p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation.

Abstract

BACKGROUND:

In vitro evidence suggests that the p38 mitogen-activated protein kinase (p38 MAPK) plays a crucial role in PMN activation and inflammatory cytokine production. However, the effect of p38 MAPK on myocardial reperfusion injury, a pathologic condition involving a typical inflammatory response, has not been fully examined. In the present study, we investigated the effect of SB 239063, a specific p38 MAPK inhibitor, on myocardial injury in a murine ischemia/reperfusion (I/R) model and elucidated the mechanism by which p38 MAPK inhibitor may exert its protective effect against I/R injury.

METHODS AND RESULTS:

I/R resulted in a significant myocardial injury (myocardial infarct 45 +/- 2.9%) and marked PMN accumulation (myeloperoxidase activity 1.03 +/- 0.16 U/100 g tissue). Administration of SB 239063 significantly inhibited the myocardial inflammatory response as evidenced by reduced PMN accumulation in I/R myocardial tissue (0.62 +/- 0.008 U/100 g tissue, P<0.01 vs. vehicle), and markedly attenuated myocardial reperfusion injury (myocardial infarct size: 28 +/- 2.4%, P<0.01 vs. vehicle). Moreover, treatment with SB 239063 significantly attenuated I/R-induced P-selectin and ICAM-1 upregulation (13.8 +/- 2.7 vs. 23.9 +/- 3.1%, and 29.4 +/- 1.6 vs. 56.3 +/- 4.8%, respectively P<0.01). In addition, pre-treatment with R15.7, a monoclonal antibody against CD 18 adhesion molecule on PMN surface that virtually abolished PMN accumulation in ischemic-reperfused myocardial tissue, significantly, but not completely, blocked the cardioprotection exerted by SB 239063.

CONCLUSION:

These results demonstrated for the first time that p38 MAPK activation plays a significant role in adhesion molecule upregulation on ischemia-reperfused endothelial cells and is an important signaling step in the pathogenesis of PMN-mediated tissue injury.

• Authors: Feng Gao, Tian-Li Yue, Dong-Wei Shi, Theodore A Christopher, Bernard L Lopez, Eliot H Ohlstein, Frank C Barone, Xin L Ma
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 53 Issue 2 Pg. 414-22 (Feb 01 2002) ISSN: 0008-6363 [Print] England
• PMID: 11827692 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Imidazoles
• P-Selectin
• Pyrimidines
• Intercellular Adhesion Molecule-1
• Peroxidase
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• SB 239063

Topics

• Analysis of Variance
• Animals
• Endothelium, Vascular (metabolism)
• Imidazoles (pharmacology)
• Intercellular Adhesion Molecule-1 (analysis)
• Male
• Mitogen-Activated Protein Kinases (analysis, antagonists & inhibitors)
• Myocardial Infarction (metabolism)
• Myocardial Reperfusion Injury (immunology, prevention & control)
• Neutrophils (physiology)
• P-Selectin (analysis)
• Peroxidase (analysis)
• Pyrimidines (pharmacology)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• p38 Mitogen-Activated Protein Kinases