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Adenovirus-mediated overexpression of extracellular superoxide dismutase improves endothelial dysfunction in a rat model of hypertension

Gene Therapy volume 9, pages 110–117 (2002)Cite this article

Abstract

Gene transfer may be appropriate for therapeutic protocols targeted at the vascular endothelium. Endothelial dysfunction is the principal phenotype associated with atherosclerosis and hypertension. Oxidative stress has been implicated in the development of endothelial dysfunction. We have explored the ability of overexpressing anti-oxidant genes (superoxide dismutases; SODs) in vitro and in vivo to assess their potential for reversing endothelial dysfunction in a rat model, the stroke-prone spontaneously hypertensive rat (SHRSP). Western blotting and immunofluorescence assays in vitro showed efficient overexpression of MnSOD and ECSOD with respect to localisation to the mitochondria and extracellular surface, respectively. Transgene functional activity was quantified with SOD activity assays. MnSOD and ECSOD overexpression in intact SHRSP vessels in vivo led to endothelial and adventitial overexpression. Pharmacological assessment of transduced vessels following in vivo delivery by basal NO availability quantification demonstrated that the ‘null’ adenovirus and MnSOD adenovirus did not significantly increase NO availability. However, AdECSOD-treated carotid arteries showed a significant increase in NO availability (1.91 ± 0.04 versus 0.75 ± 0.08 g/g, n = 6, P = 0.029). In summary, efficient overexpression of ECSOD, but not MnSOD in vivo, results in improved endothelial function in a rat model of hypertension and has important implications for the development of endothelial-based vascular gene therapy.

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Acknowledgements

This work is supported by the British Heart Foundation Program Grant RG/97009 and Project Grant PG/200023 to AFD. JPF is funded by a National Heart Research Fund studentship. We are very grateful to Professor Gwyn Gould for his help with confocal microscopy. We would also like to thank E Beattie, E Jardine and D McSharry for technical assistance.

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Authors and Affiliations

  1. Department of Medicine and Therapeutics, BHF Blood Pressure Group, University of Glasgow, Glasgow, UK

    J P Fennell, M J Brosnan, A J Frater, C A Hamilton, M Y Alexander, S A Nicklin, A H Baker & A F Dominiczak

  2. Departments of Internal Medicine and Program in Gene Therapy, University of Iowa College of Medicine and VA Medical Center, Iowa City, IA, USA

    D D Heistad

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  1. J P Fennell
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Fennell, J., Brosnan, M., Frater, A. et al. Adenovirus-mediated overexpression of extracellular superoxide dismutase improves endothelial dysfunction in a rat model of hypertension. Gene Ther 9, 110–117 (2002). https://doi.org/10.1038/sj.gt.3301633

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