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

Masaki Yada, Akira Shimamoto, Craig R Hampton, Albert J Chong, Hiroo Takayama, Christine L Rothnie, Denise J Spring, Hideto Shimpo, Isao Yada, Timothy H Pohlman, Edward D Verrier
Journal of Thoracic and Cardiovascular Surgery 2004, 128 (4): 588-94

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 kappaB activity was measured by detecting translocation of nuclear factor kappaB 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 kappaB (P =.001), and a decrease in the expression of inflammatory cytokines (tumor necrosis factor alpha: P =.023, interleukin 1beta: 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.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"