Oki Masami, Jesmin Subrina, Islam Md Majedul, Mowa Chishimba Nathan, Khatun Tanzila, Shimojo Nobutake, Sakuramoto Hideaki, Kamiyama Junko, Kawano Satoru, Miyauchi Takashi, Mizutani Taro
Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Department of Biology, Appalachian State University, Boone, NC, USA.
Life Sci. 2014 Nov 24;118(2):364-9. doi: 10.1016/j.lfs.2014.02.008. Epub 2014 Feb 16.
Sepsis is a cluster of heterogeneous syndromes associated with progressive endotoxemic developments, ultimately leading to damage of multiple organs, including the heart. However, the pathogenesis of sepsis-induced myocardial dysfunction is still not fully understood. The present study is the first to examine alterations in expression of key angiogenic signaling system mediated by vascular endothelial growth factor (VEGF) in septic heart and the effects of endothelin dual blocker (ETDB) on it.
Normal Wistar rats were either administered with: a) vehicle only (control group), b) lipopolysaccharide only (LPS: 15 mg/kg) and then sacrificed at different time points (1 h, 3 h, 6 h and 10 h), and c) the last group was co-administered with LPS and ETDB (SB-209670, 1 mg/kg body weight) for 6 h and then sacrificed.
Administration of LPS resulted in increases in levels of: a) serum tumor necrosis factor (TNF)-α, b) serum VEGF and c) serum endothelin (ET)-1 levels accompanied by up-regulation of cardiac VEGF and its downstream angiogenic signaling molecules. While cardiac TNF-α level was unchanged among experimental groups, cardiac ET-1 level was significantly higher in LPS-administered group.
We conclude that elevation in VEGF angiogenic signaling may be triggered by diminished oxygenation in the myocardium following LPS administration as a consequence of sepsis-induced microvascular dysfunction. Because of this cardiac dysfunction, oxygen supply may be inadequate at microregional level to support the normal heart metabolism and function. ETDB at 6 h further increased the elevated levels of VEGF angiogenic signaling in endotoxemic heart.
脓毒症是一组异质性综合征，与进行性内毒素血症发展相关，最终导致包括心脏在内的多个器官受损。然而，脓毒症诱导的心肌功能障碍的发病机制仍未完全明确。本研究首次检测脓毒症心脏中由血管内皮生长因子（VEGF）介导的关键血管生成信号系统的表达变化以及内皮素双重阻断剂（ETDB）对其的影响。
将正常Wistar大鼠分为以下几组给药：a）仅给予溶剂（对照组）；b）仅给予脂多糖（LPS：15mg/kg），并在不同时间点（1小时、3小时、6小时和10小时）处死；c）最后一组同时给予LPS和ETDB（SB - 209670，1mg/kg体重），持续6小时后处死。
给予LPS导致以下指标升高：a）血清肿瘤坏死因子（TNF）-α水平；b）血清VEGF水平；c）血清内皮素（ET）-1水平，同时伴有心脏VEGF及其下游血管生成信号分子的上调。虽然实验组之间心脏TNF-α水平未发生变化，但给予LPS组的心脏ET-1水平显著更高。
我们得出结论，脓毒症诱导的微血管功能障碍导致LPS给药后心肌氧合减少，可能触发VEGF血管生成信号的升高。由于这种心脏功能障碍，在微区域水平氧气供应可能不足以支持正常的心脏代谢和功能。6小时的ETDB进一步增加了内毒素血症心脏中升高的VEGF血管生成信号水平。
