(Circulation. 2000;101:1027.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Gene Transfer of Endothelial Nitric Oxide Synthase Improves Relaxation of Carotid Arteries From Diabetic Rabbits
From the Departments of Internal Medicine and Pharmacology and the Cardiovascular Center, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City.
Correspondence to Donald D. Heistad, MD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242. E-mail donald-heistad{at}uiowa.edu
Background—Diabetes mellitus is associated with impairment of NO-mediated vascular relaxation. The purpose of this study was to determine whether adenovirus-mediated gene transfer of endothelial NO synthase (eNOS) or Cu/Zn superoxide dismutase (SOD1) improves responsiveness to acetylcholine in alloxan-induced diabetic rabbits.
Methods and Results—After 8 weeks, plasma glucose was greater in
diabetic rabbits (418±35 mg/dL) (mean±SEM) than in normal rabbits
(105±4 mg/dL). Carotid arteries were removed and cut into ring
segments. Arteries were incubated for 2 hours with adenoviral vectors
driven by a CMV promoter expressing ß-galactosidase (ß-gal), eNOS,
SOD1, or vehicle. After incubation with virus, arteries were incubated
for an additional 24 hours to allow transgene expression. Vascular
reactivity was examined by recording isometric tension. After
precontraction with phenylephrine, responses to the
endothelium-independent vasodilator sodium
nitroprusside were similar in diabetic and normal arteries.
Endothelium-dependent relaxation to acetylcholine
(3x10-6 mol/L) was significantly less in arteries from
diabetic animals (68±5%) than in normal vessels (90±3%). Adenoviral
transfection of arteries with eNOS improved relaxation in response to
acetylcholine in diabetic (EC50
eNOS=0.64±0.12x10-7 mol/L versus vehicle
=1.70±0.43x10-7 mol/L) but not normal arteries.
Vasorelaxation in response to acetylcholine was inhibited by
N
-nitro-L-arginine (100
µmol/L) in all groups. Responses to acetylcholine were unchanged
after gene transfection of SOD1 or ß-gal in arteries from diabetic or
normal rabbits.
Conclusions—Adenovirus-mediated gene transfer of eNOS, but not SOD, improves impaired NO-mediated relaxation in vessels from diabetic rabbits.
Key Words: diabetes mellitus • acetylcholine • viruses • gene therapy • nitric oxide
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