Effects of Fas Ligand on Ischemia/Reperfusion Injury of Cardiomyocytes
We tested the hypothesis that shedding of membrane FasL is a mechanism for downregulating FasL/Fas signaling and both membrane and soluble FasL are involved in cardiomyocyte hypoxia/reoxygenation (H/R) injury. We examined the relative importance of mitochondrial damage and direct cleavage of the executioner caspases by activated initiator caspase-8 in the propagation of FasL/Fas signaling activated by either recombinant membrane FasL or H/R. In neonatal rat cardiomyocytes maintained under normal culture conditions, recombinant human soluble FasL increased caspase-3 activation by twofold but did not reduce cell viability. In contrast, infection with a recombinant adenoviral vector expressing the non-cleavable human FasL (Ad2/nchFasL) resulted in cardio-myocyte death that was attenuated by soluble FasL. H/R increased the mRNA levels of both FasL and Fas and activated caspases-8, -9 and -3, indicating the activation of FasL/Fas signaling. Z-IETD-fmk and Z-LEHD-fmk, selective inhibitors for caspases-8 and-9, respectively, abolished caspase-3 activation induced by Ad2/nchFasL or H/R. Z-IETD-fmk also significantly reduced Ad2/nchFasL-or H/R-induced cardiomyocyte death. H/R potentiated membrane FasL-induced cell death. Shedding of membrane FasL downregulates FasL/Fas signaling in cardiomyo-cytes and both membrane and soluble FasL contribute to H/R injury.Activation of FasL/Fas signaling by either recombinant membrane FasL under normal culture conditions or H/R causes cardiomyocyte death mainly through the mitochondrial damage/caspase -9 activation pathway.
Dong JIANG Jin-Feng GE Shi-Ying ZHENG Jun ZHAO
Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Suzhou University , Suzhou 215006, Jiangsu Province, China
国际会议
成都
英文
1-6
2010-06-18（万方平台首次上网日期，不代表论文的发表时间）