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.

METHODS AND 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: Yasuyuki Onai, Jun-Ichi Suzuki, Tsunekazu Kakuta, Yasuhiro Maejima, Go Haraguchi, Hiroshi Fukasawa, Susumu Muto, Akiko Itai, Mitsuaki Isobe
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 63 Issue 1 Pg. 51-9 (Jul 01 2004) ISSN: 0008-6363 [Print] England
• PMID: 15194461 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Chemokine CCL2
• I-kappa B Proteins
• Interleukin-1
• NF-kappa B
• Troponin T
• Tumor Necrosis Factor-alpha
• N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide

Topics

• Animals
• Benzamides (therapeutic use)
• Biological Transport (drug effects)
• Cells, Cultured
• Chemokine CCL2 (metabolism)
• Dose-Response Relationship, Drug
• I-kappa B Proteins (antagonists & inhibitors, metabolism)
• Interleukin-1 (metabolism)
• Male
• Myocardial Reperfusion Injury (immunology, metabolism, prevention & control)
• Myocytes, Cardiac (drug effects, metabolism)
• NF-kappa B (metabolism)
• Neutrophil Infiltration (drug effects)
• Phosphorylation
• Rats
• Rats, Sprague-Dawley
• Troponin T (blood)
• Tumor Necrosis Factor-alpha (pharmacology)