© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Cellular FLIP is expressed in cardiomyocytes and down-regulated in TUNEL-positive grafted cardiac tissues
aDivision of Cardiology, Department of Medicine, Wakayama Medical College, 811-1, Kimiidera, Wakayama City, Wakayama 641-8510, Japan
bDepartment of Pathology, University of Washington, Seattle, WA, USA
cDepartment of Medicine (Infectious Diseases), University of Washington, Seattle, WA, USA
dDepartment of Medicine (Cardiology), University of Washington, Seattle, WA, USA
eDepartment of Molecular Biotechnology, University of Washington, Seattle, WA, USA
fDepartment of Cardiology, University of Maastricht, Masstricht, The Netherlands
* Corresponding author. Tel.: +81-73-441-0621; fax: +81-73-446-0631 imanishi{at}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.
KEYWORDS Apoptosis; Cardiomyopathy; Heart failure; Histo(patho)logy; Myocytes
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