Inhibition of IκB Phosphorylation by a Novel IKK Inhibitor IMD-1041 Attenuates Myocardial Dysfunction After Infarction

Author(s): Ryo Matsumoto, Jun-ichi Suzuki, Ryo Watanabe, Masahito Ogawa, Mitsuaki Isobe.

Journal Name: Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Under Re-organization)

Volume 12 , Issue 2 , 2012

Abstract:

Background: Myocardial infarction (MI) frequently causes left ventricular (LV) dysfunction, and this is involved in inflammatory reactions and fibrosis of myocardium. Several studies have demonstrated that NF-&kapps;B is substantially related to inflammation and LV remodeling. However, the effects of the continuous inhibition of NF-κB for the prevention of LV dysfunction after MI are still controversial. IMD-1041, which inhibits phosphorylation of IκB via inhibition of IKK-β, is under clinical trials. The aim of this study was to investigate effects of IMD-1041 for myocardial remodeling after infarction.

Methods and Results: To analyze the effects of IMD-1041 to ischemic heart, we administered IMD-1041 (low dose; 30mg/kg/day, high dose; 100mg/kg/day) or vehicle orally to mice with ligation of the left anterior coronary artery. After 28 days of ligation, MI mice exhibited left ventricular (LV) dilatation and contractile dysfunction. However, IMD-1041 treatment significantly improved cardiac function as indicated by the preservation of fractional shortening (30mg/kg of IMD-1041, 25.8±0.8%, n=12; 100mg/kg of IMD-1041, 29.3±0.6%, n=12; vehicle, 21.6±1.6%, n=11; P<0.05). Histological analysis also showed that IMD-1041 treatment impressively reduced fibrosis area (30mg/kg of IMD-1041,21.5±2.0%, n=12; 100mg/kg of IMD-1041, 24.0±1.7%, n=12; vehicle, 33.2±3.6%, n=11; P<0.05). Although LV gelatinolytic activity of pro- and active-MMP-2 and -9 increased in the vehicle group, IMD-1041 treatment significantly inhibited the activity of MMPs.

Conclusion: These results suggest that IMD-1041 treatment is effective for the prevention of myocardial dysfunction after MI through attenuation of myocardial fibrosis.

Keywords: Fibrosis, nuclear factor-kappa B, IMD-1041, IKK-β, Ischemia, myocardial infarction, mice, matrix metalloproteinase, ventricular remodeling

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 12
ISSUE: 2
Year: 2012
Page: [137 - 142]
Pages: 6
DOI: 10.2174/187152212800389021
Price: $58

Article Metrics

PDF: 8