Prostaglandin E2 protects the heart from ischemia-reperfusion injury via its receptor subtype EP4.

نویسندگان

  • Chun-Yang Xiao
  • Koh-ichi Yuhki
  • Akiyoshi Hara
  • Takayuki Fujino
  • Shuhko Kuriyama
  • Takehiro Yamada
  • Koji Takayama
  • Osamu Takahata
  • Hideji Karibe
  • Takanobu Taniguchi
  • Shuh Narumiya
  • Fumitaka Ushikubi
چکیده

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.

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عنوان ژورنال:
  • Circulation

دوره 109 20  شماره 

صفحات  -

تاریخ انتشار 2004