Targeted disruption of the p50 subunit of NF-kB ameliorates cardiac dysfunction after myocardial infarction

Abstract

Background: We hypothesized that blockade of NF-kB ameliorates ventricular remodeling and dysfunction after myocardial infarction (MI). Methods and Results: Mice with targeted disruption of the p50 subunit of NF-kB (KO) and their wild-type littermates (WT) underwent MI by ligation of left coronary artery. By electrophoretic mobility shift assay, NF-kB was activated in infarct as well as in non-infarct myocardium in WT mice after MI. The activation of NF-kB was completely blocked in KO mice. Within one week after the ligation, 42 of 67 WT and 36 of 64 KO mice died of ventricular rupture or congestive heart failure (p = ns). Four weeks after the ligation, echocardiography and LV pressure measurement were performed. MI size was not different between WT and KO MI mice. Compared with sham-operated mice, LV end-diastolic dimension and pressure were significantly increased and LV fractional shortening and + dP/dt max were significantly decreased in WT MI mice. Although dilatation of LV was unaltered, elevation of end-diastolic pressure and decreased fractional shortening and + dP/dt max were significantly improved in KO MI mice. By cross sectional area, myocyte hypertrophy in non-infarct myocardium was significantly inhibited in KO MI mice. Conclusions: Blockade of NF-kB improves cardiac dysfunction after MI and might be a new therapeutic strategy to attenuate ventricular remodeling and heart failure.