This Article Full Text Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ooboshi, H. Articles by Heistad, D. D. Search for Related Content PubMed PubMed Citation Articles by Ooboshi, H. Articles by Heistad, D. D.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1786-1792.)
© 1997 American Heart Association, Inc.

Articles

Augmented Adenovirus-Mediated Gene Transfer to Atherosclerotic Vessels

Hiroaki Ooboshi; C. David Rios; Yi Chu; Stuart D. Christenson; Frank M. Faraci; Beverly L. Davidson; ; Donald D. Heistad

From the Departments of Internal Medicine and Pharmacology, Cardiovascular Center and Center on Aging, University of Iowa College of Medicine, and the Veterans Administration Medical Center, Iowa City, Iowa 52242.

Correspondence to Donald D. Heistad, MD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242.

Abstract Vascular endothelium is an important target for gene transfer in atherosclerosis. In this study, we examined gene transfer to normal and atherosclerotic blood vessels from two species, using an organ culture method. Using normal aorta, we determined optimal dose, duration of exposure to adenovirus, and duration of incubation of vessels in tissue culture. Aortas from normal and atherosclerotic monkeys were cut into rings and incubated for 2 hours with a recombinant adenovirus, carrying the reporter gene for ß-galactosidase driven by a cytomegalovirus (CMV) promoter. After 20 hours of incubation, transgene expression was assessed with a morphometric method after histochemical staining and a chemiluminescent assay of enzyme activity. Expression of ß-galactosidase after histochemical staining, expressed as percentage of total cells, was similar in adventitial cells of normal monkeys (21±4%, mean±SE%) and atherosclerotic monkeys (25±12%). Transgene expression in endothelium was higher in atherosclerotic than in normal vessel (53±3% versus 27±7%, P<.05). Chemiluminescent assay indicated greater ß-galactosidase activity (2.5±0.6 mU/mg of protein) in the intima and media of atherosclerotic than normal vessels (0.6±0.2 mU/mg of protein, P<.05). Aortas from normal (n=6) and atherosclerotic (n=5) rabbits also were examined. Transgene expression (after histochemical staining) in endothelium was much greater in atherosclerotic than normal rabbits (39±3% versus 9±2%, P<.05) and expression in adventitial cells was similar (normal 23±2%, atherosclerotic 24±4%). Chemiluminescent assay indicated greater ß-galactosidase activity (1.2±0.4 mU/mg of protein) in the intima and media of atherosclerotic than normal vessels (0.2±0.1 mU/mg protein, P<.05). These findings suggest that an adenoviral vector with a CMV promoter provides similar transgene expression in adventitia of both normal and atherosclerotic vessels. Gene transfer to the endothelium was much more effective in atherosclerotic than in normal vessels. Thus it may be possible to achieve greater transgene expression in atherosclerotic than in normal arteries.

Key Words: atherosclerosis • adenovirus • gene transfer • endothelium • ß-galactosidase

This article has been cited by other articles:

				J. W. Elrod, M. R. Duranski, W. Langston, J. J.M. Greer, L. Tao, T. R. Dugas, C. G. Kevil, H. C. Champion, and D. J. Lefer eNOS Gene Therapy Exacerbates Hepatic Ischemia-Reperfusion Injury in Diabetes: A Role for eNOS Uncoupling Circ. Res., July 7, 2006; 99(1): 78 - 85. [Abstract] [Full Text] [PDF]

				G. CONDORELLI, J. K. AYCOCK, G. FRATI, and C. NAPOLI Mutated p21/WAF/CIP transgene overexpression reduces smooth muscle cell proliferation, macrophage deposition, oxidation-sensitive mechanisms, and restenosis in hypercholesterolemic apolipoprotein E knockout mice FASEB J, October 1, 2001; 15(12): 2162 - 2170. [Abstract] [Full Text] [PDF]

				H. Ooboshi, S. Ibayashi, J. Takada, H. Yao, T. Kitazono, and M. Fujishima Adenovirus-Mediated Gene Transfer to Ischemic Brain : Ischemic Flow Threshold for Transgene Expression Stroke, April 1, 2001; 32(4): 1043 - 1047. [Abstract] [Full Text] [PDF]

				Y. Chu, D. D. Heistad, M. I. Cybulsky, and B. L. Davidson Vascular Cell Adhesion Molecule-1 Augments Adenovirus-Mediated Gene Transfer Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 238 - 242. [Abstract] [Full Text] [PDF]

				M.Y. Alexander, M.J. Brosnan, C. A. Hamilton, J. P. Fennell, E. C. Beattie, E. Jardine, D. D. Heistad, and A. F. Dominiczak Gene transfer of endothelial nitric oxide synthase but not Cu/Zn superoxide dismutase restores nitric oxide availability in the SHRSP Cardiovasc Res, August 18, 2000; 47(3): 609 - 617. [Abstract] [Full Text] [PDF]

				D. D. Lund, F. M. Faraci, F. J. Miller Jr, and D. D. Heistad Gene Transfer of Endothelial Nitric Oxide Synthase Improves Relaxation of Carotid Arteries From Diabetic Rabbits Circulation, March 7, 2000; 101(9): 1027 - 1033. [Abstract] [Full Text] [PDF]

				K. Toyoda, F. M. Faraci, A. F. Russo, B. L. Davidson, and D. D. Heistad Gene transfer of calcitonin gene-related peptide to cerebral arteries Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H586 - H594. [Abstract] [Full Text] [PDF]

				H. Nakane, F. J. Miller Jr, F. M. Faraci, K. Toyoda, and D. D. Heistad Gene Transfer of Endothelial Nitric Oxide Synthase Reduces Angiotensin II-Induced Endothelial Dysfunction Hypertension, February 1, 2000; 35(2): 595 - 601. [Abstract] [Full Text] [PDF]

				A. I. M. Campbell, M. A. Kuliszewski, and D. J. Stewart Cell-Based Gene Transfer to the Pulmonary Vasculature . Endothelial Nitric Oxide Synthase Overexpression Inhibits Monocrotaline-Induced Pulmonary Hypertension Am. J. Respir. Cell Mol. Biol., November 1, 1999; 21(5): 567 - 575. [Abstract] [Full Text]

				D. D. Gutterman Adventitia-dependent influences on vascular function Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1265 - H1272. [Full Text] [PDF]

				K. D. Lake-Bruse, F. M. Faraci, E. G. Shesely, N. Maeda, C. D. Sigmund, and D. D. Heistad Gene transfer of endothelial nitric oxide synthase (eNOS) in eNOS-deficient mice Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H770 - H776. [Abstract] [Full Text] [PDF]

				D. D. Lund, F. M. Faraci, H. Ooboshi, B. L. Davidson, D. D. Heistad, and C. D. Kontos Adenovirus-Mediated Gene Transfer Is Augmented in Basilar and Carotid Arteries of Heritable Hyperlipidemic Rabbits • Editorial Comment Stroke, January 1, 1999; 30(1): 120 - 125. [Abstract] [Full Text] [PDF]

				H. Ooboshi, K. Toyoda, F. M. Faraci, M. G. Lang, and D. D. Heistad Improvement of Relaxation in an Atherosclerotic Artery by Gene Transfer of Endothelial Nitric Oxide Synthase Arterioscler Thromb Vasc Biol, November 1, 1998; 18(11): 1752 - 1758. [Abstract] [Full Text] [PDF]

				K. Toyoda, H. Ooboshi, Y. Chu, A. Fasbender, B. L. Davidson, M. J. Welsh, D. D. Heistad, and G. K. Steinberg Cationic Polymer and Lipids Enhance Adenovirus-Mediated Gene Transfer to Rabbit Carotid Artery • Editorial Comment Stroke, October 1, 1998; 29(10): 2181 - 2188. [Abstract] [Full Text] [PDF]

				M. D. Rekhter, R. D. Simari, C. W. Work, G. J. Nabel, E. G. Nabel, and D. Gordon Gene Transfer Into Normal and Atherosclerotic Human Blood Vessels Circ. Res., June 29, 1998; 82(12): 1243 - 1252. [Abstract] [Full Text] [PDF]

				F. J. Miller, D. D. Gutterman, C. D. Rios, D. D. Heistad, and B. L. Davidson Superoxide Production in Vascular Smooth Muscle Contributes to Oxidative Stress and Impaired Relaxation in Atherosclerosis Circ. Res., June 29, 1998; 82(12): 1298 - 1305. [Abstract] [Full Text] [PDF]

				R. Morishita Lessons From Human Arteries : How to Design a Gene Therapy Strategy for Treatment of Cardiovascular Disease Circ. Res., June 29, 1998; 82(12): 1349 - 1351. [Full Text] [PDF]