Anti-monocyte chemoattractant protein-1 gene therapy inhibits restenotic changes (neointimal hyperplasia) after balloon injury in rats and monkeys.
Prevention of restenosis after coronary intervention is a major clinical challenge, which highlights the need of new therapeutic options. Vascular injury may involve inflammatory responses that accelerate the recruitment and activation of monocytes through the activation of chemotactic factors, including monocyte chemoattractant protein-1 (MCP-1). However, there is no definitive evidence supporting the role of MCP-1 in restenosis. We recently devised a new strategy for anti-MCP-1 gene therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into skeletal muscles. We demonstrate here that this strategy suppressed monocyte infiltration/activation in the injured site and markedly inhibited restenotic changes (neointimal hyperplasia) after balloon injury of the carotid artery in rats and monkeys. This strategy also suppressed the local production of MCP-1 and inflammatory cytokines. Therefore, monocyte infiltration and activation mediated by MCP-1 are essential in the development of restenotic changes after balloon injury. This strategy may be a useful form of gene therapy against human restenosis.
Usui
Makoto
M
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Egashira
Kensuke
K
Ohtani
Kisho
K
Kataoka
Chu
C
Ishibashi
Minako
M
Hiasa
Ken-ichi
K
Katoh
Makoto
M
Zhao
Qingwei
Q
Kitamoto
Shiro
S
Takeshita
Akira
A
D000199:Actins / Q000032:analysis; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000209:etiology / Q000517:prevention & control*; D002404:Catheterization / Q000009:adverse effects; D018932:Chemokine CCL2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006965:Hyperplasia; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D008297:Male; D009130:Muscle, Smooth / Q000737:chemistry; D009154:Mutation; D010957:Plasmids / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*; D014841:von Willebrand Factor / Q000032:analysis
D000199:Actins; C515334:CCR2 protein, human; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014841:von Willebrand Factor