Zhao Peng, Turdi Subat, Dong Feng, Xiao Xiaoyan, Su Guohai, Zhu Xinglei, Scott Glenda I, Ren Jun
Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, People's Republic of China.
Shock. 2009 Jul;32(1):100-7. doi: 10.1097/SHK.0b013e31818ec609.
Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, plays a key role in cardiac dysfunction in sepsis. Low circulating levels of insulin-like growth factor 1 (IGF-1) are found in sepsis, although the influence of IGF-1 on septic cardiac defect is unknown. This study was designed to examine the impact of IGF-1 on LPS-induced cardiac contractile and intracellular Ca2+ dysfunction, activation of stress signal and endoplasmic reticulum (ER) stress. Mechanical and intracellular Ca2+ properties were examined in cardiomyocytes from Fast Violet B and cardiac-specific IGF-1 overexpression mice treated with or without LPS (4 mg kg(-1), 6 h). Reactive oxygen species (ROS), protein carbonyl formation and apoptosis were measured. Activation of mitogen-activated protein kinase pathways (p38, c-jun N-terminal kinase [JNK] and extracellular signal-related kinase [ERK]), ER stress and apoptotic markers were evaluated using Western blot analysis. Our results revealed decreased peak shortening and maximal velocity of shortening/relengthening and prolonged duration of relengthening in LPS-treated Fast Violet B cardiomyocytes associated with reduced intracellular Ca2+ decay. Accumulation of ROS protein carbonyl and apoptosis were elevated after LPS treatment. Western blot analysis revealed activated p38 and JNK, up-regulated Bax, and the ER stress markers GRP78 and Gadd153 in LPS-treated mouse hearts without any change in ERK and Bcl-2. Total protein expression of p38, JNK, and ERK was unaffected by either LPS or IGF-1. Interestingly, these LPS-induced changes in mechanical and intracellular Ca2+ properties, ROS, protein carbonyl, apoptosis, stress signal activation, and ER stress markers were effectively ablated by IGF-1. In vitro LPS exposure (1 microg mL(-1)) produced cardiomyocyte mechanical dysfunction reminiscent of the in vivo setting, which was alleviated by exogenous IGF-1 (50 nM). These data collectively suggested a beneficial of IGF-1 in the management of cardiac dysfunction under sepsis.
脂多糖（LPS）是革兰氏阴性菌外膜的一种成分，在脓毒症引起的心脏功能障碍中起关键作用。脓毒症患者体内胰岛素样生长因子1（IGF-1）的循环水平较低，尽管IGF-1对脓毒症心脏缺陷的影响尚不清楚。本研究旨在探讨IGF-1对LPS诱导的心脏收缩和细胞内Ca2+功能障碍、应激信号激活和内质网（ER）应激的影响。对用或不用LPS（4 mg kg(-1)，6小时）处理的固紫B快染小鼠和心脏特异性IGF-1过表达小鼠的心肌细胞进行机械和细胞内Ca2+特性检测。检测活性氧（ROS）、蛋白质羰基形成和细胞凋亡情况。采用蛋白质印迹分析评估丝裂原活化蛋白激酶途径（p38、c-jun氨基末端激酶[JNK]和细胞外信号调节激酶[ERK]）的激活、内质网应激和凋亡标志物。我们的结果显示，LPS处理的固紫B快染心肌细胞的峰值缩短和最大缩短/再延长速度降低，再延长持续时间延长，同时细胞内Ca2+衰减减少。LPS处理后，ROS、蛋白质羰基积累和细胞凋亡增加。蛋白质印迹分析显示，LPS处理的小鼠心脏中p38和JNK激活，Bax上调，内质网应激标志物GRP78和Gadd153上调，而ERK和Bcl-2无变化。p38、JNK和ERK的总蛋白表达不受LPS或IGF-1的影响。有趣的是，IGF-1有效消除了LPS诱导的这些机械和细胞内Ca2+特性、ROS、蛋白质羰基、细胞凋亡、应激信号激活和内质网应激标志物的变化。体外暴露于LPS（1 microg mL(-1)）会导致心肌细胞机械功能障碍，类似于体内情况，而外源性IGF-1（50 nM）可缓解这种情况。这些数据共同表明，IGF-1在脓毒症时心脏功能障碍的管理中具有益处。
