Circulation Research. 2003;92:461-468
Published online before print January 23, 2003, doi: 10.1161/01.RES.0000057755.02845.F9
Published online before print January 23, 2003, doi: 10.1161/01.RES.0000057755.02845.F9
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© 2003 American Heart Association, Inc.
Integrative Physiology |
Gene Transfer of Extracellular Superoxide Dismutase Reduces Arterial Pressure in Spontaneously Hypertensive Rats
Role of Heparin-Binding Domain
From the Cardiovascular Center and Departments of Internal Medicine (Y.C., S.I., D.D.L., R.M.W., G.F.D., Y.W., F.M.F., D.D.H.), Pharmacology (F.M.F., D.D.H.), and Physiology (G.F.D.), University of Iowa Roy J. and Lucille A. Carver College of Medicine, and VA Medical Center (D.D.L., R.M.W., G.F.D., D.D.H.), Iowa City, Iowa.
Correspondence to Donald D. Heistad, MD, Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242. E-mail donald-heistad{at}uiowa.edu
Oxidative stress may contribute to hypertension. The goals of this study were to determine whether extracellular superoxide dismutase (ECSOD) reduces arterial pressure in spontaneously hypertensive rats (SHR) and whether its heparin-binding domain (HBD), which is responsible for cellular binding, is necessary for the function of ECSOD. Three days after intravenous injection of an adenoviral vector expressing human ECSOD (AdECSOD), mean arterial pressure (MAP) decreased from 165±4 mm Hg (mean±SE, n=7) to 124±3 mm Hg (n=7) in adult anesthetized SHR (P<0.01) but was not altered in normotensive Wistar-Kyoto rats. Cardiac output was not changed in SHR 3 days after AdECSOD. Gene transfer of ECSOD with deletion of the HBD (AdECSOD
HBD) had no effect on SHR MAP, even though plasma SOD activity was greater after AdECSODHBD than after AdECSOD. Immunohistochemistry revealed intense staining for ECSOD in blood vessels and kidneys after AdECSOD but not after AdECSODHBD. Impaired relaxation of the carotid artery to acetylcholine in SHR was significantly improved after AdECSOD. Cumulative sodium balance in SHR was reduced by AdECSOD compared with AdECSODHBD. Gene transfer of ECSOD also reduced MAP in conscious SHR, although the effect was not as profound as in anesthetized SHR. In summary, gene transfer of ECSOD, with a strict requirement for its HBD, reduces systemic vascular resistance and arterial pressure in a genetic model of hypertension. This reduction in arterial pressure may be mediated by vasomotor and/or renal mechanisms.
Key Words: hypertension • gene therapy • oxidative stress • superoxide • spontaneously hypertensive rats
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