Circulation Research. 2002;91:938-944
Published online before print October 24, 2002, doi: 10.1161/01.RES.0000043280.65241.04
Published online before print October 24, 2002, doi: 10.1161/01.RES.0000043280.65241.04
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Increased Superoxide and Vascular Dysfunction in CuZnSOD-Deficient Mice
From the Departments of Internal Medicine, Physiology, and Pharmacology, Cardiovascular Center, The University of Iowa College of Medicine, Iowa City, Iowa.
Correspondence to Frank M. Faraci, PhD, Department of Internal Medicine, E315-GH, University of Iowa College of Medicine, Iowa City, Iowa 52242-1081. E-mail frank-faraci{at}uiowa.edu
Increased superoxide is thought to play a major role in vascular dysfunction in a variety of disease states. Superoxide dismutase (SOD) limits increases in superoxide; however, the functional significance of selected isoforms of SOD within the vessel wall are unknown. We tested the hypothesis that selective loss of CuZnSOD results in increased superoxide and altered vascular responsiveness in CuZnSOD-deficient (CuZnSOD-/-) mice compared with wild-type (CuZnSOD+/+) littermates. Total SOD activity was reduced (P<0.05) by approximately 60% and CuZnSOD protein was absent in aorta from CuZnSOD-/- as compared with wild-type mice. Vascular superoxide levels, measured using lucigenin (5 µmol/L)-enhanced chemiluminescence and hydroethidine (2 µmol/L)-based confocal microscopy, were increased (approximately 2-fold; P<0.05) in CuZnSOD-/- mice as compared with wild-type mice. Relaxation of the carotid artery in response to acetylcholine and authentic nitric oxide was impaired (P<0.05) in CuZnSOD-/- mice. For example, maximal relaxation to acetylcholine (100 µmol/L) was 50±6% and 69±5% in CuZnSOD-/- and wild-type mice, respectively. Contractile responses of the carotid artery were enhanced (P<0.05) in CuZnSOD-/- mice in response to phenylephrine and serotonin, but not to potassium chloride or U46619. In vivo, dilatation of cerebral arterioles (baseline diameter=31±1 µm) to acetylcholine was reduced by approximately 50% in CuZnSOD-/- mice as compared with wild-type mice (P<0.05). These findings provide the first direct insight into the functional importance of CuZnSOD in blood vessels and indicate that this specific isoform of SOD limits increases in superoxide under basal conditions. CuZnSOD-deficiency results in altered responsiveness in both large arteries and microvessels.
Key Words: carotid artery • cerebral arterioles • genetically altered mice • nitric oxide • superoxide dismutase 1
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