Nuclear Factor-κB Protects the Adult Cardiac Myocyte Against Ischemia-Induced Apoptosis in a Murine Model of Acute Myocardial Infarction
Background— Previous studies have shown that tumor necrosis factor (TNF) confers cytoprotective responses in cardiac myocytes. However, the mechanisms for the cytoprotective effects of TNF remain unknown. Given that TNF signals through nuclear factor κB (NF-κB) and given that NF-κB mediates cytoprotective responses, we asked whether NF-κB activation conferred cytoprotective responses in acute myocardial ischemia/infarction.
Methods and Results— We examined infarct size and the prevalence of apoptosis in transgenic mice harboring cardiac-restricted expression of a mutated IκBα protein (IκBαΔN) that prevents nuclear translocation of NF-κB in cardiac myocytes. Triphenyltetrazolium chloride staining showed that infarct size was ≈50% greater (P<0.02) in the IκBαΔN mice compared with littermate controls at 24 hours. The prevalence of cardiac myocyte apoptosis was significantly greater (P<0.008) in the IκBαΔN mice compared with the littermate control mice 3 and 6 hours after left anterior descending occlusion. To explore the mechanism for these findings, we examined protein levels of c-IAP1, c-IAP2, and Bcl-2 as well as manganese superoxide dismutase and c-Jun NH2-terminal kinase activity. These studies showed that protein levels of c-IAP1 and Bcl-2 were significantly lower in the IκBαΔN mice, whereas there was no change in c-IAP2 levels, manganese superoxide dismutase, or c-Jun NH2-terminal kinase activity.
Conclusions— Transgenic mice with a defect in activation of NF-κB have increased susceptibility to tissue injury after acute left anterior descending occlusion. These studies suggest that the cytoprotective effects of NF-κB are mediated, at least in part, by Bcl-2 or c-IAP1.
Received April 2, 2002; de novo received September 15, 2003; revision received October 27, 2003; accepted October 28, 2003.