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Basic Res Cardiol. 2016 Jul;111(4):40. doi: 10.1007/s00395-016-0559-0. Epub 2016 May 10.

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

Author information

1
LAPEC, EA4278, Avignon University, 74 rue Louis Pasteur, 84000, Avignon, France.
2
Laboratoire HP2, Université Grenoble Alpes, Grenoble, 38042, France.
3
INSERM, U1042, Grenoble, 38042, France.
4
CNRS TIMC-IMAG UMR5525, Equipe PRETA, Joseph Fourier University, Grenoble, France.
5
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-University Montpellier-ENSCM and Avignon University, Avignon, France.
6
Mitochondries, Stress Oxydant et Protection Musculaire, EA 3072 Strasbourg University, Strasbourg, France.
7
PHYMEDEXP, INSERM U1046, CNRS UMR9214, Montpellier University, Montpellier, France.
8
LAPEC, EA4278, Avignon University, 74 rue Louis Pasteur, 84000, Avignon, France. Cyril.reboul@univ-avignon.fr.

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.

KEYWORDS:

Cardioprotection; Exercise; Insulin resistance; Myocardial infarction; Nitric oxide; Type 2 diabetes; β3-Adrenergic receptor

PMID:
27164904
DOI:
10.1007/s00395-016-0559-0
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