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

Authors

• Feng Gao
• Tian-Li Yue
• Dong-Wei Shi
• Theodore A Christopher
• Bernard L Lopez
• Eliot H Ohlstein
• Frank C Barone
• Xin L Ma

Publication/Presentation Date

2-1-2002

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.

Volume

53

Issue

2

First Page

414

Last Page

422

ISSN

0008-6363

Published In/Presented At

Gao, F., Yue, T. L., Shi, D. W., Christopher, T. A., Lopez, B. L., Ohlstein, E. H., Barone, F. C., & Ma, X. L. (2002). p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation. Cardiovascular research, 53(2), 414–422. https://doi.org/10.1016/s0008-6363(01)00488-6

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

11827692

Department(s)

Hematology-Medical Oncology Division

Document Type

Article