Tissue factor pathway inhibitor gene delivery using HVJ-AVE liposomes markedly reduces restenosis in atherosclerotic arteries.
OBJECTIVE
Tissue factor pathway inhibitor (TFPI), as a primary inhibitor of TF-induced coagulation, reduces neointimal formation and luminal stenosis by inhibiting coagulation and thrombosis after vessel wall injury. Here, we investigated the effect of TFPI gene delivery with a HVJ-AVE liposome vector on restenosis in atherosclerotic arteries after angioplasty in rabbits. We also evaluated the safety of the novel gene therapeutic strategy to prevent restenosis.


METHODS
Local iliac artery atherosclerosis was induced by a combination of balloon denudation and high-cholesterol diet in Japanese white rabbits, which were then subjected to angioplasty. Infusion of an HVJ-AVE liposome containing the TFPI gene or an "empty" pcDNA 3.1 expression vector, or HVJ-liposome vector only, or saline was performed at the site of angioplasty using a Dispatch((R)) catheter. Quantitative angiography and histopathology were performed before and after gene delivery and at 4 weeks follow-up. The safety of the gene therapy was evaluated over a 6-month observation period.


RESULTS
TFPI mRNA and protein were detected in local TFPI gene transferred vessels after gene transfer. The mean minimal luminal diameter of the TFPI group was markedly greater than that of the control groups (P<0.01) at 4 weeks after gene transfer. The mean neointimal area, the ratio of the neointimal to medial areas, and percent of stenosis in the TFPI group were all significantly reduced compared with the control groups (each P<0.01). The external elastic luminal area, internal elastic luminal area, and luminal area were larger in the TFPI groups versus controls (each P<0.01). Thrombosis was found in five empty plasmid control group animals, but in only one in the TFPI group (P=0.05). The systemic coagulation status of the treated animals were not significantly changed in either the TFPI group or the control groups; no toxicity was observed after HVJ-AVE liposome-mediated TFPI gene transfer.


CONCLUSIONS
HVJ-AVE liposome-mediated TFPI gene transfer significantly reduced neointimal hyperplasia, inhibited thrombosis, and attenuated vascular remodeling and lumimal stenosis after angioplasty in atherosclerotic arteries without any significant adverse effects.
Yin
Xinhua
X
Department of Pathology, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita City, Osaka, Japan.
Yutani
Chikao
C
Ikeda
Yoshihiko
Y
Enjyoji
Keiichi
K
Ishibashi-Ueda
Hatsue
H
Yasuda
Satoshi
S
Tsukamoto
Yoshitane
Y
Nonogi
Hiroshi
H
Kaneda
Yasufumi
Y
Kato
Hisao
H
D000800:Angioplasty, Balloon; D000818:Animals; D001161:Arteriosclerosis / Q000000981:diagnostic imaging / Q000517:prevention & control / Q000628:therapy*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007083:Iliac Artery / Q000000981:diagnostic imaging / Q000473:pathology; D008074:Lipoproteins / Q000235:genetics* / Q000378:metabolism; D008081:Liposomes; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D011859:Radiography; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008074:Lipoproteins; D008081:Liposomes; D012333:RNA, Messenger; C051928:lipoprotein-associated coagulation inhibitor