Hemodynamic and biochemical adaptations to vascular smooth muscle overexpression of p22phox in mice.
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 H(2)O(2). 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 H(2)O(2) 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.
Laude
Karine
K
Division of Cardiology, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Cai
Hua
H
Fink
Bruno
B
Hoch
Nyssa
N
Weber
David S
DS
McCann
Louise
L
Kojda
Georg
G
Fukai
Tohru
T
Schmidt
Harald H H W
HH
Dikalov
Sergey
S
Ramasamy
Santhini
S
Gamez
Graciela
G
Griendling
Kathy K
KK
Harrison
David G
DG
D000222:Adaptation, Physiological; D000818:Animals; D006439:Hemodynamics; D006861:Hydrogen Peroxide / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000098:blood supply* / Q000378:metabolism / Q000502:physiology*; D009252:NADPH Dehydrogenase / Q000378:metabolism*; D019255:NADPH Oxidases; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010750:Phosphoproteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism
D026901:Membrane Transport Proteins; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase