Exercise training, consisting of cycling on a leg ergometer at VO2peak for elevated plasma apelin levels in middle-aged and older adults. Thus, aerobic exercise training may be an effective way to elevate plasma apelin levels and reduce arterial stiffness in both healthy and at-risk subjects. This study demonstrated elevated NOx plasma levels and decreased arterial stiffness after aerobic exercise training in middle-aged and older adults. In a previous study, middle-aged and older women who performed aerobic exercise training exhibited elevated plasma NOx levels and reduced blood pressure. Aging leads to increased risk of arterial stiffness; this risk is associated with a enuation of NO generation. However, an animal study revealed that eNOS protein and mRNA expression levels in the aortas of older rats were ameliorated by regular exercise training. In this study, plasma apelin levels were increased by regular exercise training. Moreover, plasma NOx levels were associated with plasma apelin levels. In another study, administration of apelin induced NO production and promoted eNOS mRNA expression in the isolated rat aortic tissue, but did not alter iNOS expression. Furthermore, eNOS phosphorylation of isolated endothelial cells in mice was accelerated by the treatment with apelin. Apelin-induced eNOS activation is mediated by the activation of phosphatidylinositol-3 kinase /Akt signaling pathway in endothelial cells, resulting in increased NO production. Apelin treatment increased eNOS phosphorylation in the aorta, but in isolated endothelial cells from APJ-deficient mice, increased eNOS phosphorylation in response to apelin was inhibited. Additionally, in the left internal mammary artery of patients with stable coronary artery disease, exercise training raised eNOS expression and phosphorylation in association with change of Akt phosphorylation. Apelin is involved in regulation of eNOS gene expression, and contributes to NO production in the endothelial cells of aorta. Thus, the elevation in circulating apelin levels induced by regular exercise training may participate in the acceleration of NO generation in middle-aged and older adults. We demonstrated that exercise training in middle-aged and older adults elevated apelin plasma concentration. However, the source of the exercise training�Kaempferide Cinduced Procyanidin-B2 increase in apelin plasma levels is unclear. Zhang et al. demonstrated that aortic, myocardial, and plasma apelin concentrations were all increased by exercise training in hypertensive rats, concomitant with elevation of the apelin mRNA expression level in aorta and heart. Therefore, aorta and heart tissues are one possible source of the exercise training�Cinduced apelin production. However, apelin has also been detected in several tissues, including white adipose tissue and kidney. Further studies should investigate the source of exercise training�Cinduced increase in apelin plasma levels. After the aerobic exercise training intervention, plasma apelin levels increased, and concomitantly, plasma NOx levels were increased. The mechanism underlying these effects is unclear. Hypoxic inducible factor 1�Ca, bone morphogenetic protein receptor 2, insulin, tumor necrosis factor�Ca, and mechanical stress are all potential inducers of apelin production.