Cardiac-Specific Expression of Heat Shock Protein 27 Attenuated Endotoxin-Induced Cardiac Dysfunction and Mortality in Mice Through a PI3K/Akt-Dependent Mechanism
Cardiac dysfunction is a major consequence of septic shock and may be responsible for the high mortality of sepsis. We have reported that transgenic mice with cardiac-specific overexpression of heat shock protein 27 (Hsp27 Tg) exhibited the protection against doxorubicin-induced cardiac dysfunction. We hypothesized that overexpression of Hsp27 will attenuate cardiac dysfunction during endotoxemia. Hsp27 Tg and age-matched wild-type (WT) mice were injected with LPS. Cardiac function was evaluated by echocardiography, survival rate was carefully monitored, and activities of signaling pathways were determined by immunoblot. LPS administration significantly decreased cardiac function in WT mice. In Hsp27 Tg mice, LPS-induced cardiac dysfunction was significantly attenuated as evidenced by increased ejection fraction (27.3%) and fractional shortening (37.1%), respectively, compared with LPS-treated WT mice. Heat shock protein 27 Tg mice were more resistant to LPS-induced mortality than WT. The levels of phospho-Akt and phospho-glycogen synthase kinase 3β (phospho-GSK-3β) in the myocardium were significantly increased in Hsp27 Tg mice compared with WT after LPS administration. Nuclear factor κB-binding activity was significantly decreased in Hsp27 Tg mice compared with WT mice after LPS challenge. Similar results were observed in in vitro studies using Hsp27-transfected rat cardiomyoblasts. Importantly, phosphoinositide 3-kinase inhibition abolished the protective effect of Hsp27 in LPS-induced cardiac dysfunction and mortality of endotoxemia. Our results suggest that Hsp27 plays an important role in attenuation of cardiac dysfunction and mortality in endotoxemia and that the mechanisms of the protection may involve activation of the PI3K/Akt signaling pathway.
You, Wenjun; Min, Xiaoyan; Zhang, Xiaojin; Qian, Bo; Pang, Sisi; Ding, Zhengnian; Li, Chuanfu; Gao, Xiang; Di, Ruomin; Cheng, Yunlin; and Liu, Li. 2009. Cardiac-Specific Expression of Heat Shock Protein 27 Attenuated Endotoxin-Induced Cardiac Dysfunction and Mortality in Mice Through a PI3K/Akt-Dependent Mechanism. Shock. Vol.32(1). 108-117. https://doi.org/10.1097/SHK.0b013e318199165d PMID: 19106822 ISSN: 1073-2322