1. Prostaglandin E2 protects the heart from ischemia-reperfusion injury via its receptor subtype EP4
- Author
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Koh-ichi Yuhki, Hideji Karibe, Chun Yang Xiao, Takayuki Fujino, Shuhko Kuriyama, Akiyoshi Hara, Fumitaka Ushikubi, Shuh Narumiya, Takanobu Taniguchi, Koji Takayama, Osamu Takahata, and Takehiro Yamada
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Agonist ,Male ,Methyl Ethers ,medicine.medical_specialty ,Cardiotonic Agents ,旭川医科大学：博士（医学）（乙第376号） ,medicine.drug_class ,medicine.medical_treatment ,Heart Ventricles ,Ischemia ,Myocardial Infarction ,Prostaglandin ,Myocardial Reperfusion Injury ,Dinoprostone ,chemistry.chemical_compound ,Mice ,学位授与年月日：平成16年6月30日 ,Physiology (medical) ,Internal medicine ,medicine ,Cyclic AMP ,Animals ,Receptors, Prostaglandin E ,Myocytes, Cardiac ,Myocardial infarction ,RNA, Messenger ,Prostaglandin E2 ,Receptor ,Mice, Knockout ,business.industry ,medicine.disease ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Anesthesia ,Cardiology and Cardiovascular Medicine ,business ,Reperfusion injury ,Receptors, Prostaglandin E, EP4 Subtype ,Prostaglandin E ,medicine.drug - Abstract
Background— In the heart with acute myocardial infarction, production of prostaglandin (PG) E 2 increases significantly. In addition, several subtypes of PGE 2 receptors (EPs) have been reported to be expressed in the heart. The role of PGE 2 in cardiac ischemia-reperfusion (I/R) injury, however, remains unknown. We intended to clarify the role of PGE 2 via EP 4 , an EP subtype, in I/R injury using mice lacking EP 4 (EP 4 −/− mice). Methods and Results— In murine cardiac ventricle, competitive reverse transcription–polymerase chain reaction revealed the highest expression level of EP 4 mRNA among EP mRNAs. EP 4 −/− 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 EP 4 −/− 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 EP 4 agonist, raised cAMP concentration remarkably in noncardiomyocytes, whereas the action was weak in cardiomyocytes. When 4819-CD, another EP 4 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 PGE 2 and an exogenous EP 4 agonist protect the heart from I/R injury via EP 4 . The potent cardioprotective effects of 4819-CD suggest that the compound would be useful for treatment of acute myocardial infarction.