Role of extracellular superoxide dismutase in hypertension.
We previously found that angiotensin II-induced hypertension increases vascular extracellular superoxide dismutase (ecSOD), and proposed that this is a compensatory mechanism that blunts the hypertensive response and preserves endothelium-dependent vasodilatation. To test this hypothesis, we studied ecSOD-deficient mice. ecSOD(-/-) and C57Blk/6 mice had similar blood pressure at baseline; however, the hypertension caused by angiotensin II was greater in ecSOD(-/-) compared with wild-type mice (168 versus 147 mm Hg, respectively; P<0.01). In keeping with this, angiotensin II increased superoxide and reduced endothelium-dependent vasodilatation in small mesenteric arterioles to a greater extent in ecSOD(-/-) than in wild-type mice. In contrast to these findings in resistance vessels, angiotensin II paradoxically improved endothelium-dependent vasodilatation, reduced intracellular and extracellular superoxide, and increased NO production in aortas of ecSOD(-/-) mice. Whereas aortic expression of endothelial NO synthase, Cu/ZnSOD, and MnSOD were not altered in ecSOD(-/-) mice, the activity of Cu/ZnSOD was increased by 80% after angiotensin II infusion. This was associated with a concomitant increase in expression of the copper chaperone for Cu/ZnSOD in the aorta but not in the mesenteric arteries. Moreover, the angiotensin II-induced increase in aortic reduced nicotinamide-adenine dinucleotide phosphate oxidase activity was diminished in ecSOD(-/-) mice as compared with controls. Thus, during angiotensin II infusion, ecSOD reduces hypertension, minimizes vascular superoxide production, and preserves endothelial function in resistance arterioles. We also identified novel compensatory mechanisms involving upregulation of copper chaperone for Cu/ZnSOD, increased Cu/ZnSOD activity, and decreased reduced nicotinamide-adenine dinucleotide phosphate oxidase activity in larger vessels. These compensatory mechanisms preserve large vessel function when ecSOD is absent in hypertension.
Gongora
Maria Carolina
MC
Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Qin
Zhenyu
Z
Laude
Karine
K
Kim
Ha Won
HW
McCann
Louise
L
Folz
J Rodney
JR
Dikalov
Sergey
S
Fukai
Tohru
T
Harrison
David G
DG
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D007527:Isoenzymes / Q000378:metabolism; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation; D014666:Vasomotor System
D007527:Isoenzymes; D014662:Vasoconstrictor Agents; D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases