Long-term combined beneficial effects of physical training and metabolic treatment on atherosclerosis in hypercholesterolemic mice

Abstract

CorrectionsPHARMACOLOGY. For the article ''Beneficial effects of antioxidants and L-arginine on oxidation-sensitive gene expression and endothelial NO synthase activity at sites of disturbed shear stress,'' by Filomena de Nigris, Lilach O. Lerman, Sharon Williams Ignarro, Giacomo Sica, Amir Lerman, Wulf Palinski, Louis J. Ignarro, and Claudio Napoli, which appeared in issue 3, February 4, 2003, of Proc. Natl. Acad. Sci. USA (100, 1420-1425 first published January 13, 2003; 10.1073͞pnas.0237367100), the authors should have noted that Louis J. Ignarro developed and markets Niteworks, a dietary supplement of L-arginine, L-citrulline, vitamin E, and vitamin C. Dr. Ignarro is also a member of the Scientific Advisory Board of Herbalife, the distributor of Niteworks. The pathogenic mechanisms by which physical exercise influences atherosclerotic lesion formation remain poorly understood. Because vigorous physical training increases oxidative stress, this study tested the hypothesis that graduated and moderate physical exercise together with metabolic intervention (L-arginine and antioxidants) may contribute to increased vascular protection. Exercise training in mice was induced by graduated swimming. In hypercholesterolemic male mice on an atherogenic high-cholesterol diet, graduated and moderate exercise lowered plasma cholesterol and decreased atherosclerotic lesions compared with sedentary control mice. Antioxidants (1.0% vitamin E added to the chow and 0.05% vitamin C added to the drinking water) and L-arginine (6% in drinking water) supplementation to exercising hypercholesterolemic mice further and synergistically reduced atherosclerosis compared with untreated exercised mice. Arterial oxidation-specific epitopes and systemic oxidative stress were reduced by metabolic intervention. Graduated chronic exercise elicited an increase in production of nitric oxide through increased endothelial nitric oxide synthase expression and ameliorated scavenger activities. Thus, metabolic intervention with L-arginine and antioxidants together with graduated and moderate exercise training reduce atherosclerotic lesion formation.catalase ͉ nitric oxide synthase ͉ vitamin E ͉ oxidative stress ͉ low-density lipoprotein P hysical exercise is a deterrent of cardiovascular disease and atherogenesis in animal models (1-5). Exercise can also positively influence classical risk factors that are associated with coronary heart disease such as diabetes, hypertension, obesity, dyslipidemias, and endothelial dysfunction (6-8). The higher respiration rate during severe physical exercise leads to the generation of more free radicals than the endogenous antioxidant systems can scavenge (9), whereas moderate intensity aerobic exercise enhances endothelium dependent vasodilation in humans (10), and attenuates exercise-induced peroxidation (11) and cardiovascular mortality (12) in the elderly. Moreover, there is an inverse association between intensity of physical activity and the risk of coronary heart disease events (13). A metaanalysis of 51 con...

Physical training and metabolic supplementation reduce spontaneous atherosclerotic plaque rupture and prolong survival in hypercholesterolemic mice

“…In a recent study, we also provided clear evidence for the beneficial effects of graduated PE training (swimming) and metabolic treatment (MT) (antioxidants and L-arginine) on atherosclerotic lesion formation in hypercholesterolemic mice (6). These protective mechanisms could include increased antioxidant defenses and nitric oxide (NO) bioactivity, reduced basal production of oxidants (reduced oxidative stress), and reduction of radical leak during oxidative phosphorylation (6)(7)(8)(9)(10). Basically, early oxidation-sensitive mechanisms are associated with early stages of human atherogenesis (10)(11)(12), and these observations suggest that novel strategies could be developed in the primary prevention of atherosclerotic-related diseases.…”

“…In a recent study, we also provided clear evidence for the beneficial effects of graduated PE training (swimming) and metabolic treatment (MT) (antioxidants and L-arginine) on atherosclerotic lesion formation in hypercholesterolemic mice (6). These protective mechanisms could include increased antioxidant defenses and nitric oxide (NO) bioactivity, reduced basal production of oxidants (reduced oxidative stress), and reduction of radical leak during oxidative phosphorylation (6)(7)(8)(9)(10).…”

Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia

“…The fresh brain slices were immersed for 30 min in a 2% solution of TTC (57). The cross-sectional area of infarction in each brain slice was examined with a dissection microscope and measured by using imaging analysis software (9,25,26). For measurements in the cortex, eight fields of view from the cortical ischemic penumbra (cortical IBZ) were digitized.…”

“…Sections were counterstained with hematoxylin. Quantification of BrdU-immunoreactive cells was performed on paraffin-embedded tissue sections and counted digitally (9,25,26,59). To identify expression of cell type-specific markers in BrdU ϩ cells, double immunofluorescence was performed (9,59).…”

“…To date, virus-mediated overexpression of TIMPs has not been used as a means to confer neuroprotection in vivo. Furthermore, neuroprotection could be improved by metabolic treatment, a concept supported by a great body of evidence indicating beneficial roles of treatment with antioxidants and L-arginine, the natural precursor of NO, during vascular dysfunction (9,(25)(26)(27)(28). Antioxidants mitigate oxidative and neuronal damage after ischemic stroke (29)(30)(31).…”