Ha Tuanzhu, Hua Fang, Grant Daniel, Xia Yeling, Ma Jing, Gao Xiang, Kelley Jim, Williams David L, Kalbfleisch John, Browder I William, Kao Race L, Li Chuanfu
Dept. of Surgery, East Tennessee State Univ., Campus Box 70575, Johnson City, TN 37614-0575, USA.
Am J Physiol Heart Circ Physiol. 2006 Oct;291(4):H1910-8. doi: 10.1152/ajpheart.01264.2005. Epub 2006 Jun 9.
Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. We have previously reported that glucan phosphate (GP) significantly increased survival in a murine model of cecal ligation and puncture (CLP)-induced sepsis. In the present study, we examined the effect of GP on cardiac dysfunction in CLP-induced septic mice. GP was administered to ICR/HSD mice 1 h before induction of CLP. Sham surgically operated mice served as control. Cardiac function was significantly decreased 6 h after CLP-induced sepsis compared with sham control. In contrast, GP administration prevented CLP-induced cardiac dysfunction. Macrophage migration inhibitory factor (MIF) has been implicated as a major factor in cardiomyocyte apoptosis and cardiac dysfunction during septic shock. CLP increased myocardial MIF expression by 88.3% (P < 0.05) and cardiomyocyte apoptosis by 7.8-fold (P < 0.05) compared with sham control. GP administration, however, prevented CLP-increased MIF expression and decreased cardiomyocyte apoptosis by 51.2% (P < 0.05) compared with untreated CLP mice. GP also prevented sepsis-caused decreases in phospho-Akt, phospho-GSK-3beta, and Bcl-2 levels in the myocardium of septic mice. These data suggest that GP treatment attenuates cardiovascular dysfunction in fulminating sepsis. GP administration also activates the phosphoinositide 3-kinase/Akt pathway, decreases myocardial MIF expression, and reduces cardiomyocyte apoptosis.
心肌功能障碍是脓毒症休克的主要后果，也是脓毒症高死亡率的原因之一。我们之前报道过，磷酸葡聚糖（GP）可显著提高盲肠结扎穿孔（CLP）诱导的脓毒症小鼠模型的存活率。在本研究中，我们检测了GP对CLP诱导的脓毒症小鼠心脏功能障碍的影响。在诱导CLP前1小时给ICR/HSD小鼠注射GP。假手术操作的小鼠作为对照。与假手术对照组相比，CLP诱导的脓毒症发生6小时后心脏功能显著下降。相比之下，注射GP可预防CLP诱导的心脏功能障碍。巨噬细胞移动抑制因子（MIF）被认为是脓毒症休克期间心肌细胞凋亡和心脏功能障碍的主要因素。与假手术对照组相比，CLP使心肌MIF表达增加88.3%（P<0.05），使心肌细胞凋亡增加7.8倍（P<0.05）。然而，与未治疗的CLP小鼠相比，注射GP可预防CLP诱导的MIF表达增加，并使心肌细胞凋亡减少51.2%（P<0.05）。GP还可预防脓毒症导致的脓毒症小鼠心肌中磷酸化Akt、磷酸化糖原合成酶激酶-3β（phospho-GSK-3beta）和Bcl-2水平降低。这些数据表明，GP治疗可减轻暴发性脓毒症中的心血管功能障碍。注射GP还可激活磷酸肌醇3激酶/蛋白激酶B（PI3K/Akt）信号通路，降低心肌MIF表达，并减少心肌细胞凋亡。
