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INTEGRATIVE |
1 Center for Neuroscience
4 Institute of Biomedical Science, National Sun Yat-sen University, Kaohsiung, Taiwan, Republic of China
2 Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, Taiwan, Republic of China
3 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China
The rostral ventrolateral medulla (RVLM) is the origin of a ‘life-and-death’ signal that reflects central cardiovascular regulatory failure during brain stem death. Using an experimental endotoxaemia model, we evaluated the hypothesis that the 60 kDa heat shock protein 60 (HSP60) reduces cardiovascular fatality during brain stem death via an anti-apoptotic action in the RVLM. In Sprague-Dawley rats maintained under propofol anaesthesia, proteomic or Western blot analysis revealed a progressive augmentation of HSP60 expression in the RVLM after intravenous administration of Escherichia coli lipopolysaccharide (30 mg kg–1). Pretreatment with a microinjection of actinomycin D or cycloheximide into bilateral RVLM significantly blunted this HSP60 increase, whereas real-time PCR showed progressive augmentation of hsp60 mRNA. Intriguingly, superimposed on the augmented expression was a progressive decline in mitochondrial, or elevation in cytosolic, HSP60 in ventrolateral medulla. Loss-of-function manipulations in the RVLM using anti-HSP60 antiserum or antisense hsp60 oligonucleotide exacerbated mortality by potentiating the cardiovascular depression during experimental endotoxaemia, alongside intensified nucleosomal DNA fragmentation, elevated cytoplasmic histone-associated DNA fragments or augmented cytochromec–caspase-3 cascade of apoptotic signalling in the RVLM. Immunoprecipitation coupled with immunoblot analysis further revealed a progressive increase in the complex formed between HSP60 and mitochondrial or cytosolic Bax or mitochondrial Bcl-2 during endotoxaemia, alongside a dissociation of the cytosolic HSP60–Bcl-2 complex. We conclude that HSP60 redistributed from mitochondrion to cytosol in the RVLM confers neuroprotection against fatal cardiovascular depression during endotoxaemia via reduced activation of the cytochrome c–caspase-3 cascade of apoptotic signalling through enhanced interactions with mitochondrial or cytosolic Bax or Bcl-2.
(Received 3 April 2006;
accepted after revision 28 April 2006;
first published online 4 May 2006)
Corresponding author S. H. H. Chan: Center for Neuroscience, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, Republic of China. Email: schan{at}mail.nsysu.edu.tw
This article has been cited by other articles:
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  D. Chandra, G. Choy, and D. G. Tang Cytosolic Accumulation of HSP60 during Apoptosis with or without Apparent Mitochondrial Release: EVIDENCE THAT ITS PRO-APOPTOTIC OR PRO-SURVIVAL FUNCTIONS INVOLVE DIFFERENTIAL INTERACTIONS WITH CASPASE-3 J. Biol. Chem., October 26, 2007; 282(43): 31289 - 31301. [Abstract] [Full Text] [PDF]
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 J. Y. H. Chan, C. H. Y. Wu, C.-Y. Tsai, H.-L. Cheng, K.-Y. Dai, S. H. H. Chan, and A. Y. W. Chang Transcriptional up-regulation of nitric oxide synthase II by nuclear factor-{kappa}B at rostral ventrolateral medulla in a rat mevinphos intoxication model of brain stem death J. Physiol., June 15, 2007; 581(3): 1293 - 1307. [Abstract] [Full Text] [PDF]
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 J. Y. H. Chan, A. Y. W. Chang, L.-L. Wang, C.-C. Ou, and S. H. H. Chan Protein Kinase C-Dependent Mitochondrial Translocation of Proapoptotic Protein Bax on Activation of Inducible Nitric-Oxide Synthase in Rostral Ventrolateral Medulla Mediates Cardiovascular Depression during Experimental Endotoxemia Mol. Pharmacol., April 1, 2007; 71(4): 1129 - 1139. [Abstract] [Full Text] [PDF]
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