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In the Rostral Ventrolateral Medulla, the 70-kDa Heat Shock Protein (HSP70), but Not HSP90, Confers Neuroprotection against Fatal Endotoxemia via Augmentation of Nitric-Oxide Synthase I (NOS I)/Protein Kinase G Signaling Pathway and Inhibition of NOS II/Peroxynitrite Cascade

Center for Neuroscience and Department of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan, Republic of China (F.C.H.L., S.H.H.C., A.Y.W.C.); and Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China (J.Y.H.C.)

Heat shock proteins (HSPs) represent a group of highly conserved intracellular proteins that participate in protective adaptation against cellular stress. We evaluated the neuroprotective role of the 70-kDa HSP (HSP70) and the 90-kDa HSP (HSP90) at the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic vasomotor tone, during fatal endotoxemia. In Sprague-Dawley rats maintained under propofol anesthesia, Escherichia coli lipopolysaccharide (30 mg/kg, i.v.) induced a decrease (phase I), followed by an increase (phase II; "pro-life" phase) and a secondary decrease (phase III; "pro-death" phase) in the power density of the vasomotor component of systemic arterial pressure spectrum, along with progressive hypotension or bradycardia. Proteomic and Western blot analyses revealed that whereas HSP70 expression in the RVLM was significantly augmented during phases I and II and returned to baseline during phase III endotoxemia, HSP90 protein expression remained constant. The increase in HSP70 level was significantly blunted on pretreatment with microinjection of the transcription inhibitor actinomycin D or protein synthesis inhibitor cycloheximide into the bilateral RVLM. Functional blockade of HSP70 in the RVLM by an anti-HSP70 antiserum or prevention of synthesis by an antisense hsp70 oligonucleotide exacerbated mortality or potentiated the cardiovascular depression during experimental endotoxemia, alongside significantly reduced nitric-oxide synthase (NOS) I or protein kinase G (PKG) level or augmented NOS II or peroxynitrite level in the RVLM. We conclude that whereas HSP90 is ineffective, de novo synthesis of HSP70 in the RVLM may confer neuroprotection during fatal endotoxemia by preventing cardiovascular depression via enhancing the sympathoexcitatory NOS I/PKG signaling pathway and inhibiting the sympathoinhibitory NOS II/peroxynitrite cascade in the RVLM.

Address correspondence to: Dr. Alice Y. W. Chang, Center for Neuroscience, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, Republic of China. E-mail: achang{at}mail.nsysu.edu.tw

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