Nitric oxide synthase gene therapy rapidly reduces adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits

Background-Hypercholesterolemia reduces nitric oxide bioavailability, manif ested by reduced endothelium-dependent vascular relaxation, and also induce s vascular adhesion molecule expression and inflammatory cell infiltration. We have previously shown that gene therapy with NO synthase in hypercholes terolemic rabbits substantially reverses the deficit in vascular relaxation . In the present study, we show that NO synthase gene therapy rapidly and s ubstantially reduces vascular adhesion molecule expression, lipid depositio n, and inflammatory cell infiltration. Methods and Results-Thirty male New Zealand White rabbits were maintained o n a 1% cholesterol diet for 11 to 13 weeks, then underwent carotid artery g ene transfer with Ad.nNOS or Ad.beta Gal (recombinant adenoviruses expressi ng neuronal NO synthase or beta-galactosidase, respectively), or received m edium alone in a sham procedure. Arteries were harvested at 1 and 3 days af ter gene transfer, and the following parameters were determined by immunohi stochemical and image-analysis techniques: intercellular adhesion molecule- 1, vascular cell adhesion molecule-1, lipid deposition by oil red O stainin g, lymphocyte infiltration (CD43-positive cells), and monocyte infiltration (RAM-ll-positive cells). In Ad.nNOS-treated arteries, all markers were sig nificantly decreased relative to Ad.beta Gal or sham-treated arteries withi n 3 days after gene transfer. Ad.nNOS had a particularly striking impact on monocyte infiltration; as early as 24 hours after gene transfer, Ad.nNOS-t reated arteries had >3-fold fewer monocytes than Ad.beta Gal- or sham-treat ed arteries. Conclusions-NO synthase gene therapy rapidly ameliorates several markers of atherosclerosis in the cholesterol-fed rabbit.