Targeted Deletion of Nuclear Factor κB p50 Enhances Cardiac Remodeling and Dysfunction Following Myocardial Infarction

Myocardial infarction is commonly complicated by left ventricular remodeling, a process that leads to cardiac dilatation, congestive heart failure and death. The innate immune system plays a pivotal role in the remodeling process via nuclear factor (NF)-kappa B activation. The NF-kappa B transcription factor family includes several subunits (p50, p52, p65, c-Rel, and Rel B) that respond to myocardial ischemia. The function of NF-kappa B p50, however, is controversial in this process. To clarify the role of NF-kappa B p50 in postinfarct left ventricular remodeling, myocardial infarction was induced in wild-type 129Bl6 mice and NF-kappa B p50- deficient mice. Without affecting infarct size, deletion of NF-kappa B p50 markedly increased the extent of expansive remodeling (end-diastolic volume: 176 +/- 13 mu L versus 107 +/- 11 mu L; P = 0.003) and aggravated systolic dysfunction (left ventricular ejection fraction: 16.1 +/- 1.5% versus 24.7 +/- 3.7%; P = 0.029) in a 28-day time period. Interstitial fibrosis and hypertrophy in the noninfarcted myocardium was increased in NF-kappa B p50 knockout mice. In the infarct area, a lower collagen density was observed, which was accompanied by an increased number of macrophages, higher gelatinase activity and increased inflammatory cytokine expression. In conclusion, targeted deletion of NF-kappa B p50 results in enhanced cardiac remodeling and functional deterioration following myocardial infarction by increasing matrix remodeling and inflammation. (Circ Res. 2009; 104: 699-706.)