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, manifested by reduced endothelium-dependent vascular relaxation, and also induces vascular adhesion molecule expression and inflammatory cell infiltration. We have previously shown that gene therapy with NO synthase in hypercholesterolemic rabbits substantially reverses the deficit in vascular relaxation. In the present study, we show that NO synthase gene therapy rapidly and substantially reduces vascular adhesion molecule expression, lipid deposition, and inflammatory cell infiltration.


RESULTS
Thirty male New Zealand White rabbits were maintained on a 1% cholesterol diet for 11 to 13 weeks, then underwent carotid artery gene transfer with Ad.nNOS or Ad.betaGal (recombinant adenoviruses expressing neuronal NO synthase or beta-galactosidase, respectively), or received medium alone in a sham procedure. Arteries were harvested at 1 and 3 days after gene transfer, and the following parameters were determined by immunohistochemical and image-analysis techniques: intercellular adhesion molecule-1, vascular cell adhesion molecule-1, lipid deposition by oil red O staining, lymphocyte infiltration (CD43-positive cells), and monocyte infiltration (RAM-11-positive cells). In Ad.nNOS-treated arteries, all markers were significantly decreased relative to Ad. betaGal or sham-treated arteries within 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-treated arteries had >3-fold fewer monocytes than Ad.betaGal- or sham-treated arteries.


CONCLUSIONS
NO synthase gene therapy rapidly ameliorates several markers of atherosclerosis in the cholesterol-fed rabbit.
Qian
H
H
Cardiovascular Division, Duke University Medical Center, Durham, NC., USA.
Neplioueva
V
V
Shetty
G A
GA
Channon
K M
KM
George
S E
SE
D000818:Animals; D001161:Arteriosclerosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D016893:Carotid Stenosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002791:Cholesterol, Dietary; D004036:Diet, Atherogenic; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D007249:Inflammation; D050356:Lipid Metabolism; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D011817:Rabbits; D011994:Recombinant Proteins / Q000096:biosynthesis; D001616:beta-Galactosidase / Q000235:genetics
D015815:Cell Adhesion Molecules; D002791:Cholesterol, Dietary; D011994:Recombinant Proteins; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D001616:beta-Galactosidase