Nuclear Factor-κB Is Selectively and Markedly Activated in Humans With Unstable Angina Pectoris

Abstract

Background —Nuclear factor-κB (NF-κB) resides inactive in the cytoplasm of lymphocytes, monocytes, endothelial cells, and smooth muscle cells, where, after stimulation, it transcriptionally activates interleukins, interferon, tumor necrosis factor-α, and adhesion molecules. Because acute inflammation may play a role in coronary artery plaque rupture, it was hypothesized that NF-κB activation correlated with coronary artery disease (CAD) activity. Methods and Results —Evidence of NF-κB activation in the circulation of 102 consecutive patients without an acute myocardial infarction who were undergoing cardiac catheterization was determined. Of these, 19 had unstable angina (USA) and were within 24 hours of the last episode of chest pain. The remaining 83 were being evaluated for stable angina (53), valvular heart disease (8), atypical chest pain (12), or congestive heart failure (10). Evidence of NF-κB activation was determined by electromobility shift assays (EMSAs) with the NF-κB binding-site–specific probe and nuclear proteins isolated from the buffy coat of blood obtained at the beginning of the procedure. Specificity of this DNA-protein interaction was confirmed by competition and supershift EMSAs. Analyses showed that 17 of 19 patients with USA had marked activation of NF-κB. Despite a significant number of patients with severe CAD (69%), only 2 of the 83 without USA showed marked NF-κB activation. A lack of NF-κB activation was not due to a lack of functional cell/protein because NF-κB was appropriately activated by lipopolysaccharide ex vivo in all patients. NF-κB activation was not a nonspecific response of all transcription factors because neither Sp1 or Oct1 was activated in patients with activated NF-κB. There was no relationship between drugs used, hemodynamic status, or other clinical characteristics and state of NF-κB activation. Conclusions —These data show that NF-κB is specifically and significantly activated in unstable angina pectoris and is not affected by severity of CAD or medical therapy. Furthermore, because NF-κB is activated before a clinical event, it may be mechanistically involved in the plaque disruption that produces acute coronary artery syndromes.