Background: Exercise has beneficial effects on endothelial dysfunction in pathological conditions such as diabetes mellitus (DM), but its underlying mechanisms are poorly understood. Evidence suggest that not only nitric oxide (NO) but also hydrogen peroxide (H2O2) functions as a mediator of endothelium dependent vasodilation (EDR) and angiogenesis. Extracellular superoxide dismutase (ecSOD) is a major secreted copper (Cu) containing SOD that catalyzes the dismutation of O2•- to H2O2 in the vessel wall and its full activity requires Cu transporter ATP7A. We reported that ATP7A-ecSOD pathway is impaired in DM. Role of endogenous ecSOD in exercise-induced improvement of endothelial function in DM in which O2•- production is increased is unknown.
Hypothesis: Exercise-induced ecSOD activity via regulating ATP7A expression drives switching from NO to H2O2 mediated EDR and angiogenesis in DM.
Results: Volunteer exercise (2 weeks) improved impaired acetylcholine-induced EDR in mesenteric resistance artery and angiogenesis (CD31+ capillary) in skeletal muscle of high fat diet induced Type 2 DM mice. Enhancement of EDR by exercise in DM was associated with increase in ecSOD activity (66%) and extracellular H2O2 production (7.2 fold) in arteries and skeletal muscle. This exercise-induced effect in DM was abolished by exogenous catalase, but not eNOS inhibitor L-NAME, while that in control mice was prevented by L-NAME, suggesting that exercise selectively enhances H2O2 mediated EDR in DM. ecSOD deficient mice with DM and exercise, showed that ecSOD-derived H2O2 is involved in exercise-induced enhanced EDR and angiogenesis in DM. Of note, ecSOD activity (51% decrease) and ATP7A protein expression (69% decrease) were reduced in DM vessels, which were rescued by exercise (4.3 ± 0.2 fold) or ATP7A overexpression. Furthermore, exercise promoted COMMD1 downregulation (45.2%), a key regulator of ATP7A proteosomal degradation, thereby improved the ATP7A-ecSOD pathway.
Conclusion: Exercise in DM improves ATP7A-ecSOD pathway in part via COMMD1 downregulation, which promotes switching from NO to H2O2 mediated EDR and angiogenesis. Thus, restoring ATP7A-ecSOD pathway provides potentially therapeutic strategy for treating diabetic vascular complications.