Inhibition of NF-{kappa}B improves left ventricular remodeling and cardiac dysfunction after myocardial infarction.
Several studies have demonstrated that NF-kappaB is substantially involved in the progression of cardiac remodeling; however, it remains uncertain whether the continuous inhibition of NF-kappaB is effective for the prevention of myocardial remodeling. Myocardial infarction (MI) was produced by ligation of the left anterior coronary artery of rats. IMD-0354 (10 mg/kg per day), a novel phosphorylation inhibitor of IkappaB that acts via inhibition of IKK-beta, was injected intraperitoneally starting 24 h after induction of MI for 28 days. After 28 days, the IMD-0354-treated group showed significantly improved survival rate compared with that of the vehicle-treated group (P < 0.05). Although infarct size was similar in both groups, improved left ventricular (LV) remodeling and diastolic dysfunction, as indicated by smaller LV cavity (LV end-diastolic area: vehicle, 74.13 +/- 3.57 mm(2); IMD-0354, 55.00 +/- 3.73 mm(2); P < 0.05), smaller peak velocity of early-to-late filling wave (E/A) ratio (vehicle, 3.87 +/- 0.26; IMD-0354, 2.61 +/- 0.24; P < 0.05), and lower plasma brain natriuretic peptide level (vehicle, 167.63 +/- 14.87 pg/ml; IMD-0354, 110.75 +/- 6.41 pg/ml; P < 0.05), were observed in the IMD-0354-treated group. Moreover, fibrosis, accumulation of macrophages, and expression of several factors (transforming growth factor-beta1, monocyte chemoattractant protein-1, matrix metalloproteinase-9 and -2) in the noninfarcted myocardium was remarkably inhibited by IMD-0354. In conclusion, inhibition of NF-kappaB activation may reduce the proinflammatory reactions and modulate the extracellular matrix and provide an effective approach to prevent adverse cardiac remodeling after MI.
Onai
Yasuyuki
Y
Dept. of Cardiovascular Medicine, Tokyo Medical and Dental Univ., 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Suzuki
Jun-Ichi
J
Maejima
Yasuhiro
Y
Haraguchi
Go
G
Muto
Susumu
S
Itai
Akiko
A
Isobe
Mitsuaki
M
D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D002316:Cardiotonic Agents / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000187:drug effects*
D001549:Benzamides; D002316:Cardiotonic Agents; D016328:NF-kappa B; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide