title: The role of the Hsp90/Akt pathway in myocardial calpain-induced caspase-3 activation and apoptosis during sepsis.
abstract: 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.
authors: 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, PR China. lixiaoping0119@163.com
authors: Xiaoping
authors: X
authors: Li
authors: Rong
authors: R
authors: Luo
authors: Rongjian
authors: R
authors: Jiang
authors: Xianmin
authors: X
authors: Meng
authors: Xiushan
authors: X
authors: Wu
authors: Shu
authors: S
authors: Zhang
authors: Wei
authors: W
authors: Hua
mesh_terms: D000179:Acrylates / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D016227:Benzoquinones / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018805:Sepsis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000077191:Wortmannin
chemical_list: D000179:Acrylates; D000730:Androstadienes; D016227:Benzoquinones; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; C100442:PD 150606; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C112765:tanespimycin; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D002154:Calpain; C505409:Casp3 protein, mouse; D053148:Caspase 3; C058076:calpain inhibitor III; D000077191:Wortmannin