles Kauffenstein, Brenda R. Kwak, Cor de Wit, Pierre Abraham, Pascal Rousseau, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Cardiologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Euromov (EuroMov), Université de Montpellier (UM), Institut de Recherche en Génie Civil et Mécanique (GeM), Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Neurovasculaire Intégrée (BNVI), Center for Ultrafast Optical Sciences (CUOS), University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Clinical Neurobiology [Heidelberg, Germany] (Interdisciplinary Centre for Neurosciences), University of Heidelberg, Medical Faculty, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université libre de Bruxelles (ULB)-Université d'Europe, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), and Université d'Angers (UA)
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rho GTP-Binding Proteins ,0301 basic medicine ,Myocardial Infarction ,Blood Pressure ,ddc:616.07 ,Mechanotransduction, Cellular ,Muscle, Smooth, Vascular ,Vasoconstrictor Agents ,Myocyte ,Mesentery ,RhoA GTP-binding protein ,Ectonucleotidase ,Phosphorylation ,Receptor ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,Adenosine Triphosphatases ,Mice, Knockout ,ddc:616 ,Nucleotides ,Hydrolysis ,Arterioles ,Phenotype ,Myosin light chains ,Mitogen-Activated Protein Kinases ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,Myosin Light Chains ,Myosin light-chain kinase ,Genotype ,Myocytes, Smooth Muscle ,Biology ,Article ,Uridine Diphosphate ,Purinergic P2X Receptor Agonists ,03 medical and health sciences ,Smooth muscle ,Internal medicine ,Extracellular ,medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,Calcium Signaling ,Autocrine signalling ,Heart Failure ,Myocytes ,Dose-Response Relationship, Drug ,Receptors, Purinergic P2 ,Purinoceptor P2Y6 ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Vasoconstriction ,Connexin 43 ,Receptors, Purinergic P2X7 ,rhoA GTP-Binding Protein ,Uracil nucleotide - Abstract
Objective— Myogenic tone (MT) of resistance arteries ensures autoregulation of blood flow in organs and relies on the intrinsic property of smooth muscle to contract in response to stretch. Nucleotides released by mechanical strain on cells are responsible for pleiotropic vascular effects, including vasoconstriction. Here, we evaluated the contribution of extracellular nucleotides to MT. Approach and Results— We measured MT and the associated pathway in mouse mesenteric resistance arteries using arteriography for small arteries and molecular biology. Of the P2 receptors in mouse mesenteric resistance arteries, mRNA expression of P2X 1 and P2Y 6 was dominant. P2Y 6 fully sustained UDP/UTP-induced contraction (abrogated in P2ry6 −/− arteries). Preventing nucleotide hydrolysis with the ectonucleotidase inhibitor ARL67156 enhanced pressure-induced MT by 20%, whereas P2Y 6 receptor blockade blunted MT in mouse mesenteric resistance arteries and human subcutaneous arteries. Despite normal hemodynamic parameters, P2ry6 −/− mice were protected against MT elevation in myocardial infarction–induced heart failure. Although both P2Y 6 and P2Y 2 receptors contributed to calcium mobilization, P2Y 6 activation was mandatory for RhoA–GTP binding, myosin light chain, P42–P44, and c-Jun N-terminal kinase phosphorylation in arterial smooth muscle cells. In accordance with the opening of a nucleotide conduit in pressurized arteries, MT was altered by hemichannel pharmacological inhibitors and impaired in Cx43 +/− and P2rx7 −/− mesenteric resistance arteries. Conclusions— Signaling through P2 nucleotide receptors contributes to MT. This mechanism encompasses the release of nucleotides coupled to specific autocrine/paracrine activation of the uracil nucleotide P2Y 6 receptor and may contribute to impaired tissue perfusion in cardiovascular diseases.
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- 2016
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11. Impact of Sleeve Gastrectomy on Intestinal Permeability in Diet-Induced Obese Mice
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François Moreau, Bertrand Cariou, Michel Neunlist, Julien Chevalier, Cédric Le May, Claire Blanchard, Jean-Paul Pais de Barros, L. Arnaud, Audrey Ayer, Thomas Gautier, unité de recherche de l'institut du thorax UMR1087 UMR6291 ( ITX ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), and Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA )
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medicine.medical_specialty ,Sleeve gastrectomy ,Intestinal permeability ,business.industry ,medicine.medical_treatment ,medicine.disease ,Gastroenterology ,Sleeve Gastrectomy ,Surgery ,Internal medicine ,Medicine ,[ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,business ,Diet-induced obese ,Intestinal Permeability - Abstract
IF 4.942 (2013); International audience
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- 2016
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12. Resveratrol Decreases TXNIP mRNA and Protein Nuclear Expressions With an Arterial Function Improvement in Old Mice
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Tatiana Bedarida, Elizabeth Thioulouse, Valérie Nivet-Antoine, Stéphanie Baron, Daniel Henrion, Audrey Ayer, Jean-Louis Beaudeux, Charles-Henry Cottart, Carmen Marchiol, Francoise Vibert, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA)
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0301 basic medicine ,Male ,Aging ,[SDV]Life Sciences [q-bio] ,Arterial aging ,Resveratrol ,medicine.disease_cause ,chemistry.chemical_compound ,Mice ,Random Allocation ,Thioredoxins ,Stilbenes ,Thioredoxin-interacting protein ,Nuclear protein ,Aorta ,Glucose tolerance test ,medicine.diagnostic_test ,Nuclear Proteins ,Immunohistochemistry ,Echocardiography, Doppler ,3. Good health ,Phenotype ,Original Article ,medicine.symptom ,TXNIP ,medicine.medical_specialty ,Thioredoxin-Interacting Protein ,Inflammation ,Mice, Transgenic ,Carbohydrate metabolism ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Glucose intolerance ,business.industry ,Glucose Tolerance Test ,Mice, Inbred C57BL ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,chemistry ,Calcium ,Geriatrics and Gerontology ,business ,Carrier Proteins ,Oxidative stress - Abstract
International audience; Aging leads to a high prevalence of glucose intolerance and cardiovascular diseases, with oxidative stress playing a potential role. Resveratrol has shown promising effects on glucose tolerance and tends to improve endothelial function in elderly patients. Thioredoxin-interacting protein (TXNIP) was recently proposed as a potential link connecting glucose metabolism to oxidative stress. Here, we investigated the resveratrol-induced improvement of arterial aging phenotype in old mice and the expression of aortic TXNIP. Using an in vivo model of old mice with or without 3-month resveratrol treatment, we investigated the effects of resveratrol on age-related impairments from a cardiovascular Doppler analysis, to a molecular level, by studying inflammation and oxidative stress factors. We found a dual effect of resveratrol, with a decrease of age-related glucose intolerance and oxidative stress imbalance leading to reduced matrix remodeling that forestalls arterial aging phenotype in terms of intima-media thickness and arterial distensibility. These results provide the first evidence that aortic TXNIP mRNA and protein nuclear expressions are increased in the arterial aging and decreased by resveratrol treatment. In conclusion, we demonstrated that resveratrol helped to restore several aging impaired processes in old mice, with a decrease of aortic TXNIP mRNA and protein nuclear expressions
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- 2016
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13. Effet des chirurgies bariatriques sur le métabolisme du cholestérol chez la souris
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Claire Blanchard, François Moreau, V. Ferchaud, Michel Krempf, Audrey Ayer, F. Borel, C. Le May, Bertrand Cariou, Physiologie des Adaptations Nutritionnelles (PhAN), and Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)
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0303 health sciences ,03 medical and health sciences ,0302 clinical medicine ,Nutrition and Dietetics ,030309 nutrition & dietetics ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,030209 endocrinology & metabolism ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition ,ComputingMilieux_MISCELLANEOUS ,3. Good health - Abstract
Introduction et but de l’etude Les chirurgies bariatriques representent une alternative therapeutique de choix chez les patients obeses morbides. Outre la perte de poids, ces chirurgies induisent une reduction significative des complications metaboliques associees, notamment les dyslipidemies. Cette etude vise a determiner chez la souris les consequences de 2 methodes de chirurgies bariatriques, i.e. la gastrectomie de type sleeve (sleeve) et de type bypass roux en Y (RYGB), sur les voies regulant le metabolisme du cholesterol. Materiel et methodes Des souris mâles C57BL6/J âgees de 10 semaines ont recu un regime hyperlipidique pendant 8 (sleeve) a 12 semaines (RYGB) avant les chirurgies. Les souris ont ete randomisees sur le poids et la cholesterolemie puis ont beneficie d’une chirurgie de type sham (laparotomie), sleeve ou d’un RYGB. Nous avons mesure les consequences des chirurgies sur le poids et le metabolisme glucidique et lipidique. L’analyse de l’excretion biliaire, transintestinale et fecale de cholesterol a ete determinee in vivo par spectrometrie de masse (GC-MS). Resultats et analyse statistique La duree operatoire moyenne mesuree a ete de 49,33 ± 5,1 minutes pour le groupe sleeve et de 93,63 ± 1,7 minutes pour le groupe RYGB. Quatorze jours apres chirurgie (j+14), la chirurgie de type sleeve et RYGB ont induit une reduction significative du poids corporel (respectivement −15,63 % et −25 % par rapport a la valeur mesuree avant la chirurgie [p Conclusion En conclusion, nous avons mis en place, avec succes, deux modeles de chirurgie bariatrique chez la souris. L’effet hypocholesterolemiant observe apres chirurgie de type sleeve est modeste et semble etre principalement lie a des modifications de la prise alimentaire. En revanche, la chirurgie de type RYGB induit une hypocholesterolemie marquee et une forte induction de l’excretion fecale de cholesterol.
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- 2015
14. Resveratrol Directly Binds to Mitochondrial Complex I and Increases Oxidative Stress in Brain Mitochondria of Aged Mice
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Stéphanie Baron, Valérie Nivet-Antoine, Emilie Vessières, Audrey Ayer, Stéphanie Chupin, Géraldine Leman, Valérie Desquiret-Dumas, Daniel Henrion, Naïg Gueguen, Guy Lenaers, Vincent Procaccio, Pascal Reynier, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Male ,Models, Molecular ,endocrine system diseases ,[SDV]Life Sciences [q-bio] ,lcsh:Medicine ,Mitochondrion ,Pharmacology ,Resveratrol ,medicine.disease_cause ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Stilbenes ,lcsh:Science ,skin and connective tissue diseases ,Cells, Cultured ,0303 health sciences ,Multidisciplinary ,Age Factors ,Brain ,food and beverages ,Mitochondria ,3. Good health ,Molecular Docking Simulation ,Mitochondrial respiratory chain ,Electron Transport Complex I ,medicine.symptom ,hormones, hormone substitutes, and hormone antagonists ,Research Article ,Cellular respiration ,Cell Respiration ,Biology ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,medicine ,Animals ,Humans ,030304 developmental biology ,Binding Sites ,Dose-Response Relationship, Drug ,organic chemicals ,lcsh:R ,NAD ,Oxidative Stress ,Mechanism of action ,chemistry ,lcsh:Q ,NAD+ kinase ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
International audience; Resveratrol is often described as a promising therapeutic molecule for numerous diseases, especially in metabolic and neurodegenerative disorders. While the mechanism of action is still debated, an increasing literature reports that resveratrol regulates the mitochondrial respiratory chain function. In a recent study we have identified mitochondrial complex I as a direct target of this molecule. Nevertheless, the mechanisms and consequences of such an interaction still require further investigation. In this study, we identified in silico by docking study a binding site for resveratrol at the nucleotide pocket of complex I. In vitro, using solubilized complex I, we demonstrated a competition between NAD+ and resveratrol. At low doses (
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- 2015
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15. Dual effects of resveratrol on arterial damage induced by insulin resistance in aged mice
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Audrey Ayer, Valérie Nivet-Antoine, Gilles Renault, Charles-Henry Cottart, Vincent Procaccio, Jean-Louis Beaudeux, Tatiana Bedarida, Emilie Vessières, Stéphanie Baron, Francoise Vibert, Daniel Henrion, Baptiste Hommeril, Jean-Louis Paul, Bruno Saubaméa, Prévention et traitement de la perte protéique musculaire en situation de résistance à l'anabolisme (PRETRRAM (URP_4466)), Université de Paris (UP), 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), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Lipides membranaires et régulation fonctionnelle du coeur et des vaisseaux, Université Paris-Sud - Paris 11 (UP11), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Université Paris Cité (UPCité), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Univ Angers, Okina
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Blood Glucose ,Leptin ,Male ,Aging ,Antioxidant ,Chemokine CXCL1 ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,030204 cardiovascular system & hematology ,Resveratrol ,medicine.disease_cause ,Antioxidants ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Superoxides ,Stilbenes ,Medicine ,Resistin ,Chemokine CCL5 ,Aorta ,2. Zero hunger ,0303 health sciences ,Superoxide ,Renutrition ,3. Good health ,Vasodilation ,[SDV] Life Sciences [q-bio] ,Dietary Proteins ,medicine.symptom ,medicine.medical_specialty ,Nutritional Status ,Mice, Inbred Strains ,Inflammation ,Vascular disease ,03 medical and health sciences ,Insulin resistance ,Phenols ,Internal medicine ,Ribonucleotide Reductases ,Vascular Capacitance ,Animals ,Vascular Diseases ,Serum Albumin ,030304 developmental biology ,Tumor Necrosis Factor-alpha ,business.industry ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,Endocrinology ,chemistry ,Geriatrics and Gerontology ,business ,Homeostasis ,Oxidative stress - Abstract
International audience; Aging leads to increased insulin resistance and arterial dysfunction, with oxidative stress playing an important role. This study explored the metabolic and arterial effects of a chronic treatment with resveratrol, an antioxidant polyphenol compound that has been shown to restore insulin sensitivity and decrease oxidative stress, in old mice with or without a high-protein diet renutrition care. High-protein diet tended to increase insulin resistance and atheromatous risk. Resveratrol improved insulin sensitivity in old mice fed standard diet by decreasing homeostasis model of assessment-insulin resistance and resistin levels. However, resveratrol did not improve insulin resistance status in old mice receiving the high-protein diet. In contrast, resveratrol exhibited deleterious effects by increasing inflammation state and superoxide production and diminishing aortic distensibility. In conclusion, we demonstrate that resveratrol has beneficial or deleterious effects on insulin sensitivity and arterial function, depending on nutritional status in our models.
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- 2014
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16. Resveratrol induces a mitochondrial complex I-dependent increase in NADH oxidation responsible for sirtuin activation in liver cells
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Audrey Ayer, Dominique Bonneau, Valérie Nivet-Antoine, Stéphanie Chupin, Valérie Desquiret-Dumas, Arnaud Chevrollier, Marc Ferré, Daniel Henrion, Vincent Procaccio, Géraldine Leman, Naïg Gueguen, Pascal Reynier, Stéphanie Baron, Emilie Vessières, 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), Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Prévention et traitement de la perte protéique musculaire en situation de résistance à l'anabolisme (PRETRRAM (URP_4466)), Université de Paris (UP), Université Paris Cité (UPCité), and Univ Angers, Okina
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endocrine system diseases ,SIRT3 ,[SDV]Life Sciences [q-bio] ,Mitochondria, Liver ,Bioenergetics ,Mitochondrion ,Biochemistry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Sirtuin 3 ,Stilbenes ,Complex I ,Animals ,Humans ,Sirtuins ,skin and connective tissue diseases ,Molecular Biology ,Beta oxidation ,030304 developmental biology ,0303 health sciences ,Electron Transport Complex I ,Mitochondrial Metabolism ,biology ,organic chemicals ,NADH dehydrogenase ,food and beverages ,NADH Dehydrogenase ,Hep G2 Cells ,Cell Biology ,respiratory system ,NAD ,3. Good health ,Cell biology ,Mitochondria ,[SDV] Life Sciences [q-bio] ,Enzyme Activation ,Mice, Inbred C57BL ,Citric acid cycle ,Resveratrol ,Sirtuin ,Hepatocytes ,biology.protein ,NAD+ kinase ,Oxidation-Reduction ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - Abstract
International audience; Resveratrol (RSV) has been shown to be involved in the regulation of energetic metabolism, generating increasing interest in therapeutic use. SIRT1 has been described as the main target of RSV. However, recent reports have challenged the hypothesis of its direct activation by RSV, and the signaling pathways remain elusive. Here, the effects of RSV on mitochondrial metabolism are detailed both in vivo and in vitro using murine and cellular models and isolated enzymes. We demonstrate that low RSV doses (1-5 muM) directly stimulate NADH dehydrogenases and, more specifically, mitochondrial complex I activity (EC50 approximately 1 muM). In HepG2 cells, this complex I activation increases the mitochondrial NAD(+)/NADH ratio. This higher NAD(+) level initiates a SIRT3-dependent increase in the mitochondrial substrate supply pathways (i.e. the tricarboxylic acid cycle and fatty acid oxidation). This effect is also seen in liver mitochondria of RSV-fed animals (50 mg/kg/day). We conclude that the increase in NADH oxidation by complex I is a crucial event for SIRT3 activation by RSV. Our results open up new perspectives in the understanding of the RSV signaling pathway and highlight the critical importance of RSV doses used for future clinical trials.
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- 2013
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17. Key role of estrogens and endothelial estrogen receptor alpha in blood flow-mediated remodeling of resistance arteries
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Laurent Loufrani, Bertrand Toutain, Audrey Ayer, K. Tarhouni, Christophe Baufreton, Daniel Henrion, Frédéric Pinaud, Jean-François Arnal, Vincent Procaccio, Anne-Laure Guihot, B. Henrion, Françoise Lenfant, Linda Grimaud, Mohamed Lamine Freidja, Université d'Angers (UA), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Cardioprotection, Remodelage et Thrombose (CRT), PRES Université Nantes Angers Le Mans (UNAM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CHU Toulouse [Toulouse], Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Univ Angers, Okina
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medicine.medical_specialty ,Time Factors ,Nitric Oxide Synthase Type III ,Ovariectomy ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Caveolin 1 ,Estrogen receptor ,Blood Pressure ,030204 cardiovascular system & hematology ,Biology ,Nitric Oxide ,Revascularization ,medicine.disease_cause ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Estrogen Receptor beta ,Splanchnic Circulation ,Phosphorylation ,Rats, Wistar ,Ovariectomized female ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Pregnancy ,Estradiol ,Macrophage infiltration ,Estrogen Replacement Therapy ,Estrogen Receptor alpha ,Endothelial Cells ,Blood flow ,medicine.disease ,Mesenteric Arteries ,Rats ,[SDV] Life Sciences [q-bio] ,Mice, Inbred C57BL ,Vasodilation ,Endocrinology ,Regional Blood Flow ,Female ,Vascular Resistance ,Cardiology and Cardiovascular Medicine ,Oxidative stress - Abstract
Objective— Flow- (shear stress–)mediated outward remodeling of resistance arteries is involved in collateral growth during postischemic revascularization. As this remodeling is especially important during pregnancy, we hypothesized that estrogens may be involved. A surgical model eliciting a local increase in blood flow in 1 mesenteric resistance artery was used in 3-month-old ovariectomized female rats either treated with 17-β-estradiol (E2) or left untreated. Methods and Results— After 14 days, arterial diameter was greater in high-flow arteries than in normal-flow vessels. An ovariectomy suppressed high-flow remodeling, while E2 restored it. High-flow remodeling was absent in mice lacking the estrogen receptor α but not estrogen receptor β. The kinetics of inflammatory marker expression, macrophage infiltration, oxidative stress, and metaloproteinases expression were not altered by the absence of E2 after 2 and 4 days, that is, during remodeling. Nevertheless, E2 was required for the increase in endothelial nitric oxide synthase expression and activation at day 4 when diameter expansion occurs. Finally, the impact of E2 on the endothelium appeared crucial for high-flow remodeling, as this E2 action was abrogated in mice lacking endothelial NOS, as well as in Tie2-Cre(+) ERα f/f mice. Conclusion— We demonstrate the essential role of E2 and endothelial estrogen receptor α in flow-mediated remodeling of resistance arteries in vivo.
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- 2013
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