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Anti-inflammation therapy targeting monocyte chemoattractant protein-1 as novel strategy to treat cardiovascular disease

针对单核细胞趋化蛋白-1的抗炎治疗作为治疗心血管疾病的新策略

基本信息

批准号：
14207036
负责人：
EGASHIRA Kensuke
金额：
$ 30.62万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207036/
关键词：
restenosis atherosclerosis inflammation gene therapy monocytes

项目摘要

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 … More 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

心血管疾病的临床挑战包括再狭窄、斑块破裂导致的动脉粥样硬化事件、移植后动脉硬化、缺血再灌注损伤等，需要新的治疗选择。新出现的证据表明，炎症过程参与了这些顽固性疾病的发病机制。尤其是动脉损伤后的炎症反应，主要通过激活单核细胞趋化蛋白-1(MCP-1)途径引起单核细胞的持续募集和激活，在再狭窄和动脉粥样硬化形成中起核心作用。我们最近设计了一种新的抗炎(MCP-1)治疗方法，将MCP-1基因的N端缺失突变体导入骨骼肌中。这种突变的MCP-1缺乏N端氨基酸2到8，称为7ND，并作为MCP-1的显性负抑制因子发挥作用。我们证实，7ND基因转移抑制了动脉损伤后单核细胞的浸润/激活，并减弱了…球囊损伤或支架置入后发生更多再狭窄改变。以支架为载体或以腺病毒为载体的7ND基因局部转导减少了支架内新生内膜的形成，但不影响血管内皮细胞的再生和组织修复过程，提示局部转导策略是预防包括猴子在内的动物支架内再狭窄的一种实用而有前景的方法。此外，7ND基因转移不仅可以抑制动脉粥样硬化病变的发生，而且可以限制原有动脉粥样硬化病变的进展，并使病变成分变为更稳定的表型，即巨噬细胞减少，脂质减少，MCP-1介导的血管炎症可能通过激活皮损单核细胞而形成正反馈环，促进再狭窄和动脉粥样硬化的改变。我们还报道了7ND基因转移可减轻缺血再灌注损伤、移植后动脉硬化、心肌梗死后左室重构和衰竭。结论：用7ND基因转移阻断MCP-1不仅可以减少实验性再狭窄、动脉粥样硬化和导致急性冠脉综合征的斑块失稳，而且还可以减轻其他形式的心血管疾病。我们在非人类灵长类动物中的发现具有重要的临床意义，这意味着这种针对MCP-1的抗炎策略可能是一种有前途的治疗人类再狭窄和动脉粥样硬化并发症的方法。较少