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J Thorac Cardiovasc Surg 2004;128:588-594
© 2004 The American Association for Thoracic Surgery

Cardiopulmonary support and physiology

FR167653 diminishes infarct size in a murine model of myocardial ischemia-reperfusion injury

^a Department of Thoracic & Cardiovascular Surgery, Mie University School of Medicine, Tsu, Japan
^b Division of Cardiothoracic Surgery, Department of Surgery, University of Washington School of Medicine, Seattle, Wash, USA

Received for publication October 21, 2003; revisions received January 16, 2004; accepted for publication February 2, 2004.

^* Address for reprints: Akira Shimamoto, MD, PhD, Division of Cardiothoracic Surgery, Department of Surgery, University of Washington School of Medicine, 1959 NE Pacific St, Box 356310, Seattle, WA 98195-6310, USA
jj6jdv{at}u.washington.edu

OBJECTIVE: During myocardial ischemia-reperfusion injury, p38 mitogen-activated protein kinase is activated. We examined the effect of a highly specific inhibitor of p38 mitogen-activated protein kinase, FR167653, in an experimental model of regional myocardial ischemia-reperfusion.

METHODS: CD-1 mice received FR167653 intraperitoneally 24 hours before 30 minutes of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. The p38 mitogen-activated protein kinase activation and kinase activity were determined by Western blotting with monoclonal antibodies for the phosphorylated from of p38 mitogen-activated protein kinase or its substrate, activating transcription factor 2. Nuclear factor B activity was measured by detecting translocation of nuclear factor B to the nucleus. The expression of inflammatory cytokines was measured by ribonuclease protection assay.

RESULTS: Pretreatment of mice with FR167653 before myocardial ischemia-reperfusion resulted in a reduction in p38 mitogen-activated protein kinase phosphorylation (P = .018), an inhibition of p38 mitogen-activated protein kinase activity (P = .047), a smaller amount of nuclear factor B (P = .001), and a decrease in the expression of inflammatory cytokines (tumor necrosis factor : P = .023, interleukin 1ß: P = .038, monocyte chemotactic protein 1: P = .0001) in the heart and the development of a significantly smaller infarct (P = .0069) relative to hearts from mice treated with vehicle alone. Activation of c-Jun N-terminal kinase and extracellular signal–regulated kinase were observed after myocardial ischemia-reperfusion without inhibition by FR167653.

CONCLUSION: We conclude that FR167653 selectively inhibits p38 mitogen-activated protein kinase activation and activity during regional myocardial ischemia-reperfusion injury and efficaciously reduces infarct size (by 73.6%). Thus p38 mitogen-activated protein kinase inhibition may have a role in the treatment of myocardial ischemia-reperfusion.

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