Toll-like receptors 2-deficient mice are protected against postischemic coronary endothelial dysfunction
Toll-like receptors 2-deficient mice are protected against postischemic coronary endothelial dysfunction
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DOI：
10.1161/atvbaha.107.140723
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发表时间：
2007-05-01
影响因子：
8.7
通讯作者：
Richard, Vincent
中科院分区：
文献类型：
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作者：
Favre, Julie;Musette, Philippe;Richard, Vincent
目标 - Toll 样受体 (TLR) 2 在心脏和炎症细胞中表达，并调节白细胞功能。由于白细胞粘附是缺血/再灌注 (I/R) 诱导的内皮损伤中的关键事件，因此我们评估了 TLR2 是否参与了 I/R 诱导的冠状动脉内皮损伤。 方法和结果 - 与离体评估的乙酰胆碱相比，缺血再灌注显着降低了 NO 介导的冠状动脉松弛。相反，在 TLR2 缺陷小鼠中，I/R 反而改善了 NO 介导的乙酰胆碱反应。为了精确表达参与内皮损伤的TLR2的细胞区室，我们通过将TLR2(-/-)骨髓移植到WT小鼠或将WT骨髓移植到TLR2(-/-)小鼠来培育骨髓嵌合小鼠，并在移植后5周将它们进行I/R。两种嵌合小鼠都表现出与 TLR2(-/-) 小鼠类似的针对 I/R 诱导的内皮功能障碍的保护作用，表明 TLR2 在非骨髓细胞（在我们的情况下可能是内皮细胞和/或心肌细胞）和骨髓来源的细胞（可能是中性粒细胞）上表达的作用。 TLR2 缺陷还与较小的梗塞面积、再灌注诱导的活性氧产生和白细胞浸润减少有关。结论 - TLR2 可能通过刺激中性粒细胞（和自由基）介导的内皮损伤，导致 I/R 后冠状动脉内皮功能障碍。
Objectives - Toll-like receptors (TLR) 2 are expressed in cardiac and inflammatory cells, and regulate leukocyte function. Because leukocyte adhesion is a critical event in endothelial injury induced by ischemia/reperfusion (I/R), we assessed whether TLR2 were involved in I/R - induced coronary endothelial injury.Methods and Results - Ischemia-reperfusion markedly decreased NO-mediated coronary relaxations to acetylcholine assessed ex vivo. In contrast, in TLR2 deficient mice, I/R paradoxically improved the NO-mediated responses to acetylcholine. To precise the cellular compartment expressing TLR2 which is involved in endothelial injury, we developed bone-marrow chimeric mice by transplanting TLR2(-/-) bone marrow to WT mice or WT bone marrow to TLR2(-/-) mice and submitted them to I/R 5 weeks after transplant. Both chimeric mice displayed similar protection as TLR2(-/-) mice against I/R-induced endothelial dysfunction, suggesting a role of TLR2 expressed on both non-bone marrow cells (in our case presumably endothelial cells and/or cardiomyocytes) and cells of bone marrow origin (presumably neutrophils). TLR2 deficiency was also associated with a smaller infarct size, and reduced reperfusion-induced production of reactive oxygen species and leukocyte infiltration.Conclusions - TLR2 contribute to coronary endothelial dysfunction after I/R, possibly through stimulation of neutrophil- (and free radical-) mediated endothelial injury.