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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1796.)
© 2005 American Heart Association, Inc.

Vascular Biology

Vascular Endothelium Has a Local Anti-Adenovirus Vector System and Glucocorticoid Optimizes Its Gene Transduction

Takahisa Murata; Masatoshi Hori; Sheng Lee; Akio Nakamura; Kazuhiro Kohama; Hideaki Karaki; Hiroshi Ozaki

From the Department of Veterinary Pharmacology (T.M., M.H., H.O., H. K.), Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan; and the Department of Molecular and Cellular Pharmacology (S.L., A.N., K.K.), Gunma University Graduate School of Medicine, Gunma 371-8511, Japan.

Correspondence to Masatoshi Hori, DVM, PhD, Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. E-mail ahori{at}mail.ecc.u-tokyo.ac.jp

Objective— Although adenovirus is a powerful tool for vascular research and therapy, endothelial impairment after infection has been reported. We investigated the mechanisms of this impairment and the effect of dexamethasone (DEX) on gene transfer into the vascular endothelial cells.

Methods and Results— ß-Galactosidase gene encoding adenovirus vector (ß-gal-Ad) (7.5x10⁸ plaque-forming units/mL) transduced ß-gal into the rabbit organ–cultured pulmonary endothelium, followed by an apoptosis and an impairment of endothelium-dependent relaxation (EDR). Endothelial cell infected by ß-gal-Ad expressed proinflammatory genes mRNAs and suppressed endothelial nitric oxide synthase (eNOS) mRNA. Treatment with DEX dramatically increased ß-gal protein expression in the endothelium, attenuated ß-gal-Ad–induced apoptosis, and prevented the impairment of EDR. DEX also suppressed the mRNAs expressions of proinflammatory genes and recovered eNOS mRNA expression in organ-cultured vascular endothelium. In addition, we confirmed the DEX’s beneficial effects in an endothelial cell line (in vitro) and rat femoral artery (in vivo) experiments.

Conclusion— These results suggest that adenovirus vector induces host-immune responses and apoptosis in vascular endothelial cells. DEX is found to be a useful and potent tool to prevent the Ad-induced impairments of the endothelium and to optimize gene expression efficiency by adenovirus vector at the protein translation level in both in vitro and in vivo experiments.

We investigated the mechanisms of this impairment and the effect of DEX on adenovirus-mediated gene transfer into the vascular endothelial cells using organ-cultured pulmonary endothelium. Based on these results, we applied DEX treatment to in vitro and in vivo gene transfection.

Key Words: adenovirus • apoptosis • endothelial cells • gene therapy • inflammation