Pharmacological Activation of the Prostaglandin E2 Receptor EP4 Improves Cardiac Function After Myocardial Ischaemia/reperfusion Injury

Overview

Journal Cardiovasc Res

Specialty Cardiology & Vascular Diseases

Date 2008 Sep 23

PMID 18805784

Citations 38

Authors

Keiichi Hishikari

Jun-Ichi Suzuki

Masahito Ogawa

Kazuya Isobe

Teisuke Takahashi

Michihito Onishi

Kiyoshi Takayama

Mitsuaki Isobe

Affiliations

Soon will be listed here.

Abstract

Aims: Increased expression of several subtypes of prostaglandin E(2) 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.

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