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Cardiovascular Research Advance Access originally published online on September 18, 2008
Cardiovascular Research 2009 81(1):123-132; 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 ischaemia/reperfusion injury

Keiichi Hishikari1, Jun-ichi Suzuki1,2,*, Masahito Ogawa1, Kazuya Isobe1, 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

* Corresponding author. Tel: +81 3 5800 9116; fax: 81 3 5800 9182. E-mail address: junichisuzuki-circ{at}umin.ac.jp

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

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

Conclusion: The data suggest that 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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