Abstract
Fas ligand (FasL) is a member of tumor necrosis factor family that induces apoptosis in target cells that express Fas. The function of FasL during inflammation remains controversial. In this study, we examined the role of vascular endothelial FasL during acute myocardial ischemia-reperfusion that is closely associated with inflammation. Transgenic mouse lines were established that overexpress human FasL on endothelium under the control of the vascular endothelial cadherin promoter. Expression of FasL transgene was detected at both mRNA and protein levels, and functional transgene-encoded FasL protein was specifically expressed on the surface of vascular endothelial cells. Transgenic mice developed normally and had normal hearts. When subjected to 30 min of myocardial ischemia and 72 h of reperfusion, myocardial infarct size was reduced by 42% in the transgenic mice compared with nontransgenic littermates (p < 0.05). Moreover, hemodynamic data demonstrated that transgenic hearts performed better following ischemia and reperfusion compared with nontransgenic hearts. Myocardial neutrophil infiltration was reduced by 54% after 6 h of reperfusion in transgenic hearts (p < 0.01). Neutrophil depletion prior to ischemia-reperfusion injury led to smaller infarcts that were not different between transgenic and nontransgenic mice, suggesting that endothelial FasL may attenuate ischemia-reperfusion injury by abating the inflammatory response. These results indicate that vascular endothelial FasL may exert potent anti-inflammatory actions in the setting of myocardial ischemia-reperfusion injury.
Highlights
Fas ligand (FasL)1 is a type II membrane protein belonging to the tumor necrosis factor (TNF) family
Neutrophils play a critical role in reperfusion injury, and it has PLB, phospholamban; left ventricular area (LV), left ventricle; PBS, phosphate-buffered saline; MI/R, myocardial ischemia-reperfusion injury; INF, infarction; AAR, area at risk; MyHC, myosin heavy chain; VEcadherin, vascular endothelial cadherin; LAD, left anterior descending; PMN, polymorphonuclear leukocytes; SERCA, Serca2a
The probes used in RNase protection assay and the primers used in RT-PCR were all specific for the human FasL transgene, and no signals were detected in nontransgenic (NTg) littermates
Summary
FasL, Fas ligand; TNF, tumor necrosis factor; RT, reverse transcriptase; Tg, transgenic; NTg, nontransgenic; FACS, fluorescence-activated cell sorter; ANF, atrial natriuretic factor; in various cell types that bear the receptor Fas ( called APO-1 or CD95) [1]. Neutrophils play a critical role in reperfusion injury, and it has PLB, phospholamban; LV, left ventricle; PBS, phosphate-buffered saline; MI/R, myocardial ischemia-reperfusion injury; INF, infarction; AAR, area at risk; MyHC, myosin heavy chain; VEcadherin, vascular endothelial cadherin; LAD, left anterior descending; PMN, polymorphonuclear leukocytes; SERCA, Serca2a. It has been shown that FasL overexpression on the vascular endothelium of carotid arteries inhibits transplant-associated intimal hyperplasia [20] and that adenovirus-mediated delivery of FasL to injured vessels inhibits intimal hyperplasia in animals with preexisting immunity to adenovirus [21, 22] These data suggest that when expressed in endothelial cells, FasL may have anti-inflammatory actions. These data support the hypothesis that endothelial FasL acts to minimize neutrophil extravasation and organ damage following ischemia-reperfusion injury
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
