High-mobility group box-1 in ischemia-reperfusion injury of the heart
High-mobility group box-1 in ischemia-reperfusion injury of the heart
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DOI：
10.1161/circulationaha.108.769331
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发表时间：
2008-06-24
期刊：
影响因子：
37.8
通讯作者：
Bierhaus, Angelika
中科院分区：
文献类型：
--
作者：
Andrassy, Martin;Volz, Hans C.;Bierhaus, Angelika
高迁移率族蛋白1（HMGB 1）是一种由坏死细胞和活化的免疫细胞释放的核因子。HMGB 1通过Toll样受体家族成员和晚期糖基化终末产物受体（receptor for advanced glycation end products，简写为AGEs）传递信号。虽然HMGB 1已牵连在缺血/再灌注（I/R）损伤的肝脏和肺，其作用在I/R损伤的心脏仍然不清楚。方法和结果-在这里，我们证明，HMGB 1作为一个早期介质的炎症和器官损伤的I/R损伤的心脏。HMGB 1水平在体外缺氧后30分钟和体内心脏缺血性损伤后已经升高。用重组HMGB 1治疗小鼠使I/R损伤恶化，而用HMGB 1盒A治疗显著减少梗死面积和组织损伤标记物。此外，重组HMGB 1 box A对HMGB 1的抑制作用表明，有丝分裂原活化蛋白激酶jun N-末端激酶和细胞外信号调节激酶1/2以及核转录因子核因子-κ B参与了I/R损伤。有趣的是，在RAGE（-/-）小鼠中给予重组HMGB 1或HMGB 1拮抗剂并不影响梗死面积和组织损伤标志物，这表明与野生型小鼠相比，再灌注心脏的损伤显着减少。共孵育研究使用重组HMGB 1在体外诱导的炎症反应，在分离的巨噬细胞从野生型小鼠，但不是在巨噬细胞从mouse（-/-）mice.Conclusions -HMGB 1发挥了重要作用，在早期事件的I/R损伤结合到mouse，导致激活的促炎通路和增强心肌损伤。因此，阻断HMGB 1可能是I/R损伤的一种新的治疗策略。
Background - High-mobility group box-1 (HMGB1) is a nuclear factor released by necrotic cells and by activated immune cells. HMGB1 signals via members of the toll-like receptor family and the receptor for advanced glycation end products ( RAGE). Although HMGB1 has been implicated in ischemia/reperfusion (I/R) injury of the liver and lung, its role in I/R injury of the heart remains unclear.Methods and Results - Here, we demonstrate that HMGB1 acts as an early mediator of inflammation and organ damage in I/R injury of the heart. HMGB1 levels were already elevated 30 minutes after hypoxia in vitro and in ischemic injury of the heart in vivo. Treatment of mice with recombinant HMGB1 worsened I/R injury, whereas treatment with HMGB1 box A significantly reduced infarct size and markers of tissue damage. In addition, HMGB1 inhibition with recombinant HMGB1 box A suggested an involvement of the mitogen-activated protein kinases jun N-terminal kinase and extracellular signal-regulated kinase 1/2, as well as the nuclear transcription factor nuclear factor-kappa B in I/R injury. Interestingly, infarct size and markers of tissue damage were not affected by administration of recombinant HMGB1 or HMGB1 antagonists in RAGE(-/-) mice, which demonstrated significantly reduced damage in reperfused hearts compared with wild-type mice. Coincubation studies using recombinant HMGB1 in vitro induced an inflammatory response in isolated macrophages from wild-type mice but not in macrophages from RAGE(-/-) mice.Conclusions - HMGB1 plays a major role in the early event of I/R injury by binding to RAGE, resulting in the activation of proinflammatory pathways and enhanced myocardial injury. Therefore, blockage of HMGB1 might represent a novel therapeutic strategy in I/R injury.