| Co-Investigator(Kenkyū-buntansha) |
TAKESHITA Akira Kyushu University, Emeritus Professor, 名誉教授 (30038814)
ICHIKI Toshihiro KYUSHU UNIVERSITY, Department of Cardiovascular Medicine, Research Associate, 大学病院, 助手 (80311843)
SUEISHI Katsuo KYUSHU UNIVERSITY, Department of Pathological Sciences, Professor, 医学研究院, 教授 (70108710)
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| Research Abstract |
Clinical challenges for cardiovascular disease, which need new therapeutic options, include restenosis, atherosclerotic events resulting from plaque rupture, post-transplantation arteriosclerosis, ischemia-reperfusion injury and so on. Emerging evidence suggests that an inflammatory process is involved in the pathogenesis of such intractable diseases. In particular, inflammatory responses to arterial injury, which cause continuous recruitment and activation of monocytes mainly through activation of the monocyte chemoattractant protein-1(MCP-1) pathway, have a central role in restenosis and atherogenesis.
We recently devised a new anti-inflammation (MCP-1) therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into skeletal muscles. This mutant MCP-1 lacks the N-terminal amino acid 2 to 8, called 7ND, and works as a dominant-negative inhibitor of MCP-1. We demonstrated that 7ND gene transfer suppressed monocyte infiltration/activation after arterial injury and attenuated
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restenotic changes after balloon injury or stent placement. Stent-based or adenovirus-mediated local transfection of 7ND gene reduced in-stent neointimal formation but did not affect process of endothelial regeneration or tissue repair, suggesting that local transfection strategy is a practical and promising means for prevention of in-stent restenosis in animals including monkeys.
Furthermore, 7ND gene transfer not only attenuated the initiation of atherosclerotic lesions, but also limited progression of pre-existing atherosclerotic lesions and changed the lesion composition into a more stable phenotype, i.e., containing fewer macrophages, less lipid, more smooth muscle cells and collagen in hypercholesterolemic mice and monkeys.
Vascular inflammation mediated by MCP-1 might create a positive feedback loop to enhance restenotic and atherosclerotic changes through activating lesional monocytes. We also reported that 7ND gene transfer attenuated ischemia-reperfusion injury, post-transplantation arteriosclerosis, and left ventricular remodeling and failure after myocardial infarction.
In conclusion, blockade of MCP-1 with 7ND gene transfer is effective not only in reducing experimental restenosis, atherosclerosis, and plaque destabilization leading to acute coronary syndrome, but also in attenuating other forms of cardiovascular diseases. Our finding in nonhuman primates has significant clinical significance, implying that this anti-inflammation strategy targeting MCP-1 might be a promising therapy against human restenosis and atherosclerotic complications. Less
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