title: Endothelial cell overexpression of fas ligand attenuates ischemia-reperfusion injury in the heart.
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.
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yang
authors.forename: Steven P
authors.initials: SP
authors.lastname: Jones
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Suhara
authors.forename: James J M
authors.initials: JJ
authors.lastname: Greer
authors.forename: Paul D
authors.initials: PD
authors.lastname: Ware
authors.forename: Nhan P
authors.initials: NP
authors.lastname: Nguyen
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
authors.forename: David P
authors.initials: DP
authors.lastname: Nelson
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics; D002460:Cell Line; D002634:Chemotaxis, Leukocyte; D004730:Endothelium, Vascular / Q000378:metabolism*; D053222:Fas Ligand Protein; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009504:Neutrophils; D009929:Organ Size; D011401:Promoter Regions, Genetic
chemical_list: D015820:Cadherins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins