Inhibition of IkappaB phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury.
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.
Onai
Yasuyuki
Y
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8519, Japan.
Suzuki
Jun-Ichi
J
Kakuta
Tsunekazu
T
Maejima
Yasuhiro
Y
Haraguchi
Go
G
Fukasawa
Hiroshi
H
Muto
Susumu
S
Itai
Akiko
A
Isobe
Mitsuaki
M
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
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