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Cellular FLIP is expressed in cardiomyocytes and down-regulated in TUNEL-positive grafted cardiac tissues
T Imanishi1, C E Murry, H Reinecke
1Division of Cardiology, Department of Medicine, Wakayama Medical College, 811-1, Kimiidera, Wakayama 641-8510, Wakayama City, Japan. imanishi@wakayama.hosp.go.jp
Objective:
c-FLIP is a natural homologue of caspase 8, and may antagonize activation of death pathways mediated by FADD. c-FLIP is highly expressed in the heart, and a recent report suggests that c-FLIP may protect against certain types of myocyte death. The present study was designed to define the expression patterns of c-FLIP in the heart.
Methods:
The expression pattern of c-FLIP in end-stage human hearts, and rat cardiomyocyte grafting models was analyzed by in situ hybridization, immunohistochemistry and TUNEL assay. In addition, to determine whether Fas-dependent pathway is active in cardiomyocytes in vitro, we examined whether activated monocytes can kill neonatal cardiomyocytes in a co-culture system.
Results:
c-FLIP mRNA and protein were abundantly expressed in normal cardiomyocytes from failing human heart. In animal models, c-FLIP protein was absent in TUNEL-positive grafted cardiomyocytes. Double staining demonstrated that c-FLIP-positive cells rarely had fragmented DNA, while TUNEL-positive cells rarely contained c-FLIP. Finally, activated monocytes induced death of neonatal rat cardiomyocytes via the Fas/FasL system.
Conclusions:
Loss of c-FLIP expression correlates with cardiomyocyte cell death. We hypothesize that diminished c-FLIP expression may predispose cardiomyocytes to apoptotic death.
Insights
Loss of cellular FLICE-inhibitory protein (c-FLIP) expression correlates with cardiomyocyte death. Diminished c-FLIP may increase susceptibility to apoptotic death in heart cells.
Area of Science:
- Cardiovascular Biology
- Cell Death Pathways
- Molecular Cardiology
Background:
- Cellular FLICE-inhibitory protein (c-FLIP) is a homologue of caspase 8 and may inhibit FADD-mediated death pathways.
- High c-FLIP expression in the heart suggests a protective role against myocyte death.
Purpose of the Study:
- To define the expression patterns of c-FLIP in the heart.
- To investigate the correlation between c-FLIP expression and cardiomyocyte death.
Main Methods:
- In situ hybridization and immunohistochemistry analyzed c-FLIP expression in human hearts and rat cardiomyocyte grafts.
- TUNEL assay identified apoptotic cells.
- Co-culture systems assessed monocyte-induced cardiomyocyte death via the Fas/FasL pathway.
Main Results:
- c-FLIP mRNA and protein were abundant in normal cardiomyocytes from failing human hearts.
- c-FLIP protein was absent in TUNEL-positive grafted cardiomyocytes, indicating loss of expression during cell death.
- Activated monocytes induced neonatal rat cardiomyocyte death through the Fas/FasL system.
Conclusions:
- Loss of c-FLIP expression is associated with cardiomyocyte cell death.
- Reduced c-FLIP expression may predispose cardiomyocytes to apoptotic death.
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