期刊
CIRCULATION RESEARCH
卷 93, 期 7, 页码 622-629出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000092140.81594.A8
关键词
superoxide dismutase; oxidative stress; angiotensin; endothelium; hypertension
The bioavailability of nitric oxide (NO) within the vascular wall is limited by superoxide anions (O-2(.-)). The relevance of extracellular superoxide dismutase (ecSOD) for the detoxification of vascular O-2(.-) is unknown. We determined the involvement of ecSOD in the control of blood pressure and endothelium-dependent responses in angiotensin II-induced hypertension and renovascular hypertension induced by the two-kidney, one-clip model in wild-type mice and mice lacking the ecSOD gene. Blood pressure was identical in sham-operated ecSOD(+/+) and ecSOD(-/-) mice. After 6 days of angiotensin II - treatment and 2 and 4 weeks after renal artery clipping, blood pressure was significantly higher in ecSOD(-/-) than ecSOD(+/+) mice. Recombinant ecSOD selectively decreased blood pressure in hypertensive ecSOD(-/-) mice, whereas ecSOD had no effect in normotensive and hypertensive ecSOD(+/+) mice. Compared with sham-operated ecSOD(+/+) mice, sham-operated ecSOD(-/-) mice exhibited attenuated acetylcholine-induced relaxations. These responses were further depressed in vessels from clipped animals. Vascular O-2(.-), as measured by lucigenin chemiluminescence, was higher in ecSOD(-/-) compared with ecSOD(+/+) mice and was increased by clipping. The antioxidant tiron normalized relaxations in vessels from sham-operated and clipped ecSOD(-/-), as well as from clipped ecSOD(+/+) mice. In contrast, in vivo application of ecSOD selectively enhanced endothelium-dependent relaxation in vessels from ecSOD(-/-) mice. These data reveal that endogenous ecSOD is a major antagonistic principle to vascular O-2(.-), controlling blood pressure and vascular function in angiotensin II - dependent models of hypertension. ecSOD is expressed in such an abundance that even in situations of high oxidative stress no relative lack of enzyme activity occurs.
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