Submitted on November 30, 2005
Accepted on May 5, 2006
Glucan Phosphate Attenuates Cardiac Dysfunction and Inhibits Cardiac MIF Expression and Apoptosis in Septic Mice
Tuanzhu Ha1, Fang Hua1, Daniel Grant1, Yeling Xia1, Jing Ma1, Xiang Gao2, Jim Kelley3, David L Williams1, John Kalbfleisch4, I William Browder1, and Chuanfu Li1*
1 Surgery, East Tennessee State University, Johnson City, Tennessee, United States
2 Animal Model Research Center, Nanjing University, Nnajing, Jiangsu, China
3 Internal Medicine, East Tennessee State University, Johnson City, Tennessee, United States
4 Section of Medical Education, East Tennessee State University, Nanjing, Tennessee, United States
* To whom correspondence should be addressed. E-mail: li{at}etsu.edu.
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 hr before induction of CLP. Sham surgical operated mice served as control. Cardiac function was significantly decreased six hrs 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-3
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 PI3K/Akt pathway, decreases myocardial MIF expression and reduces cardiomyocyte apoptosis.
