Myocardial Ischemia/Reperfusion Injury Is Mediated by Leukocytic Toll-Like Receptor-2 and Reduced by Systemic Administration of a Novel Anti-Toll-Like Receptor-2 Antibody
Myocardial Ischemia/Reperfusion Injury Is Mediated by Leukocytic Toll-Like Receptor-2 and Reduced by Systemic Administration of a Novel Anti-Toll-Like Receptor-2 Antibody
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DOI：
10.1161/circulationaha.109.880187
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发表时间：
2010-01-05
期刊：
影响因子：
37.8
通讯作者：
de Kleijn, Dominique P. V.
中科院分区：
文献类型：
--
作者：
Arslan, Fatih;Smeets, Mirjam B.;de Kleijn, Dominique P. V.
心肌梗死的再灌注治疗受到部分通过Toll样受体（TLR）激活的有害炎症反应的阻碍。靶向TLR信号传导可以优化再灌注治疗，并增强心肌梗死后的细胞存活和心脏功能。在这里，我们评估的作用TLR2作为一个治疗目标，使用一种新的单克隆抗TLR2 antibody. Method and Results-Mice缺血30分钟，然后再灌注。在再灌注前5分钟施用化合物。在基线和梗死后28天，用9.4-T小鼠磁共振成像评估心脏功能和尺寸。生理盐水和IgG同种型治疗分别导致34.5 +/-3.3%和31.4 +/-2.7%的梗死。野生型和TLR2缺失小鼠之间的骨髓移植实验表明，最终的梗死面积是由循环TLR2表达决定的。单次静脉推注抗TLR2抗体使梗死面积减少至18.9 +/-2.2%（P = 0.001）。与盐水处理的小鼠相比，抗TLR2处理的小鼠表现出更少的扩张性重塑（舒张末期容积68.2 +/-2.5 vs. 76.8 +/-3.5 mu L; P = 0.046）和保留的收缩功能（射血分数51.0 +/-2.1%vs39.9 +/-2.2%，P = 0.009;收缩期室壁增厚3.3 +/-6.0%vs22.0 +/-4.4%，P = 0.038）。抗TLR2治疗显著减少嗜中性粒细胞、巨噬细胞和T淋巴细胞浸润。此外，肿瘤坏死因子-α，白细胞介素-1 α，粒细胞-巨噬细胞集落刺激因子，白细胞介素-10显着减少，是磷酸化的c-jun N-末端激酶，磷酸化p38丝裂原活化蛋白激酶，半胱天冬酶3/7的活性levels.Conclusions循环TLR2表达介导心肌缺血/再灌注损伤。在再灌注前5分钟拮抗TLR2可减少梗死面积并保护心脏功能和几何形状。抗TLR2治疗通过减少白细胞流入、细胞因子产生和促凋亡信号传导发挥其作用。因此，抗TLR2单克隆抗体是心肌梗死患者再灌注治疗的潜在候选药物。（循环。2010; 121：80 - 90.）
Background-Reperfusion therapy for myocardial infarction is hampered by detrimental inflammatory responses partly via Toll-like receptor (TLR) activation. Targeting TLR signaling may optimize reperfusion therapy and enhance cell survival and heart function after myocardial infarction. Here, we evaluated the role of TLR2 as a therapeutic target using a novel monoclonal anti-TLR2 antibody.Method and Results-Mice underwent 30 minutes of ischemia followed by reperfusion. Compounds were administered 5 minutes before reperfusion. Cardiac function and dimensions were assessed at baseline and 28 days after infarction with 9.4-T mouse magnetic resonance imaging. Saline and IgG isotype treatment resulted in 34.5+/-3.3% and 31.4+/-2.7% infarction, respectively. Bone marrow transplantation experiments between wild-type and TLR2-null mice revealed that final infarct size is determined by circulating TLR2 expression. A single intravenous bolus injection of anti-TLR2 antibody reduced infarct size to 18.9+/-2.2% (P=0.001). Compared with saline-treated mice, anti-TLR2-treated mice exhibited less expansive remodeling (end-diastolic volume 68.2+/-2.5 versus 76.8+/-3.5 mu L; P=0.046) and preserved systolic performance (ejection fraction 51.0+/-2.1% versus 39.9+/-2.2%, P=0.009; systolic wall thickening 3.3+/-6.0% versus 22.0+/-4.4%, P=0.038). Anti-TLR2 treatment significantly reduced neutrophil, macrophage, and T-lymphocyte infiltration. Furthermore, tumor necrosis factor-alpha, interleukin-1 alpha, granulocyte macrophage colony-stimulating factor, and interleukin-10 were significantly reduced, as were phosphorylated c-jun N-terminal kinase, phosphorylated p38 mitogen-activated protein kinase, and caspase 3/7 activity levels.Conclusions-Circulating TLR2 expression mediates myocardial ischemia/reperfusion injury. Antagonizing TLR2 just 5 minutes before reperfusion reduces infarct size and preserves cardiac function and geometry. Anti-TLR2 therapy exerts its action by reducing leukocyte influx, cytokine production, and proapoptotic signaling. Hence, monoclonal anti-TLR2 antibody is a potential candidate as an adjunctive for reperfusion therapy in patients with myocardial infarction. (Circulation. 2010; 121: 80-90.)