The cardiac Fas (APO-1/CD95) receptor/Fas ligand system -: Relation to diastolic wall stress in volume-overload hypertrophy in vivo and activation of the transcription factor AP-1 in cardiac myocytes

Background-Fas (APO-1/CD95) is a transmembrane receptor belonging to the tumor necrosis factor receptor superfamily, Cross-linking of Fas by Fas ligand (FasL), a turner necrosis factor-alpha-related cytokine, promotes apoptosis and/or transcription factor activation in a highly cell-type-specific manner. The biological consequences of Fas activation in cardiomyocytes and the regulation of Fas and Fast abundance in the myocardium in vivo remain largely unknown. Methods and Results-As shown by immunohistochemistry, Fas was expressed on the sarcolemma of cardiomyocytes in left ventricular tissue sections. Moreover, Fast was constitutively expressed in the myocardium and in isolated cardiomyocytes, as revealed by reverse transcription polymerase chain reaction and Western blotting. Left ventricular abundance of Fas but not Fast was upregulated in a rat model of compensated volume-overload hypertrophy and was closely related to diastolic but not systolic wall stress as determined by MRI, Cardiomyocyte apoptosis was not enhanced in volume-overload hypertrophy despite the increased expression of Fas and the presence of Fast in the myocardium. Moreover, injection of mice with an agonistic anti-Fas antibody promoted hepatocyte but not cardiomyocyte apoptosis in vivo. Stimulation of isolated cardiomyocytes with recombinant Fast promoted an activation of the transcription factor AP-1 as shown by electrophoretic mobility shift assays but did not induce cell death. Conclusions-Fas and Fast are constitutively expressed in the myocardium and in cardiomyocytes, Myocardial expression of Fas is closely related to diastolic loading conditions in vivo. Signaling pathways emanating from I;as are coupled to an activation of the transcription factor AP-1 in cardiomyocytes.