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.

Exercise-induced circulating extracellular vesicles protect against cardiac ischemia–reperfusion injury

“…It was recently reported that exercise is able to enhance cardiomyocyte renewal [34, 42], which is necessary to mediate the protective effect of exercise against I/R injury [5]. Moreover, exercise is efficient to reduce cardiac I/R injury both at baseline and in obese diabetic condition, though different molecular mechanisms might be involved [9, 29]. It was previously reported that acute exercise (cycling) could trigger rapid release of EVs into the circulation that might be responsible for mediating its systemic beneficial effects also including the heart [18].…”

Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart

“…This susceptibility to ischemia-reperfusion injury has been reproduced in animal models [59, 60]. It remains unclear if mitochondrial dysfunction is the cause or the consequence of metabolic impairment, but it has clearly been associated with metabolic dysfunction in various metabolic tissues including pancreas, liver, skeletal muscle or adipose tissue [61, 62].…”

Coronary angiogenic effect of long-term administration of Nigella sativa

“…[34]. In a recent study, exercise training stimulated eNOS and reduced iNOS in control rats and normalized iNOS and showed no effect on eNOS in high fat fructose diet rats after ischemia reperfusion injury [36]. In the current experiment, exercise training demonstrated a significant reduction in the expression of NOS-2 in the cross-section of the left ventricles of the exercise-trained rats.…”