Critical involvement of hydrogen peroxide in exercise-induced up-regulation of endothelial NO synthase

Objective: Recent studies from our groups have indicated that endothelial nitric oxide synthase (eNOS) expression is increased in cell culture by both shear stress and by hydrogen peroxide (H₂O₂). In vivo, exercise training, known to increase both endothelial shear stress and oxidative stress, also increases eNOS expression. It is unclear if H₂O₂ contributes to an increase in eNOS expression in response to exercise training.

Methods: To address this question, we generated mice overexpressing human catalase (hCat) driven by the murine Tie-2 promoter to specifically target this transgene to the endothelium (cat⁺⁺).

Results: Vessels of cat⁺⁺ expressed significantly higher levels of catalase mRNA and catalase protein and activity but normal levels of eNOS. Exercise alone had no effect on catalase expression in C57BL/6. Wild-type littermates of cat⁺⁺ showed an increase in eNOS expression with 3 weeks of exercise (2.53 ± 0.42-fold) comparable to C57BL/6 (2.93 ± 0.45-fold). In striking contrast, 3 weeks of exercise had no effect on aortic (1.33 ± 0.32-fold) and myocardial (1.1 ± 0.2-fold) eNOS expression in catalase transgenic mice.

Conclusions: These data suggest that endogenous H₂O₂ plays a key role in the endothelial adaptation to exercise training by stimulating an up-regulation of eNOS.