Regular Physical Activity Improves Endothelial Function in Patients With Coronary Artery Disease by Increasing Phosphorylation of Endothelial Nitric Oxide Synthase

Abstract

Background-In stable coronary artery disease (CAD), exercise training has well-documented positive effects on arterial endothelial function. NO derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. The aim of the present study was to investigate the effects of exercise training on the endothelial function in relation to the expression of eNOS and Akt-dependent eNOS phosphorylation in the left internal mammary artery (LIMA) of patients with stable CAD. Methods and Results-In 17 training patients (T) and 18 control patients (C), endothelium-dependent vasodilation and average peak flow velocity (APV) in response to acetylcholine were measured invasively at study beginning and after 4 weeks in the LIMA. In LIMA tissue sampled during bypass surgery, eNOS expression and content of pospho-eNOSSer 1177 , Akt, and phospho-Akt were determined by Western blot and quantitative reverse transcriptase-polymerase chain reaction. After exercise training, LIMA APV in response to acetylcholine was increased by 56Ϯ8% (from ϩ48Ϯ8% at beginning to ϩ104Ϯ11% after 4 weeks, PϽ0.001). Patients in T had a 2-fold higher eNOS protein expression (T 1.0Ϯ0.7 versus C 0.5Ϯ0.3 arbitrary units, PϽ0.05) and 4-fold higher eNOS Ser 1177 -phosphorylation levels in LIMA-endothelium (1.2Ϯ0.9 versus 0.3Ϯ0.2 arbitrary units, PϽ0.01). A linear correlation was confirmed between Akt phosphorylation and phospho-eNOS levels (Rϭ0.80, PϽ0.05) and between phospho-eNOS and ⌬ APV (Rϭ0.59, PϽ0.05). Conclusions-Exercise training in stable CAD leads to an improved agonist-mediated endothelium-dependent vasodilatory capacity. The change in acetylcholine-induced vasodilatation was closely related to a shear stress-induced/Aktdependent phosphorylation

Physical Activity in the Prevention and Treatment of Coronary Artery Disease

“…An increase in shear stress (eg, during physical activity) has been proved to enhance eNOS mRNA and protein expression and promote phosphorylation of the serine 1177 residue of the enzyme, thereby boosting vascular NO production 31, 32, 33, 34. However, animal studies suggest that after a few months of exercise training, eNOS expression levels reduce to the preexercise state 35.…”

“…However, in humans, molecular adaptations of the coronary circulation in CAD are poorly understood because of difficulties in tissue harvesting before and after exercise training. Some details have been provided by a study from Hambrecht et al that assessed the molecular adaptation of the left internal mammary artery (LIMA) in response to exercise training in patients with severe CAD undergoing elective coronary artery bypass grafting 32. Again, these patients were randomized to 4 weeks of in‐hospital rowing machine and bicycle ergometer training or a physically inactive control group.…”

“…The fact that chest wall muscles were not directly trained in this study suggests that exercise training exerts circulation‐wide effects rather than only local adaptations in the blood vessels supplying trained muscles. Hambrecht's milestone studies on human endothelial function combining exercise training intervention, in vivo measurements, and molecular analysis stimulated a vast amount of work on the mechanism of improved endothelial function 32, 36, 57. The impact of exercise training on the multistep activation of eNOS on the one hand and reduced ROS production on the other hand was recently reviewed by Adams et al 81…”

Effect of Endothelin 1 Genotype on Blood Pressure Is Dependent on Physical Activity or Fitness Levels

“…14,15,29,30 The majority of the research in this area has focused on the activation of endothelial NO synthase gene expression and, by extension, increased NO production. In addition to vasodilatory substances, such as NO, the net peripheral resistance and, consequently, BP are also influenced by compounds promoting vasoconstriction, the most potent being the EDN1.…”

“…9 -12 Increased shear stress because of enhanced blood flow has been proposed as a major mechanism for the blood pressure-lowering effect of exercise training. [13][14][15] Although high shear stress has been shown to inhibit EDN1 expression in endothelial cells, 6 there are few data available on the interactions among the EDN1 locus DNA sequence variation, exercise training, and cardiorespiratory fitness on blood pressure phenotypes. The purpose of the present study was to investigate these interactions in 2 large cohorts: endurance training-induced changes in blood pressure were targeted in the HEalth, RIsk factors, exercise Training And GEnetics (HERITAGE) Family Study and the risk of hypertension was focused on in the Genetics, Fitness, Obesity and Risk of Hypertension (HYPGENE) Study.…”