Abstract 15776: Protective Role of Copper Transporter ATP7A-Extracellular SOD Pathway in Endothelial Dysfunction in Murine Model of Type I Diabetes Mellitus
Endothelial dysfunction, in part caused by oxidative inactivation of nitric oxide (NO•) by excess level of O2•-, contributes to various cardiovascular diseases including diabetes (DM). Extracellular superoxide dismutase (ecSOD), a secretory Cu enzyme, is the major antioxidant enzyme against O2•- in the vascular extracellular space. However, role of endogenous ecSOD in diabetic vessels remains unclear. Here we show that specific activity of ecSOD, but not cytosolic Cu/Zn SOD, is decreased by 35% in aortas of streptozotocin (STZ)-induced DM mice. This is associated with significantly increased L-NAME-sensitive O2•- production (P<0.05) and increased 3-nitrotyrosine (3-NT) level, a marker of ONOO-, implicating eNOS uncoupling. Functionally, acetylcholine-induced NO-mediated vasorelaxation is impaired (P<0.05) in mesenteric arteries of DM, which is rescued by SOD mimetic tempol or adenovirus mediated gene transfer of ecSOD. Importantly, supplementation of catalytic cofactor copper (Cu) partially rescues ecSOD activity in isolated DM aortas, suggesting that decreased ecSOD activity in diabetic vessels is due to deficiency of Cu-bound ecSOD. Mechanistically, we found that expression of Cu transporter ATP7A which transfers Cu to ecSOD in DM aorta is dramatically decreased (60%). Transgenic mice overexpressing ATP7A rescue DM-induced impaired endothelial function and ecSOD activity. Furthermore, ecSOD deficient DM mice or ATP7A mutant DM mice show augmented (P<0.001) endothelial dysfunction, increased O2•- production and 3-NT level vs. DM mice. These findings suggest that significant reduction of ATP7A expression in DM contributes to decrease in ecSOD activity, thereby inducing endothelial dysfunction. These effects may be due to hypoinsulinemia in STZ-DM mice, since insulin treatment of vascular smooth muscle cells increases ATP7A expression (1.7-fold) and ecSOD activity, but hyperglycemia has no effect. In summary, Cu transporter ATP7A-ecSOD pathway plays a protective role in DM-induced endothelial dysfunction by preventing vascular O2•- overproduction and ONOO- formation. Thus, ATP7A, a key regulator of ecSOD activity, is a potential therapeutic target for oxidant stress-dependent cardiovascular and metabolic diseases.
- © 2012 by American Heart Association, Inc.