title: Exercise does not activate the β3 adrenergic receptor-eNOS pathway, but reduces inducible NOS expression to protect the heart of obese diabetic mice.
abstract: Obesity and diabetes are associated with higher cardiac vulnerability to ischemia-reperfusion (IR). The cardioprotective effect of regular exercise has been attributed to β3-adrenergic receptor (β3AR) stimulation and increased endothelial nitric oxide synthase (eNOS) activation. Here, we evaluated the role of the β3AR-eNOS pathway and NOS isoforms in exercise-induced cardioprotection of C57Bl6 mice fed with high fat and sucrose diet (HFS) for 12 weeks and subjected or not to exercise training during the last 4 weeks (HFS-Ex). HFS animals were more sensitive to in vivo and ex vivo IR injuries than control (normal diet) and HFS-Ex mice. Cardioprotection in HFS-Ex mice was not associated with increased myocardial eNOS activation and NO metabolites storage, possibly due to the β3AR-eNOS pathway functional loss in their heart. Indeed, a selective β3AR agonist (BRL37344) increased eNOS activation and had a protective effect against IR in control, but not in HFS hearts. Moreover, iNOS expression, nitro-oxidative stress (protein s-nitrosylation and nitrotyrosination) and ROS production during early reperfusion were increased in HFS, but not in control mice. Exercise normalized iNOS level and reduced protein s-nitrosylation, nitrotyrosination and ROS production in HFS-Ex hearts during early reperfusion. The iNOS inhibitor 1400 W reduced in vivo infarct size in HFS mice to control levels, supporting the potential role of iNOS normalization in the cardioprotective effects of exercise training in HFS-Ex mice. Although the β3AR-eNOS pathway is defective in the heart of HFS mice, regular exercise can protect their heart against IR by reducing iNOS expression and nitro-oxidative stress.
authors.affiliation: LAPEC, EA4278, Avignon University, 74 rue Louis Pasteur, 84000, Avignon, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Kleindienst
authors.affiliation: LAPEC, EA4278, Avignon University, 74 rue Louis Pasteur, 84000, Avignon, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Battault
authors.affiliation: Laboratoire HP2, Université Grenoble Alpes, Grenoble, 38042, France.|INSERM, U1042, Grenoble, 38042, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Belaidi
authors.affiliation: CNRS TIMC-IMAG UMR5525, Equipe PRETA, Joseph Fourier University, Grenoble, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Tanguy
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-University Montpellier-ENSCM and Avignon University, Avignon, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Rosselin
authors.affiliation: LAPEC, EA4278, Avignon University, 74 rue Louis Pasteur, 84000, Avignon, France.
authors.forename: Doria
authors.initials: D
authors.lastname: Boulghobra
authors.affiliation: LAPEC, EA4278, Avignon University, 74 rue Louis Pasteur, 84000, Avignon, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Meyer
authors.affiliation: LAPEC, EA4278, Avignon University, 74 rue Louis Pasteur, 84000, Avignon, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Gayrard
authors.affiliation: LAPEC, EA4278, Avignon University, 74 rue Louis Pasteur, 84000, Avignon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Walther
authors.affiliation: Mitochondries, Stress Oxydant et Protection Musculaire, EA 3072 Strasbourg University, Strasbourg, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Geny
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-University Montpellier-ENSCM and Avignon University, Avignon, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Durand
authors.affiliation: PHYMEDEXP, INSERM U1046, CNRS UMR9214, Montpellier University, Montpellier, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cazorla
authors.affiliation: LAPEC, EA4278, Avignon University, 74 rue Louis Pasteur, 84000, Avignon, France. Cyril.reboul@univ-avignon.fr.
authors.forename: Cyril
authors.initials: C
authors.lastname: Reboul
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000150:complications*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism
chemical_list: D022702:Receptors, Adrenergic, beta-3; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III
keywords: Cardioprotection; Exercise; Insulin resistance; Myocardial infarction; Nitric oxide; Type 2 diabetes; β3-Adrenergic receptor