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(Stroke. 2003;34:1293.)
© 2003 American Heart Association, Inc.

Original Contributions

In Vivo Gene Transfer of Inducible Nitric Oxide Synthase to Carotid Arteries From Hypercholesterolemic Rabbits

Michela Zanetti, MD, PhD; Livius V. d’Uscio, PhD; Imre Kovesdi, PhD; Zvonimir S. Katusic, MD, PhD Timothy O’Brien, MD, PhD

From the Departments of Endocrinology (M.Z., T.O’B.) and Anesthesiology (L.V.d’U., Z.S.K.), Mayo Clinic and Foundation, Rochester, Minn, and Gene Vec Inc, Gaithersburg, Md (I.K.).

Correspondence to Timothy O’Brien, MD, PhD, Department of Medicine, Clinical Science Institute, University College Hospital, Galway, Ireland. E-mail timothy.obrien{at}nuigalway.ie

Background and Purpose— Hypercholesterolemia is associated with endothelial dysfunction. Inducible nitric oxide synthase (iNOS) is upregulated in atherosclerotic vessels. However, its role in the regulation of vascular function is not completely understood. We examined the effect of adenovirus-mediated gene transfer of iNOS to the hypercholesterolemic rabbit carotid artery in vivo.

Methods— Rabbits were fed a high-cholesterol or chow diet for 10 weeks. Two doses (1x10⁸ and 1x10⁹ plaque-forming units [pfu]/mL) of adenoviral vectors encoding iNOS (AdiNOS) or ß-galactosidase (Adßgal) were luminally delivered to the carotid arteries from chow- and cholesterol-fed animals. Vascular reactivity and superoxide levels were assessed in Adßgal- and AdiNOS-transduced vessels from chow- and cholesterol-fed animals after 3 days.

Results— Endothelium-dependent vasorelaxation was impaired in the carotid artery from cholesterol-fed animals. In AdiNOS-transduced arteries, transgene expression was demonstrated by positive immunostaining in the endothelium. Transduction with low-dose (1x10⁸ pfu/mL) AdiNOS did not affect vascular reactivity in arteries from chow- and cholesterol-fed animals. In contrast, high-dose (1x10⁹ pfu/mL) AdiNOS significantly reduced endothelium-dependent relaxation in vessels from cholesterol- but not chow-fed rabbits. After both low- and high-dose iNOS gene transfer, levels of O₂·^- were significantly (P<0.05) elevated in carotid arteries from cholesterol-fed animals. Incubation with an O₂·^- scavenger did not reverse vascular dysfunction in these arteries.

Conclusions— Adenoviral-mediated overexpression of iNOS results in increased production of O₂·^- in carotid arteries from cholesterol- but not chow-fed animals. High-dose AdiNOS gene transfer is associated with reduced endothelium-dependent and -independent relaxation in vessels from cholesterol-fed animals.

Key Words: carotid arteries • gene transfer • nitric oxide synthase • reactive oxygen species • superoxides • rabbits

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