© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Inhibition of I
B phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury
aDepartment of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
bMedical Molecular Design, Inc., 5-24-5 Hongo, Bunkyo, Tokyo, Japan
*Corresponding author. Tel.: +81-3-5803-5951; fax: +81-3-5803-0238. Email address: isobemi.cvm{at}tmd.ac.jp
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 I
B phosphorylation blockade in a rat myocardial ischemia/reperfusion injury model. Methods and results: IMD-0354 inhibited phosphorylation of IB
and nuclear translocation of nuclear factor-kappa B (NF-B) induced by tumor necrosis factor- (TNF-) in cultured cardiomyocytes. TNF--induced production of interleukin-1β 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-B by IB 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.
KEYWORDS Myocardial infarction; Reperfusion injury; Nuclear factor-kappaB; Cytokine; Chemokine; Cardiomyocyte
Time for primary review 28 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Frantz, J. Bauersachs, and G. Ertl Post-infarct remodelling: contribution of wound healing and inflammation Cardiovasc Res, February 15, 2009; 81(3): 474 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hishikari, J.-i. Suzuki, M. Ogawa, K. Isobe, T. Takahashi, M. Onishi, K. Takayama, and M. Isobe Pharmacological activation of the prostaglandin E2 receptor EP4 improves cardiac function after myocardial ischaemia/reperfusion injury Cardiovasc Res, January 1, 2009; 81(1): 123 - 132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Yanai, S. Maeda, W. Shibata, Y. Hikiba, K. Sakamoto, H. Nakagawa, T. Ohmae, Y. Hirata, K. Ogura, S. Muto, et al. Activation of I{kappa}B Kinase and NF-{kappa}B Is Essential for Helicobacter pylori-Induced Chronic Gastritis in Mongolian Gerbils Infect. Immun., February 1, 2008; 76(2): 781 - 787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. C. Moss, W. E. Stansfield, M. S. Willis, R.-H. Tang, and C. H. Selzman IKKbeta inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2248 - H2253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Frantz, J. Tillmanns, P. J. Kuhlencordt, I. Schmidt, A. Adamek, C. Dienesch, T. Thum, S. Gerondakis, G. Ertl, and J. Bauersachs Tissue-Specific Effects of the Nuclear Factor {kappa}B Subunit p50 on Myocardial Ischemia-Reperfusion Injury Am. J. Pathol., August 1, 2007; 171(2): 507 - 512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Onai, J.-i. Suzuki, Y. Maejima, G. Haraguchi, S. Muto, A. Itai, and M. Isobe Inhibition of NF-{kappa}B improves left ventricular remodeling and cardiac dysfunction after myocardial infarction Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H530 - H538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Inayama, Y. Nishioka, M. Azuma, S. Muto, Y. Aono, H. Makino, K. Tani, H. Uehara, K. Izumi, A. Itai, et al. A Novel I{kappa}B Kinase-beta Inhibitor Ameliorates Bleomycin-induced Pulmonary Fibrosis in Mice Am. J. Respir. Crit. Care Med., May 1, 2006; 173(9): 1016 - 1022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hall, I. S. Singh, L. Hester, J. D. Hasday, and T. B. Rogers Inhibitor-{kappa}B kinase-{beta} regulates LPS-induced TNF-{alpha} production in cardiac myocytes through modulation of NF-{kappa}B p65 subunit phosphorylation Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2103 - H2111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Brown, M. McGuinness, T. Wright, X. Ren, Y. Wang, G. P. Boivin, H. Hahn, A. M. Feldman, and W. K. Jones Cardiac-specific blockade of NF-{kappa}B in cardiac pathophysiology: differences between acute and chronic stimuli in vivo Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H466 - H476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Gottlieb ICE-ing the Heart Circ. Res., May 27, 2005; 96(10): 1036 - 1038. [Full Text] [PDF]
|
|
|
|
|
|
C. Thiemermann Inhibition of the activation of nuclear factor kappa B to reduce myocardial reperfusion injury and infarct size Cardiovasc Res, July 1, 2004; 63(1): 8 - 10. [Full Text] [PDF]
|
|