Abstract 3307: Tissue Specific Effects of the Transcription Factor Nuclear Factor Kappa B on Myocardial Ischemic Injury
Nuclear factor kappa B (NF-κB) is a ubiquitous transcription factor activated by various stimuli implicated in ischemic injury including reactive oxygen species, hypoxia, and inflammatory cytokines. We demonstrated a detrimental role of NF-κB activation after myocardial infarction using mice with targeted deletion of the NF-κB subunit p50. However, the tissue specific role of NF-κB in cardiac ischemic injury has not been defined yet. Thus, we generated mice with cardiomyocyte restricted deletion of IKKγ(IκB-Kinase) by breeding floxed IKKγ with αMHC-Cre mice. IKK can phosphorylate the inhibitor of NF-κB IκB, a process necessary for NF-κB translocation to the nucleus. Thus, NF-κB activation is absent in IKK knockout (KO) mice. Offspring of αMHC-IKK-KO mice were vital with no cardiovascular phenotype. To study effects of the genotype on left ventricular remodeling wild type (WT) and MHC-IKK-KO mice underwent left coronary artery ligation followed by serial transthoracic echocardiography on day 1, 21, and 56 after myocardial infarction (MI). Mortality, left ventricular dilatation, collagen deposition (Sirius red staining), and VEGF/TNF expression (real time PCR) were not influenced by the genotype. Ischemia/reperfusion experiments in p50 KO mice suggested that especially NF-κB activation in inflammatory cells would be important for ischemic injury. We thus deleted in the next step NF-κB in macrophages by crossing the floxed IKK mice with LysM-Cre mice. Offspring was vital with no cardiovascular phenotype. After experimental MI survival (WT vs. LysM-IKK-KO, 49% vs. 100%, p<0.01) as well as left ventricular remodeling (echocardiography, apical, end-diastolic area, WT vs. LysM-IKK-KO, 27.6±2.6 vs. 18.1±1.8 mm2, p=0.02) and hemodynamics were significantly improved in LysM-IKK-KO mice. This was accompanied by a significant reduction of myocardial TNF and an increase in septal collagen deposition in LysM-IKK-KO mice. In summary, NF-κB activation in inflammatory cells, but not in cardiac myocytes contributes to mortality, adverse left ventricular and extracellular matrix remodeling after MI.