A novel IKK inhibitor suppresses heart failure and chronic remodeling after myocardial ischemia via MMP alteration.
OBJECTIVE
Amplification of inflammatory response in the non-infarct area plays an important role in the pathogenesis of ventricular remodeling after myocardial ischemia. Activation of nuclear factor-kappa B (NF-kappaB) is involved in this amplification through a positive feedback loop of pro- inflammatory cytokines. We investigated the efficacy of IKK blockade with IMD-0560, a novel inhibitor of IKK, in a rat myocardial ischemia model.


RESULTS
Left coronary artery occlusion (28 days) was carried out in Sprague-Dawley rats. Daily intraperitoneal injections of IMD-0560 (5 mg/kg) were done after the operation. Treatment with IMD-0560 significantly improved cardiac function as indicated by the preservation of fractional shortening and lower serum brain natriuretic peptide level. Histological analysis showed that IMD-0560 treatment suppressed thinning in the infarcted area compared with vehicle-treated hearts. Moreover, in situ zymography showed matrix metalloprotease-9 activity was inhibited in the infarct area.


CONCLUSIONS
We revealed that the IKK blockade is potent for the suppression of chronic ventricular remodeling after myocardial ischemia.
Wakatsuki
Shin
S
Tokyo Medical and Dental University, Department of Cardiovascular Medicine, 1-5-45 Yushima, Bunkyo, Tokyo, Japan,.
Suzuki
Jun-ichi
J
Ogawa
Masahito
M
Masumura
Mayumi
M
Muto
Susumu
S
Shimizu
Tomoko
T
Takayama
Kiyoshi
K
Itai
Akiko
A
Isobe
Mitsuaki
M
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001794:Blood Pressure; D001835:Body Weight; D006333:Heart Failure / Q000517:prevention & control*; D006339:Heart Rate; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009203:Myocardial Infarction / Q000150:complications*; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000187:drug effects*
D001549:Benzamides; C503742:N-(2,5-bis(trifluoromethyl)phenyl)-5-bromo-2-hydroxybenzamide; D016328:NF-kappa B; D051550:I-kappa B Kinase; D020782:Matrix Metalloproteinases