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(Circulation. 2004;109:2462-2468.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Prostaglandin E₂ Protects the Heart From Ischemia-Reperfusion Injury via Its Receptor Subtype EP₄

Chun-Yang Xiao, PhD^*; Koh-ichi Yuhki, MS^*; Akiyoshi Hara, PhD; Takayuki Fujino, MD; Shuhko Kuriyama, MD; Takehiro Yamada, MS; Koji Takayama, MD; Osamu Takahata, MD; Hideji Karibe, PhD; Takanobu Taniguchi, MD; Shuh Narumiya, MD; Fumitaka Ushikubi, MD

From the Departments of Pharmacology (C.-Y.X., K.Y., A.H., T.F., S.K., T.Y., K.T., O.T., H.K., F.U.) and Biochemistry (T.T.), Asahikawa Medical College, and the Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto (S.N.), Japan.

Correspondence to Fumitaka Ushikubi, MD, Department of Pharmacology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan. E-mail ushikubi{at}asahikawa-med.ac.jp

Received October 15, 2003; revision received February 3, 2004; accepted February 10, 2004.

Background— In the heart with acute myocardial infarction, production of prostaglandin (PG) E₂ increases significantly. In addition, several subtypes of PGE₂ receptors (EPs) have been reported to be expressed in the heart. The role of PGE₂ in cardiac ischemia-reperfusion (I/R) injury, however, remains unknown. We intended to clarify the role of PGE₂ via EP₄, an EP subtype, in I/R injury using mice lacking EP₄ (EP₄^–/– mice).

Methods and Results— In murine cardiac ventricle, competitive reverse transcription–polymerase chain reaction revealed the highest expression level of EP₄ mRNA among EP mRNAs. EP₄^–/– mice had larger infarct size than wild-type mice in a model of I/R; the left anterior descending coronary artery was occluded for 1 hour, followed by 24 hours of reperfusion. In addition, isolated EP₄^–/– hearts perfused according to the Langendorff technique had greater functional and biochemical derangements in response to I/R than wild-type hearts. In vitro, AE1-329, an EP₄ agonist, raised cAMP concentration remarkably in noncardiomyocytes, whereas the action was weak in cardiomyocytes. When 4819-CD, another EP₄ agonist, was administered 1 hour before coronary occlusion, it reduced infarct size significantly in wild-type mice. Notably, a similar cardioprotective effect was observed even when it was administered 50 minutes after coronary occlusion.

Conclusions— Both endogenous PGE₂ and an exogenous EP₄ agonist protect the heart from I/R injury via EP₄. The potent cardioprotective effects of 4819-CD suggest that the compound would be useful for treatment of acute myocardial infarction.

Key Words: prostaglandins • ischemia • reperfusion • myocardial infarction

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