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J. Biol. Chem., Vol. 280, Issue 52, 42619-42626, December 30, 2005

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Human Serum from Patients with Septic Shock Activates Transcription Factors STAT1, IRF1, and NF-B and Induces Apoptosis in Human Cardiac Myocytes^*

Aseem Kumar1, Anand Kumar¶, Paul Michael, Danielle Brabant, Amadeo M. Parissenti, Chilakamarti V. Ramana||, Xiulong Xu**, and Joseph E. Parrillo¶

From the Department of Chemistry and Biochemistry and the Biomolecular Sciences Programme, Laurentian University, Sudbury, Ontario P3E 2C6, Canada, the Section of Critical Care Medicine, University of Manitoba, Winnipeg, Manitoba R3A 1R9, Canada, the ^||Department of Medicine, Yale University, New Haven, Connecticut 06516, the ^**Department of General Surgery, Rush-Presbyterian-St. Luke's Medical Center and University, Chicago, Illinois 60612, and the ^¶Division of Cardiovascular Disease and Critical Care Medicine, Cooper University Hospital, Robert Wood Johnson Medical School, Camden, New Jersey 08103

Proinflammatory cytokines have been linked to depression of myocardial contractility in vivo in patients with acute septic shock and in vitro models employing isolated myocytes exposed to serum from such patients. The key pathways involved in mediating this septic organ dysfunction (cell adhesion molecule expression, inducible nitric-oxide synthase induction, and apoptosis) are known to be regulated by transcription factors STAT1, IRF1, and NF-B. Utilizing a model that mimics human disease, we have demonstrated activation of the transcription factors STAT1, IRF1, and NF-B in human fetal myocytes exposed to human septic serum. Both reporter and electrophoretic mobility shift assays demonstrated a 5–19-fold increase in activation of transcription factors STAT1, IRF1, and NF-B in response to incubation with human septic serum. The addition of human septic serum to human fetal myocytes induced apoptosis in human fetal myocytes and activation of the mitogen-activated protein kinase c-Jun NH -terminal kinase and caspase 1 as measured by Western blot. These data suggest that transcription factor activation and early myocyte apoptosis play a mechanistic role in septic myocardial depression and sepsis-induced organ dysfunction.

Received for publication, August 1, 2005 , and in revised form, October 12, 2005.

^* 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.

¹ To whom correspondence should be addressed: Dept. of Chemistry and Biochemistry, Biomolecular Sciences Programme, Laurentian University, 935 Ramsey Lake Rd., Sudbury, Ontario P3E 2C6, Canada. Tel.: 705-675-1151 (ext. 2103); Fax: 705-675-4844; E-mail: akumar{at}laurentian.ca.

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