© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Gene transfer of endothelial nitric oxide synthase but not Cu/Zn superoxide dismutase restores nitric oxide availability in the SHRSP
aDepartment of Medicine and Therapeutics, University of Glasgow, Western Infirmary, Church St., Glasgow G11 6NT, Scotland, UK
bDepartment of Internal Medicine, University of Iowa, Iowa, IA 52242, USA
* Corresponding author. Tel.: +44-141-211-2111; fax: +44-141-211-1763 yalexander{at}clinmed.gla.ac.uk
Objective: Previous studies from our group have shown a deficit in nitric oxide (NO) bioavailability and an excess production of the superoxide anion (O2–) in the stroke prone spontaneously hypertensive rat (SHRSP) compared to the normotensive Wistar Kyoto (WKY) strain. This present study has investigated whether adenoviral-mediated gene transfer of human eNOS or Cu/ZnSOD can alter the NO/O2– balance, thereby improving endothelial function. Methods: A recombinant adenovirus, Ad/Hu/eNOS, containing the human eNOS cDNA fragment was generated by homologous recombination in 293 cells. Ad/Hu/eNOS or Ad/Cu/ZnSOD was delivered into SHRSP carotid arteries in vivo, using a titre of 2x109–2x1010 plaque forming units (pfu)/ml, and the effect on gene expression was observed 24 h later. Results: Western blotting confirmed increased enzyme levels of eNOS and Cu/ZnSOD in the viral-infused vessels. Ex vivo, the pressor response to phenylephrine (PE) in the presence of L-NAME was increased in the eNOS-infused arteries relative to the contralateral controls, indicating restoration of basal NO availability to that observed in untreated control WKY rats. Infusion of the SOD virus produced a statistically insignificant increase in NO bioavailability. Conclusions: Our results support our previous findings obtained using a bovine eNOS recombinant adenovirus, that recombinant adenoviral gene transfer of human eNOS has a significant effect on NO bioavailability. In contrast, AdCu/ZnSOD gene transfer does not elicit an effect in our model. These results indicate that short-term overexpression of a recombinant eNOS, but not Cu/ZnSOD gene, in carotid arteries of the SHRSP is an effective means of locally increasing NO bioavailability to improve endothelial function.
KEYWORDS Endothelial function; Free radicals; Gene therapy; Gene expression; Hypertension; Nitric oxide; Vasoconstriction/dilation.
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