Proapoptotic effects of caspase-1/interleukin-converting enzyme dominate in myocardial ischemia

Faisal M. Syed, Harvey S. Hahn, Amy Odley, Yiru Guo, Jesus G. Vallejo, Roy A. Lynch, Douglas L. Mann, Roberto Bolli, Gerald W. Dorn

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Caspase-1/interleukin-converting enzyme (ICE) is a cysteine protease traditionally considered to have importance as an inflammatory mediator, but not as an apoptotic effector. Because of the dual functions of this caspase, the pathophysiological impact of its reported upregulation in hypertrophy and heart failure is not known. Here, the consequences of increased myocardial expression of procaspase-1 were examined on the normal and ischemically injured heart. In unstressed mouse hearts with a 30-fold increase in procaspase-1 content, unprocessed procaspase-1 was well tolerated, without detectable pathology. Cardiomyocyte processing and activation of caspase-1 and caspase-3 occurred after administration of endotoxin or with transient myocardial ischemia. In post-ischemic hearts, procaspase-1 overexpression was associated with strikingly increased cardiac myocyte apoptosis in the peri- and noninfarct regions and with 50% larger myocardial infarctions. Tissue culture studies revealed that procaspase-1 processing/activation is stimulated by hypoxia, and that caspase-1 acts in synergy with hypoxia to stimulate caspase-3 mediated apoptosis without activating upstream caspases. These data demonstrate that the proapoptotic effects of caspase-1 can significantly impact the myocardial response to ischemia and suggest that conditions in which procaspase-1 in the heart is increased may predispose to apoptotic myocardial injury under conditions of physiological stress.

Original languageEnglish
Pages (from-to)1103-1109
Number of pages7
JournalCirculation research
Volume96
Issue number10
DOIs
StatePublished - May 27 2005

Keywords

  • Apoptosis
  • Caspase
  • Myocardial infarction
  • Myocardial ischemia

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