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

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，越来越多的证据表明炎症过程参与了这些难治性疾病的发病机制。特别是，动脉损伤的炎症反应，导致单核细胞的持续招募和激活，主要是通过激活单核细胞趋化蛋白-1（MCP-1）途径，在再狭窄和动脉粥样硬化形成中具有核心作用，我们最近设计了一种新的抗炎（MCP-1）疗法，通过将MCP-1基因的N端缺失突变体导入骨骼肌。这种突变型MCP-1缺乏N-末端氨基酸2至8，称为7 ND，并作为MCP-1的显性负抑制剂。我们证明，7 ND基因转移抑制动脉损伤后单核细胞浸润/活化， ...更多信息 球囊损伤或支架置入后的再狭窄变化。支架或腺病毒介导的7 ND基因局部转染可减少支架内新生内膜的形成，但不影响内皮再生或组织修复过程，表明局部转染策略是预防动物支架内再狭窄的一种实用和有前景的手段。此外，7 ND基因转染不仅可减轻动脉粥样硬化病变的发生，而且限制了预先存在的动脉粥样硬化病变的进展并将病变组成改变为更稳定的表型，即，MCP-1介导的血管炎症可能通过激活病变单核细胞而产生正反馈环，从而增强再狭窄和动脉粥样硬化的变化。我们还报道了7 ND基因转移减轻了缺血再灌注损伤、移植后动脉硬化和心肌梗死后左心室重构和衰竭。总之，用7 ND基因转移阻断MCP-1不仅在减少实验性再狭窄、动脉粥样硬化和导致急性冠状动脉综合征的斑块不稳定方面有效，而且在减轻其他形式的心血管疾病方面也有效。我们在非人灵长类动物中的发现具有重要的临床意义，这意味着这种靶向MCP-1的抗炎策略可能是一种有希望的治疗人类再狭窄和动脉粥样硬化并发症的方法。少

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