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(Circulation. 2004;110:3560-3566.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Heat Shock Protein 70 Confers Cardiovascular Protection During Endotoxemia via Inhibition of Nuclear Factor-B Activation and Inducible Nitric Oxide Synthase Expression in the Rostral Ventrolateral Medulla

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

Correspondence to Samuel H.H. Chan, PhD, Center for Neuroscience, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, Republic of China. E-mail schan{at}mail.nsysu.edu.tw

Received May 15, 2004; revision received July 22, 2004; accepted July 27, 2004.

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-B (NF-B) 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-B activation.

Methods and Results— Adult male Sprague-Dawley rats subjected to a brief hyperthermic heat shock (42°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-B were detected during endotoxemia. Heat shock preconditioning significantly decreased DNA binding activity of NF-B, which was reversed by microinjection of an hsp70 antisense oligonucleotide bilaterally into the RVLM. Heat shock preconditioning also blocked inhibitory B (IB) kinase activity or degradation of IB 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-B activation in cellular processes that include prevention of IB kinase activation and inhibition of IB degradation.

Key Words: blood pressure • cardiovascular diseases • nitric oxide synthase • shock • signal transduction

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