Intraluminal gene transfer of endothelial cell-nitric oxide synthase suppresses intimal hyperplasia of vein grafts in cholesterol-fed rabbit: a limited biological effect as a result of the loss of medial smooth muscle cells.
BACKGROUND
The intimal hyperplasia of vein grafts is a major cause of late graft failure and is more pronounced under hyperlipidemia. We previously reported that endothelial cell (ec)-type nitric oxide synthase (NOS) gene transfer inhibited graft intimal hyperplasia under poor runoff conditions. However, little information is available on either ecNOS gene transfer or intimal thickening under hypercholesterolemia.


METHODS
Using the hemagglutinating virus of Japan liposomes, bovine ecNOS complentary DNA (5000 hemagglutinating activity units/mL) was transfected intraluminally to the right jugular vein, and these veins were then implanted as reversed vein grafts in an end-to-side fashion to the ipsilateral carotid artery.


RESULTS
The cyclic guanosine 3',5'-monophosphate content of the ecNOS vein significantly increased in the grafts at 4 days after gene transfer, but the levels were only 25% greater than those found in the untreated veins. An immunohistochemical analysis at the same time suggested a large loss of medial smooth muscle cells that might have led to a reduction in the exogenous gene expression. The neointima of the ecNOS grafts was significantly reduced 4 weeks after implantation (P <.05), but the effect of ecNOS was limited to about a 30% inhibition. This reduction was associated with a reduced population of proliferating cells and decreased macrophage accumulation in the graft wall.


CONCLUSIONS
These results demonstrated that the ecNOS gene transfer suppressed intimal hyperplasia of the vein grafts under hyperlipidemic conditions. However, this effect may be limited because of the smooth muscle cell loss related to the use of an intraluminal delivery methods. These data lead to speculation that the outcome of ecNOS gene transfer could be improved using different methods of gene delivery.
Ohta
Shinji
S
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Komori
Kimihiro
K
Yonemitsu
Yoshikazu
Y
Onohara
Toshihiro
T
Matsumoto
Takuya
T
Sugimachi
Keizo
K
D000818:Animals; D002339:Carotid Arteries / Q000601:surgery; D002417:Cattle; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006937:Hypercholesterolemia / Q000473:pathology; D006965:Hyperplasia / Q000517:prevention & control; D007601:Jugular Veins / Q000378:metabolism / Q000637:transplantation*; D007700:Kinetics; D008081:Liposomes; D008264:Macrophages / Q000473:pathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D011817:Rabbits; D029082:Sendai virus / Q000235:genetics; D017539:Tunica Intima / Q000473:pathology*
D002791:Cholesterol, Dietary; D008081:Liposomes; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP