Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes: Involvement of the sphingolipid signaling cascade in cardiac cell death

Kevin A. Krown, M. Trevor Page, Cuong Nguyen, Dietmar Zechner, Veronica Gutierrez, Kevyn L. Comstock, Christopher C. Glembotski, Penelope J.E. Quintana, Roger A. Sabbadini

Research output: Contribution to journalArticlepeer-review

685 Scopus citations

Abstract

In the present study, it was shown that physiologically relevant levels of the proinflammatory cytokine TNFα induced apoptosis in rat cardiomyocytes in vitro, as quantified by single cell microgel electrophoresis of nuclei ("cardiac comets") as well as by morphological and biochemical criteria. It was also shown that TNFα stimulated production of the endogenous second messenger, sphingosine, suggesting sphingolipid involvement in TNFα-mediated cardiomyocyte apoptosis. Consistent with this hypothesis, sphingosine strongly induced cardiomyocyte apoptosis. The ability of the appropriate stimulus to drive cardiomyocytes into apoptosis indicated that these cells were primed for apoptosis and were susceptible to clinically relevant apoptotic triggers, such as TNFα. These findings suggest that the elevated TNFa levels seen in a variety of clinical conditions, including sepsis and ischemic myocardial disorders, may contribute to TNFα-induced cardiac cell death. Cardiomyocyte apoptosis is also discussed in terms of its potential beneficial role in limiting the area of cardiac cell involvement as a consequence of myocardial infarction, viral infection, and primary cardiac tumors.

Original languageEnglish (US)
Pages (from-to)2854-2865
Number of pages12
JournalJournal of Clinical Investigation
Volume98
Issue number12
DOIs
StatePublished - Dec 15 1996
Externally publishedYes

Keywords

  • Apoptosis
  • Cardiomyocytes
  • Comet assay
  • Sphingosine
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Medicine(all)

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