Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Endothelial dysfunction associated with hypercholesterolemia is an early event in atherosclerosis characterized by redox imbalance associated with high superoxide production and reduced nitric oxide (NO) and hydrogen peroxide (H2O2) production. Aerobic exercise training (AET) has been demonstrated to ameliorate atherosclerotic lesions and oxidative stress in advanced atherosclerosis. However, whether AET protects against the early mechanisms of endothelial dysfunction in familial hypercholesterolemia remains unclear. This study investigated the effects of AET on endothelial dysfunction and vascular redox status in the aortas of LDL receptor knockout mice (LDLr-/-), a genetic model of familial hypercholesterolemia. Methods: Twelve-week-old C57BL/6J (WT) and LDLr-/- mice were divided into sedentary and exercised (AET on a treadmill 1 h/5 x per week) groups for 4 weeks. Changes in lipid profiles, endothelial function, and aortic NO, H2O2 and superoxide production were examined. Results: Total cholesterol and triglycerides were increased in sedentary and exercised LDLr-/- mice. Endothelium-dependent relaxation induced by acetylcholine was impaired in aortas of sedentary LDLr-/- mice but not in the exercised group. Inhibition of NO synthase (NOS) activity or H2O2 decomposition by catalase abolished the differences in the acetylcholine response between the animals. No changes were noted in the relaxation response induced by NO donor sodium nitroprusside or H2O2. Neuronal NOS expression and endothelial NOS phosphorylation (Ser1177), as well as NO and H2O2 production, were reduced in aortas of sedentary LDLr-/- mice and restored by AET. Incubation with apocynin increased acetylcholine-induced relaxation in sedentary, but not exercised LDLr-/- mice, suggesting a minor participation of NADPH oxidase in the endothelium-dependent relaxation after AET. Consistent with these findings, Nox2 expression and superoxide production were reduced in the aortas of exercised compared to sedentary LDLr-/- mice. Furthermore, the aortas of sedentary LDLr-/- mice showed reduced expression of superoxide dismutase (SOD) isoforms and minor participation of Cu/Zn-dependent SODs in acetylcholine-induced, endothelium-dependent relaxation, abnormalities that were partially attenuated in exercised LDLr-/- mice. Conclusion: The data gathered by this study suggest AET as a potential non-pharmacological therapy in the prevention of very early endothelial dysfunction and redox imbalance in familial hypercholesterolemia via increases in NO bioavailability and H2O2 production.14Sao Paulo Research Foundation-FAPESP [10/50323-2]University of Campinas fund (FAEPX-PAPDIC Program) [25810]Coordination for the Improvement of Higher Education Personnel-CAPESBrazilian National Council for Scientific and Technological Development-CNPqFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)