title: Targeted deletion of nuclear factor kappaB p50 enhances cardiac remodeling and dysfunction following myocardial infarction.
abstract: 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)-kappaB activation. The NF-kappaB transcription factor family includes several subunits (p50, p52, p65, c-Rel, and Rel B) that respond to myocardial ischemia. The function of NF-kappaB p50, however, is controversial in this process. To clarify the role of NF-kappaB p50 in postinfarct left ventricular remodeling, myocardial infarction was induced in wild-type 129Bl6 mice and NF-kappaB p50-deficient mice. Without affecting infarct size, deletion of NF-kappaB p50 markedly increased the extent of expansive remodeling (end-diastolic volume: 176+/-13 microL versus 107+/-11 microL; 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-kappaB 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-kappaB p50 results in enhanced cardiac remodeling and functional deterioration following myocardial infarction by increasing matrix remodeling and inflammation.
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Leo
authors.initials: L
authors.lastname: Timmers
authors.forename: J Karlijn
authors.initials: JK
authors.lastname: van Keulen
authors.forename: Imo E
authors.initials: IE
authors.lastname: Hoefer
authors.forename: Matthijs F L
authors.initials: MF
authors.lastname: Meijs
authors.forename: Ben
authors.initials: B
authors.lastname: van Middelaar
authors.forename: Krista
authors.initials: K
authors.lastname: den Ouden
authors.forename: Cees J A
authors.initials: CJ
authors.lastname: van Echteld
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Dominique P V
authors.initials: DP
authors.lastname: de Kleijn
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D052002:NF-kappa B p50 Subunit / Q000172:deficiency* / Q000235:genetics; D013318:Stroke Volume; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects; D014945:Wound Healing
chemical_list: D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA; D003094:Collagen