Tissue-specific effects of the nuclear factor κB subunit p50 on myocardial ischemia-reperfusion injury

Nuclear factor KB (NF-kappa B) is a ubiquitous transcription factor activated by various stimuli implicated in ischemia-reperfusion injury. However, the role of NF-kappa B in cardiac ischemia-reperfusion injury has not yet been well defined. Therefore, we investigated reperfusion damage in mice with targeted deletion of the NF-KB subunit p50. Electrophoretic mobility shift assays validated NF-KB activation in wild-type (wi) 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-kappa B subunit p50 reduces ischemia-reperfusion injury in vivo, associated with less neutrophil infiltration. Bone marrow transplantation experiments indicate that impaired NF-KB activation in P50 KO leukocytes attenuates cardiac damage.