Abstract 379: Fas Signal Inhibition With a soluble Fas Gene Therapy Mitigates Doxorubicin-induced Cardiac Dysfunction Through Anti-inflammatory, but Not Anti-apoptotic, Action
Fas (CD95/APO-1) signaling is known to not only mediate apoptosis but also evoke inflammatory response. In the present study, we investigated pathophysiological roles for Fas signaling in doxorubicin (DOX)-induced cardiomyopathy. DOX-induced cardiomyopathy was generated in mice by a single intraperitoneal injection of DOX (15mg/kg). The mice simultaneously received an injection of adenovirus encoding mouse soluble Fas (sFas) gene (Ad.CAG-sFas, 1 × 109 pfu/mouse), an inhibitor of Fas/Fas ligand interaction, into hindlimb muscles. Two weeks later, left ventricular (LV) dilatation and dysfunction were apparent in the LacZ-treated control group, which were significantly mitigated in the sFas-treated group. The incidence of cardiac cells positive for in situ nick-end labeling (TUNEL) was very rare and similar between the LacZ- and sFas-treated groups, electron microscopic examination failed in detecting apoptotic cardiomyocytes, and neither activated caspase-3 nor caspase-8 was detectable in each group; these suggest an insignificant role of apoptosis in the present model. Instead, Dox induced significant CD45-positive leukocyte infiltration, fibrosis, and oxidative damage (assessed by 8-hydroxy-2′-deoxyguanosine) in myocardium, all of which were markedly attenuated by the sFas treatment. Moreover, the Fas treatment suppressed DOX-induced cyclooxygenase-2 expression and activation of c-Jun N terminal kinase (JNK) and IkB. In conclusion, inhibition of Fas/Fas ligand interaction by the sFas gene therapy mitigated left ventricular dilatation and dysfunction of DOX-induced cardiomyopathy, and such beneficial effects were likely to be attributable to the actions against Fas signaling-mediated inflammation, but not to the anti-apoptotic action.