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

  • Adrien Kleindienst
  • Sylvain Battault
  • Elise Belaidi
  • Stephane Tanguy
  • Marie Rosselin
  • Doria Boulghobra
  • Gregory Meyer
  • Sandrine Gayrard
  • Guillaume Walther
  • Bernard Geny
  • Gregory Durand
  • Olivier Cazorla
  • Cyril Reboul
Original Contribution

DOI: 10.1007/s00395-016-0559-0

Cite this article as:
Kleindienst, A., Battault, S., Belaidi, E. et al. Basic Res Cardiol (2016) 111: 40. doi:10.1007/s00395-016-0559-0

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

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

Supplementary material

395_2016_559_MOESM1_ESM.docx (2.3 mb)
Supplementary material 1 (DOCX 2335 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Adrien Kleindienst
    • 1
  • Sylvain Battault
    • 1
  • Elise Belaidi
    • 2
    • 3
  • Stephane Tanguy
    • 4
  • Marie Rosselin
    • 5
  • Doria Boulghobra
    • 1
  • Gregory Meyer
    • 1
  • Sandrine Gayrard
    • 1
  • Guillaume Walther
    • 1
  • Bernard Geny
    • 6
  • Gregory Durand
    • 5
  • Olivier Cazorla
    • 7
  • Cyril Reboul
    • 1
  1. 1.LAPEC, EA4278, Avignon UniversityAvignonFrance
  2. 2.Laboratoire HP2Université Grenoble AlpesGrenobleFrance
  3. 3.INSERM, U1042GrenobleFrance
  4. 4.CNRS TIMC-IMAG UMR5525, Equipe PRETA, Joseph Fourier UniversityGrenobleFrance
  5. 5.Institut des Biomolécules Max MousseronUMR 5247 CNRS-University Montpellier-ENSCM and Avignon UniversityAvignonFrance
  6. 6.Mitochondries, Stress Oxydant et Protection MusculaireEA 3072 Strasbourg UniversityStrasbourgFrance
  7. 7.PHYMEDEXP, INSERM U1046, CNRS UMR9214, Montpellier UniversityMontpellierFrance