Adenovirus-mediated gene transfer is augmented in basilar and carotid arteries of heritable hyperlipidemic rabbits

Background and Purpose-There are major differences in susceptibility of int racranial and extracranial arteries to atherosclerosis. The goal of this st udy was to examine adenovirus-mediated gene transfer to basilar and carotid arteries of Watanabe heritable hyperlipidemic (WHHL) rabbits, which have s pontaneous hypercholesterolemia and atherosclerosis, and normal New Zealand White (NZW) rabbits. We used 2 different adenoviral vectors, driven by eit her cytomegalovirus (CMV) or Rous sarcoma virus (RSV) promoters. Methods-Basilar and carotid arteries were removed from WHHL and NZW rabbits and cut into rings. The arteries were incubated with an adenoviral vector that expresses beta-galactosidase and is driven by either a cytomegalovirus (CMV) or Rous sarcoma virus (RSV) promoter (AdCMV beta gal or AdRSV beta g al). Arteries were. incubated with virus for 2 hours, and then incubated in medium for 24 hours to allow expression of transgene. Transgene expression was assessed by enzyme activity (Galacto-Light assay) and by a histochemic al method after X-Gal staining. Results-After gene transfer, beta-galactosidase was expressed in endotheliu m and adventitia but not media. There were moderately severe atheroscleroti c lesions in carotid arteries and early lesions in basilar arteries, Enzyme activity after gene transfer with AdCMV beta gal (3x10(11) particles/mL) w as greater in the basilar artery of WHHL than NZW (137+/-40 versus 25+/-10 mU/mg protein, P<0.05) (mean+/-SE) and in the carotid artery (133+/-27 vers us 34+/-11 mU/mg protein, P<0.05). After gene transfer with AdRSV beta gal, transgene expression was similar in arteries from WHHL and normal NZW rabb its. Conclusions-This is the first study to examine gene transfer to intracrania l and extracranial arteries from atherosclerotic animals. The findings sugg est that an adenoviral vector with a CMV, but not RSV, promoter provides gr eater transgene expression in the basilar and carotid arteries from spontan eously atherosclerotic rabbits than from normal rabbits.