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1 Division of Cardiology, Emory University, Atlanta, GA, USA
* To whom correspondence should be addressed. E-mail: dharr02{at}emory.edu.
Protein levels and polymorphisms of p22phox have been suggested to modulate vascular NADPH oxidase activity and vascular production of reactive oxygen species (ROS). We sought to determine if increasing p22phox expression would alter vascular ROS production and hemodynamics by targeting p22phox expression to smooth muscle in transgenic mice. Aortas of Tgp22smc mice had increased p22phox and Nox1 protein levels and produced more superoxide and hydrogen peroxide (H2O2). Surprisingly, endothelium-dependent relaxation and blood pressure in Tgp22smc mice were normal. Aortas of Tgp22smc mice produced two-fold more NO at baseline and 7-fold more NO in response to calcium ionophore, as detected by electron spin resonance. Western analysis revealed a 2-fold increase in eNOS protein expression in Tgp22smc mice. Both eNOS expression and NO production were normalized by infusion of the glutathione peroxidase mimetic ebselen, or by crossing Tgp22smc mice with mice overexpressing catalase. We have previously found that NO stimulates extracellular superoxide dismutase (ecSOD) expression in vascular smooth muscle. In keeping with this, aortic segments from Tgp22smc mice expressed two-fold more ecSOD, and chronic treatment with the NOS inhibitor L-NAME normalized this,suggesting that NO regulates ecSOD protein expression in vivo. These data indicate that chronic oxidative stress caused by excessive H2O2 production evokes a compensatory response involving increased eNOS expression and NO production. NO in turn increases ecSOD protein expression and counterbalances increased ROS production leading to the maintenance of normal vascular function and hemodynamics.
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