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2004 CARDIOVASCULAR AND KIDNEY INVESTIGATORS MEETING

Hemodynamic and biochemical adaptations to vascular smooth muscle overexpression of p22^phox in mice

¹Division of Cardiology, Emory University, Atlanta, Georgia; and ²Institut für Pharmakologie und Klinische Pharmakologie, Duesseldorf, and ³Rudolf-Bucheim Institut für Pharmacology, Justus-Liebig-Universtat, Giessen, Germany

Submitted 25 June 2004 ; accepted in final form 25 August 2004

Protein levels and polymorphisms of p22^phox have been suggested to modulate vascular NAD(P)H oxidase activity and vascular production of reactive oxygen species (ROS). We sought to determine whether increasing p22^phox expression would alter vascular ROS production and hemodynamics by targeting p22^phox expression to smooth muscle in transgenic (Tg) mice. Aortas of Tg^p22smc mice had increased p22^phox and Nox1 protein levels and produced more superoxide and H₂O₂. Surprisingly, endothelium-dependent relaxation and blood pressure in Tg^p22smc mice were normal. Aortas of Tg^p22smc mice produced twofold more nitric oxide (NO) at baseline and sevenfold more NO in response to calcium ionophore as detected by electron spin resonance. Western blot analysis revealed a twofold increase in endothelial NO synthase (eNOS) protein expression in Tg^p22smc mice. Both eNOS expression and NO production were normalized by infusion of the glutathione peroxidase mimetic ebselen or by crossing Tg^p22smc 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 Tg^p22smc mice expressed twofold more ecSOD, and chronic treatment with the NOS inhibitor N^G-nitro-L-arginine methyl ester 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.

transgenic animals; oxidant stress; endothelium; nitric oxide

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