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J. Biol. Chem., Vol. 282, Issue 7, 4585-4600, February 16, 2007

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Heat Shock Protein 60 or 70 Activates Nitric-oxide Synthase (NOS) I- and Inhibits NOS II-associated Signaling and Depresses the Mitochondrial Apoptotic Cascade during Brain Stem Death^*

Julie Y. H. Chan, Hsiao-Lei Cheng, Jimmy L. J. Chou, Faith C. H. Li, Kuang-Yu Dai, Samuel H. H. Chan^¶1, and Alice Y. W. Chang^¶2

From the Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81346, the Center for Neuroscience, National Sun Yat-sen University, Kaohsiung 80424, and the ^¶Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 70101, Taiwan

The cellular and molecular basis of brain stem death remains an enigma. As the origin of a "life-and-death" signal that reflects the progression toward brain stem death, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this phenomenon. Here, we evaluated the hypothesis that heat shock proteins (HSPs) play a neuroprotective role in the RVLM during brain stem death and delineated the underlying mechanisms, using a clinically relevant animal model that employed the organophosphate pesticide mevinphos (Mev) as the experimental insult. In Sprague-Dawley rats, proteomic, Western blot, and real-time PCR analyses demonstrated that Mev induced de novo synthesis of HSP60 or HSP70 in the RVLM without affecting HSP90 level. Loss-of-function manipulations of HSP60 or HSP70 in the RVLM using anti-serum or antisense oligonucleotide potentiated Mev-elicited cardiovascular depression alongside reduced nitric-oxide synthase (NOS) I/protein kinase G signaling, enhanced NOS II/peroxynitrite cascade, intensified nucleosomal DNA fragmentation, elevated cytoplasmic histone-associated DNA fragments or activated caspase-3, and augmented the cytochrome c/caspase-3 cascade of apoptotic signaling in the RVLM. Co-immunoprecipitation experiments further revealed a progressive increase in the complex formed between HSP60 and mitochondrial or cytosolic Bax or mitochondrial Bcl-2 during Mev intoxication, alongside a dissociation of the cytosolic HSP60-Bcl-2 complex. We conclude that HSP60 and HSP70 confer neuroprotection against Mev intoxication by ameliorating cardiovascular depression via an anti-apoptotic action in the RVLM. The possible underlying intracellular processes include enhancing NOS I/protein kinase G signaling and inhibiting the NOS II/peroxynitrite cascade. In addition, HSP60 exerts its effects against apoptosis by blunting Mev-induced activation of the Bax/cytochrome c/caspase-3 cascade.

Received for publication, April 10, 2006 , and in revised form, November 27, 2006.

^* This work was supported in part by the National Science Council (Research Grants NSC-95-2752-B-075B-001-PAE to J. Y. H. C. and NSC-95-2752-B-110-001-PAE and NSC-95-2752-B-110-002-PAE to A. Y. W. C. and S. H. H. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and Table S1.

¹ National Chair Professor of Neuroscience appointed by the Ministry of Education and Sun Yat-sen Research Chair Professor appointed by National Sun Yat-sen University, Taiwan, Republic of China.

² To whom correspondence should be addressed: Center for Neuroscience, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, Republic of China. Tel.: 886-7-525-5800; Fax: 886-7-525-5801; E-mail: achang{at}mail.nsysu.edu.tw.

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