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Exercise does not activate the β3 adrenergic receptor–eNOS pathway, but reduces inducible NOS expression to protect the heart of obese diabetic mice

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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.

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    Authors and Affiliations

    1. LAPEC, EA4278, Avignon University, 74 rue Louis Pasteur, 84000, Avignon, France

      Adrien Kleindienst, Sylvain Battault, Doria Boulghobra, Gregory Meyer, Sandrine Gayrard, Guillaume Walther & Cyril Reboul

    2. Laboratoire HP2, Université Grenoble Alpes, Grenoble, 38042, France

      Elise Belaidi

    3. INSERM, U1042, Grenoble, 38042, France

      Elise Belaidi

    4. CNRS TIMC-IMAG UMR5525, Equipe PRETA, Joseph Fourier University, Grenoble, France

      Stephane Tanguy

    5. Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-University Montpellier-ENSCM and Avignon University, Avignon, France

      Marie Rosselin & Gregory Durand

    6. Mitochondries, Stress Oxydant et Protection Musculaire, EA 3072 Strasbourg University, Strasbourg, France

      Bernard Geny

    7. PHYMEDEXP, INSERM U1046, CNRS UMR9214, Montpellier University, Montpellier, France

      Olivier Cazorla

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    This work was supported by the “Société Francophone du Diabète”, the “région Provence Alpes Côtes d’Azur”, the “Structure Fédérative de Recherche” TERSYS. SB was granted by the” Groupe de reflexion sur la Recherche Cardiovasculaire (GRRC)” for its experimental work conducted in Grenoble.

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    A. Kleindienst and S. Battault contributed equally to this work.

    O. Cazorla, C. Reboul are senoir co-authors.

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    Kleindienst, A., Battault, S., Belaidi, E. et al. Exercise does not activate the β3 adrenergic receptor–eNOS pathway, but reduces inducible NOS expression to protect the heart of obese diabetic mice. Basic Res Cardiol 111, 40 (2016). https://doi.org/10.1007/s00395-016-0559-0

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