title: Blockade of NF-kappaB improves cardiac function and survival after myocardial infarction.
abstract: NF-kappaB is a key transcription factor that regulates inflammatory processes. In the present study, we tested the hypothesis that blockade of NF-kappaB ameliorates cardiac remodeling and failure after myocardial infarction (MI). Knockout mice with targeted disruption of the p50 subunit of NF-kappaB (KO) were used to block the activation of NF-kappaB. MI was induced by ligation of the left coronary artery in male KO and age-matched wild-type (WT) mice. NF-kappaB was activated in noninfarct as well as infarct myocardium in WT+MI mice, while the activity was completely abolished in KO mice. Blockade of NF-kappaB significantly reduced early ventricular rupture after MI and improved survival by ameliorating congestive heart failure. Echocardiographic and pressure measurements revealed that left ventricular fractional shortening and maximum rate of rise of left ventricular pressure were significantly increased and end-diastolic pressure was significantly decreased in KO+MI mice compared with WT+MI mice. Histological analysis demonstrated significant suppression of myocyte hypertrophy as well as interstitial fibrosis in the noninfarct myocardium of KO+MI mice. Blockade of NF-kappaB did not ameliorate expression of proinflammatory cytokines in infarct or noninfarct myocardium. In contrast, phosphorylation of c-Jun NH2-terminal kinase was almost completely abolished in KO+MI mice. The present study demonstrates that targeted disruption of the p50 subunit of NF-kappaB reduces ventricular rupture as well as improves cardiac function and survival after MI. Blockade of NF-kappaB might be a new therapeutic strategy to attenuate cardiac remodeling and failure after MI.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Kawano
authors.forename: Toru
authors.initials: T
authors.lastname: Kubota
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Monden
authors.forename: Takaki
authors.initials: T
authors.lastname: Tsutsumi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Inoue
authors.forename: Natsumi
authors.initials: N
authors.lastname: Kawamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006984:Hypertrophy / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000378:metabolism / Q000473:pathology; D009203:Myocardial Infarction / Q000378:metabolism / Q000401:mortality* / Q000503:physiopathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D018754:Ventricular Dysfunction / Q000473:pathology / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D016207:Cytokines; D016328:NF-kappa B