Heat shock protein 70 confers cardiovascular protection during endotoxemia via inhibition of nuclear factor-kappaB activation and inducible nitric oxide synthase expression in the rostral ventrolateral medulla.
BACKGROUND
Overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons are located, plays a pivotal role in the manifestation of fatal cardiovascular depression during endotoxemia. The iNOS gene is regulated transcriptionally by nuclear factor-kappaB (NF-kappaB) activation. The present study tested the hypothesis that heat shock protein 70 (HSP70) may confer protection against sepsis-induced circulatory fatality via inhibition of iNOS gene expression in the RVLM through prevention of NF-kappaB activation.


RESULTS
Adult male Sprague-Dawley rats subjected to a brief hyperthermic heat shock (42 degrees C for 15 minutes) exhibited significant upregulation of HSP70 in the RVLM. Brief heat shock preconditioning also significantly suppressed iNOS mRNA or protein surge and alleviated hypotension, bradycardia, and reduction in neurogenic sympathetic vasomotor activity manifested during experimental endotoxemia induced by intravenous administration of Escherichia coli lipopolysaccharide. An increase in DNA binding activity and nuclear translocation of transcription factor NF-kappaB were detected during endotoxemia. Heat shock preconditioning significantly decreased DNA binding activity of NF-kappaB, which was reversed by microinjection of an hsp70 antisense oligonucleotide bilaterally into the RVLM. Heat shock preconditioning also blocked inhibitory kappaB (IkappaB) kinase activity or degradation of IkappaB in the RVLM during endotoxemia.


CONCLUSIONS
We conclude that HSP70 confers protection against sepsis-related circulatory fatality via inhibition of iNOS gene expression in the RVLM through prevention of NF-kappaB activation in cellular processes that include prevention of IkappaB kinase activation and inhibition of IkappaBalpha degradation.
Chan
Julie Y H
JY
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Republic of China.
Ou
Chen-Chun
CC
Wang
Ling-Lin
LL
Chan
Samuel H H
SH
D000818:Animals; D001794:Blood Pressure; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000494:pharmacology; D019446:Endotoxemia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D004789:Enzyme Activation; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006339:Heart Rate; D018869:Heat-Shock Response; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D008526:Medulla Oblongata / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000503:physiopathology* / Q000517:prevention & control; D015854:Up-Regulation
D018840:HSP70 Heat-Shock Proteins; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D004247:DNA; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase