Sakata Yasushi, Dong Jian-Wen, Vallejo Jesus G, Huang Chien-Hua, Baker J Scott, Tracey Kevin J, Tacheuchi Osamu, Akira Shizuo, Mann Douglas L
Winters Center for Heart Failure Research, 1709 Dryden-BCM, 620-Rm 9.83, Houston, TX 77030, USA.
Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H503-9. doi: 10.1152/ajpheart.00642.2006. Epub 2006 Sep 15.
Production of proinflammatory cytokines contributes to cardiac dysfunction during ischemia-reperfusion. The principal mechanism responsible for the induction of this innate stress response during periods of myocardial ischemia-reperfusion remains unknown. Toll-like receptor 2 (TLR2) is a highly conserved pattern recognition receptor that has been implicated in the innate immune response to a variety of pathogens. However, TLR2 may also mediate inflammation in response to noninfectious injury. We therefore hypothesized that TLR2 is essential for modulating myocardial inflammation and left ventricular (LV) function during ischemia-reperfusion injury. Susceptibility to myocardial ischemia-reperfusion injury following ischemia-reperfusion was determined in Langendorff-perfused hearts isolated from wild-type mice and mice deficient in TLR2 (TLR2D) and Toll interleukin receptor domain-containing adaptor protein. After ischemia-reperfusion, contractile performance was significantly impaired in hearts from wild-type mice as demonstrated by a lower recovery of LV developed pressure relative to TLR2D hearts. Creatinine kinase levels were similar in both groups after reperfusion. Contractile dysfunction in wild-type hearts was associated with elevated cardiac levels of TNF and IL-1beta. Ischemia-reperfusion-induced LV dysfunction was reversed by treatment with the recombinant TNF blocking protein etanercept. These studies show for the first time that TLR2 signaling importantly contributes to the LV dysfunction that occurs following ischemia-reperfusion. Thus disruption of TLR2-mediated signaling may be helpful to induce immediate or delayed myocardial protection from ischemia-reperfusion injury.
促炎细胞因子的产生会导致缺血再灌注期间的心脏功能障碍。在心肌缺血再灌注期间引发这种先天性应激反应的主要机制仍不清楚。Toll样受体2（TLR2）是一种高度保守的模式识别受体，已被证明参与对多种病原体的先天性免疫反应。然而，TLR2也可能介导对非感染性损伤的炎症反应。因此，我们假设TLR2对于在缺血再灌注损伤期间调节心肌炎症和左心室（LV）功能至关重要。在从野生型小鼠和缺乏TLR2（TLR2D）及含Toll白细胞介素受体结构域的衔接蛋白的小鼠分离的Langendorff灌注心脏中，测定缺血再灌注后对心肌缺血再灌注损伤的易感性。缺血再灌注后，野生型小鼠心脏的收缩性能明显受损，相对于TLR2D心脏，左心室舒张末压的恢复较低。再灌注后两组的肌酐激酶水平相似。野生型心脏的收缩功能障碍与心脏中TNF和IL-1β水平升高有关。用重组TNF阻断蛋白依那西普治疗可逆转缺血再灌注诱导的左心室功能障碍。这些研究首次表明，TLR2信号通路对缺血再灌注后发生的左心室功能障碍有重要影响。因此，破坏TLR2介导的信号通路可能有助于诱导对缺血再灌注损伤的即时或延迟心肌保护。
