The role of the Hsp90/Akt pathway in myocardial calpain-induced caspase-3 activation and apoptosis during sepsis

BMC Cardiovascular Disorders

Wei Hua¹  Shu Zhang¹  Xiushan Wu⁴  Xianmin Meng²  Rongjian Jiang³  Rong Luo⁴  Xiaoping Li³ 

[1] Cardiac Arrhythmia Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China;Central Laboratory, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, People’s Republic of China;Department of Cardiology, Sichuan Provincial People’s Hospital, Chengdu 610072, P.R. China;The Center of Heart Development, Key Lab of MOE for Development Biology and Protein Chemistry, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, PR China

关键词: Sepsis;    Apoptosis;    Caspase-3 activation;    Hsp90/Akt;    Calpain;   

Others  :  857866
DOI  :  10.1186/1471-2261-13-8

 received in 2012-10-19, accepted in 2013-02-18,  发布年份 2013

【 摘 要 】

Background

Recent studies have demonstrated that myocardial calpain triggers caspase-3 activation and myocardial apoptosis in models of sepsis, whereas the inhibition of calpain activity down-regulates myocardial caspase-3 activation and apoptosis. However, the mechanism underlying this pathological process is unclear. Therefore, in this study, our aim was to explore whether the Hsp90/Akt signaling pathway plays a role in the induction of myocardial calpain activity, caspase-3 activation and apoptosis in the septic mice.

Methods

Adult male C57 mice were injected with lipopolysaccharide (LPS, 4 mg/kg, i.p.) to induce sepsis. Next, myocardial caspase-3 activity and the levels of Hsp90/p-Akt (phospho-Akt) proteins were detected, and apoptotic cells were assessed by performing the TUNEL assay.

Results

In the septic mice, there was an increase in myocardial calpain and caspase-3 activity in addition to an increase in the number of apoptotic cells; however, there was a time-dependent decrease in myocardial Hsp90/p-Akt protein levels. The administration of calpain inhibitors (calpain inhibitor-Ш or PD150606) prevented the LPS-induced degradation of myocardial Hsp90/p-Akt protein and its expression in cardiomyocytes in addition to inhibiting myocardial caspase-3 activation and apoptosis. The inhibition of Hsp90 by pretreatment with 17-AAG induced p-Akt degradation, and the inhibition of Akt activity by pretreatment with wortmannin resulted in caspase-3 activation in wildtype C57 murine heart tissues.

Conclusions

Myocardial calpain induces myocardial caspase-3 activation and apoptosis in septic mice via the activation of the Hsp90/Akt pathway.

【 授权许可】

   
2013 Li et al; licensee BioMed Central Ltd.

【 图 表 】

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