ALTERNATIVE SPLICING OF THE PRIMARY FAS TRANSCRIPT GENERATING SOLUBLEFAS ANTAGONISTS IS SUPPRESSED IN THE FAILING HUMAN VENTRICULAR MYOCARDIUM

Apoptosis of cardiomyocytes has been proposed as a facto ar contributi ng to severe heart failure, Since the trigger for apoptotic cellular s uicide in nonischemic myocardium is unknown, we analyzed in human myoc ardial tissue the expression of the apoptosis-inducing membrane recept or Fas/APO-1 and of its alternatively spliced soluble isoforms which a ntagonize Fas by binding of the Fas ligand. Using reverse transcriptio n polymerase chain reaction (RT-PCR) we found mRNA for Fas and 5 isofo rms in nonfailing left ventricles, whereas Fas and only one isoform (F asEXo6DeI) were detectable in failing left ventricles, Standard calibr ated, competitive BT-PCR revealed no significant increase of Fas mRNA in failing compared to nonfailing ventricles. However, title mRNA for FasExo6Del, expressed nearly on the same level as Fas in nonfailing ve ntricles, 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 ire end-stage heart failu re. (C) 1997 Academic Press.