期刊
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
卷 56, 期 22, 页码 1847-1857出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2010.04.066
关键词
chemokines; inflammation; leukocyte; myocardial infarction; neointima formation
资金
- Deutsche Forschungsgemeinschaft [WE1913/7, FOR809]
- Interdisciplinary Center for Clinical Research Biomat [K1-1, K1-2, T5]
- Austrian Science Fund (FWF) [T5] Funding Source: Austrian Science Fund (FWF)
Objectives A nonagonist monocyte chemotactic protein-1 (MCP-1/CCL2) mutant (PA508) with increased affinity for glycosaminoglycans and thus competing with CCL2 was evaluated as a candidate for preventing neointima formation or myocardial ischemia/reperfusion injury. Background Myocardial infarction (MI) remains a major cause of death worldwide despite improved interventional and therapeutic options. Therefore, the discovery of drugs that limit restenosis after intervention and post-MI damage remains an important challenge. Methods The function of PA508 was assessed in functional assays in vitro and in mouse models of wire-induced neointima formation and experimental MI. Results PA508 was functionally inactive in CC chemokine receptor 2 (CCR2) binding and calcium influx but inhibited monocyte chemotaxis or transendothelial migration toward CCL2, suggesting that it interferes with CCL2 presentation. In wild-type but not CCR2-deficient mice, PA508 reduced inflammatory leukocyte recruitment without affecting differential leukocyte counts, CCL2 levels, organ function, or morphology, indicating that it specifically attenuates the CCL2-CCR2 axis. Compared with vehicle, daily intraperitoneal injection of PA508 significantly (p < 0.05, n = 5) reduced neointimal plaque area and mononuclear cell infiltration in carotid arteries of hyper-lipidemic apolipoprotein E-deficient mice while increasing smooth muscle cell content. In C57BI/6J mice that underwent myocardial ischemia/reperfusion, treatment with PA508 significantly reduced infarction size, monocyte infiltration, and collagen and myofibroblast content in the infarction area and preserved heart function compared with vehicle (p < 0.05, n = 4 to 8). Conclusions Here we demonstrate that administration of a rationally designed CCL2 competitor reduced inflammatory monocyte recruitment, limited neointimal hyperplasia, and attenuated myocardial ischemia/reperfusion injury in mice and could therefore be envisioned as a combined therapeutic approach for restenosis and MI. (J Am Coll Cardiol 2010;56:1847-57) (C) 2010 by the American College of Cardiology Foundation
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据