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Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 18, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn254
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Pharmacological Activation of the Prostaglandin E2 Receptor EP4 Improves Cardiac Function After Myocardial Ischemia/Reperfusion Injury

Keiichi Hishikari1, Jun-ichi Suzuki1,2,*, Masahito Ogawa1, Kazuya Isobe,1, Teisuke Takahashi3, Michihito Onishi3, Kiyoshi Takayama3 and Mitsuaki Isobe1

1 Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
2 Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan
3 Central Research Institute, Taisho Pharmaceutical Co., LTD, 1-403 Yoshino, Kita, Saitama 331-9530, Japan

* Correspondence to Jun-ichi Suzuki, Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan; Phone, 81-3-5800-9116; Fax, 81-3-5800-9182; e-mail, junichisuzuki-circ{at}umin.ac.jp

Aims: Increased expression of several subtypes of prostaglandin E2 (PGE2) receptors (EP1-4) has recently been described in clinical and experimental myocardial ischemia/reperfusion (I/R) injury. However, their pathophysiological significance in I/R remains obscure. Thus, we determined whether activation of the prostanoid receptor, EP4, suppresses myocardial I/R injury.

Methods: To analyze the role of EP4, we administered an EP4 selective agonist (EP4RAG, 1 or 3 mg/kg) or vehicle to rats with myocardial I/R injury.

Results: After 7 days of reperfusion, I/R rats exhibited left ventricular dilatation and contractile dysfunction with myocyte hypertrophy and interstitial fibrosis. EP4RAG significantly reduced infarction area/ischemic myocardium (72.4±0.7 versus 23.3±0.6 %; P<0.05) and improved the left ventricular contraction and dilatation compared to that of vehicle. EP4RAG also attenuated recruitment of inflammatory cells, especially macrophages, and interstitial fibrosis in hearts. Monocyte chemoattractant protein (MCP)-1 and other cytokines were increased in both nonischemic (area not at risk, ANAR) and ischemic (area at risk, AAR) myocardium, however Western blot analysis and RNase protection assay showed EP4RAG suppressed these changes. Gelatin zymography revealed EP4RAG significantly reduced matrix metalloproteinase (MMP) -2 and -9 activities in both ANAR and AAR. Chemoattractant assay demonstrated EP4RAG suppressed the migration of cytokine-stimulated macrophages and decreased the level of MCP-1 production in the supernatant (587.3±55.3 versus 171.5±47.5 pg/mL; P<0.05).

Conclusion: The data suggest the EP4 agonist is effective for attenuation of I/R injury by suppressing MCP-1 and the infiltration of inflammatory cells, especially macrophages.

KEYWORDS prostaglandins; inflammation; reperfusion injury

Time for primary review: 28 Days


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