title: Inhibition of IkappaB phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury.
abstract: OBJECTIVE
  Reperfusion injury is related closely to inflammatory reactions such as activation of inflammatory cells and expression of cytotoxic cytokines. We investigated the efficacy of IkappaB phosphorylation blockade in a rat myocardial ischemia/reperfusion injury model.
  
  
  RESULTS
  IMD-0354 inhibited phosphorylation of IkappaBalpha and nuclear translocation of nuclear factor-kappa B (NF-kappaB) induced by tumor necrosis factor-alpha (TNF-alpha) in cultured cardiomyocytes. TNF-alpha-induced production of interleukin-1beta and monocyte chemoattractant protein-1 from cultured cardiomyocytes was reduced significantly by IMD-0354. Transient left coronary artery occlusion (30 min) and reperfusion (24 h) were carried out in Sprague-Dawley rats. IMD-0354 (1, 5, 10 mg/kg) was injected intraperitoneally 5 min before the start of reperfusion. Treatment with IMD-0354 resulted in a significant dose-dependent reduction of the infarction area/area at risk ratio (vehicle, 47.0+/-3.4%; 10 mg/kg of IMD-0354, 19.4+/-4.0%; P<0.01) and the preservation of fractional shortening ratio (vehicle, 25.0+/-1.5%; 10 mg/kg of IMD-0354, 42.3+/-1.7%; P<0.01). Histological analysis showed that accumulation of polymorphonuclear neutrophils in the area at risk was decreased significantly.
  
  
  CONCLUSIONS
  Inhibition of nuclear translocation of NF-kappaB by IkappaBalpha phosphorylation blockade could provide an effective approach to attenuation of ischemia/reperfusion injury. The cardioprotective effects of IMD-0354 include not only reduction of harmful neutrophil accumulation in myocardium but also inhibition of harmful cytokine and chemokine production by cardiomyocytes.
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8519, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Onai
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Kakuta
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.forename: Go
authors.initials: G
authors.lastname: Haraguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukasawa
authors.forename: Susumu
authors.initials: S
authors.lastname: Muto
authors.forename: Akiko
authors.initials: A
authors.lastname: Itai
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
mesh_terms: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020107:Troponin T / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001549:Benzamides; D018932:Chemokine CCL2; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D020107:Troponin T; D014409:Tumor Necrosis Factor-alpha; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide