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(Circulation Research. 2009;104:699.)
© 2009 American Heart Association, Inc.

Integrative Physiology

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

Leo Timmers^*, J. Karlijn van Keulen^*, Imo E. Hoefer, Matthijs F.L. Meijs, Ben van Middelaar, Krista den Ouden, Cees J.A. van Echteld, Gerard Pasterkamp, Dominique P.V. de Kleijn

From the Department of Cardiology (L.T., J.K.v.K., I.E.H., M.F.L.M., B.v.M., K.d.O., C.J.A.v.E., G.P., D.P.V.d.K.), University Medical Center Utrecht; and Interuniversity Cardiology Institute of The Netherlands (J.K.v.K., D.P.V.d.K.), Utrecht.

Correspondence to Dominique P.V. de Kleijn, PhD, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Room G02.523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail d.dekleijn{at}umcutrecht.nl

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)-B activation. The NF-B transcription factor family includes several subunits (p50, p52, p65, c-Rel, and Rel B) that respond to myocardial ischemia. The function of NF-B p50, however, is controversial in this process. To clarify the role of NF-B p50 in postinfarct left ventricular remodeling, myocardial infarction was induced in wild-type 129Bl6 mice and NF-B p50-deficient mice. Without affecting infarct size, deletion of NF-B p50 markedly increased the extent of expansive remodeling (end-diastolic volume: 176±13 µL versus 107±11 µL; 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-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-B p50 results in enhanced cardiac remodeling and functional deterioration following myocardial infarction by increasing matrix remodeling and inflammation.

Key Words: myocardial infarction • ischemic heart disease • remodeling • NF-B • wound healing

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