Alternative Splicing of the Primary Fas Transcript Generating Soluble Fas Antagonists Is Suppressed in the Failing Human Ventricular Myocardium

Abstract

Apoptosis of cardiomyocytes has been proposed as a factor contributing to severe heart failure. Since the trigger for apoptotic cellular suicide in nonischemic myocardium is unknown, we analyzed in human myocardial tissue the expression of the apoptosis-inducing membrane receptor Fas/APO-1 and of its alternatively spliced soluble isoforms which antagonize Fas by binding of the Fas ligand. Using reverse transcription polymerase chain reaction (RT-PCR) we found mRNA for Fas and 5 isoforms in nonfailing left ventricles, whereas Fas and only one isoform (FasExo6Del) were detectable in failing left ventricles. Standard calibrated, competitive RT-PCR revealed no significant increase of Fas mRNA in failing compared to nonfailing ventricles. However, the mRNA for FasExo6Del, expressed nearly on the same level as Fas in nonfailing ventricles, was decreased about 3-fold in failing ventricles. We propose that this altered expression of the Fas system renders the myocardium more susceptible for Fas-mediated apoptosis in end-stage heart failure.