Tissue-specific effects of the nuclear factor kappaB subunit p50 on myocardial ischemia-reperfusion injury.
Nuclear factor kappaB (NF-kappaB) is a ubiquitous transcription factor activated by various stimuli implicated in ischemia-reperfusion injury. However, the role of NF-kappaB in cardiac ischemia-reperfusion injury has not yet been well defined. Therefore, we investigated reperfusion damage in mice with targeted deletion of the NF-kappaB subunit p50. Electrophoretic mobility shift assays validated NF-kappaB activation in wild-type (WT) but not p50 knockout (KO) mice. KO and WT animals underwent 30 minutes of coronary artery ligation and 24 hours of reperfusion in vivo. Ischemia-reperfusion damage was significantly reduced in the p50 KO when compared with matching WT mice. Although adhesion molecules such as intercellular adhesion molecule were up-regulated in left ventricles of p50 KO animals, fewer neutrophils infiltrated the infarct area, suggesting leukocytes as a potential mediator of the protection observed in the p50 KO. This was confirmed in adoptive transfer experiments: whereas transplantation of KO bone marrow in KO animals sustained the protective effect on ischemia-reperfusion injury, transplantation of WT bone marrow in KO animals abolished it. Thus, deletion of the NF-kappaB subunit p50 reduces ischemia-reperfusion injury in vivo, associated with less neutrophil infiltration. Bone marrow transplantation experiments indicate that impaired NF-kappaB activation in p50 KO leukocytes attenuates cardiac damage.
Frantz
Stefan
S
Medizinische Klinik und Poliklinik I, Herz-/Kreislaufzentrum, Universität Würzburg,Würzburg, Germany. frantz_s@medizin.uni-wuerzburg.de
Tillmanns
Jochen
J
Kuhlencordt
Peter J
PJ
Schmidt
Isabel
I
Adamek
Anna
A
Dienesch
Charlotte
C
Thum
Thomas
T
Gerondakis
Steve
S
Ertl
Georg
G
Bauersachs
Johann
J
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015870:Gene Expression; D005838:Genotype; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology* / Q000601:surgery; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D052002:NF-kappa B p50 Subunit / Q000235:genetics* / Q000378:metabolism; D019007:P-Selectin / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
C090509:Icam1 protein, mouse; D052002:NF-kappa B p50 Subunit; D019007:P-Selectin; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1