Prostacyclin attenuates oxidative damage of myocytes by opening mitochondrial ATP-sensitive K+ channels via the EP3 receptor

Ken Shinmura, Kayoko Tamaki, Toshiaki Sato, Hideyuki Ishida, Roberto Bolli

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Prostacyclin (PGI2) and the PGE family alleviate myocardial ischemia-reperfusion injury and limit oxidative damage. The cardioprotective effects of PGI2 have been traditionally ascribed to activation of IP receptors. Recent advances in prostanoid research have revealed that PGI 2 can bind not only to IP, but also to EP, receptors, suggesting cross talk between PGI2 and PGEs. The mechanism(s) whereby PGI 2 protects myocytes from oxidative damage and the specific receptors involved remain unknown. Thus fresh isolated adult rat myocytes were exposed to 200 μM H2O2 with or without carbaprostacyclin (cPGI2), IP-selective agonists, and ONO-AE-248 (an EP 3-selective agonist). Cell viability was assessed by trypan blue exclusion after 30 min of H2O2 superfusion. cPGI 2 and ONO-AE-248 significantly improved cell survival during H 2O2 superfusion; IP-selective agonists did not. The protective effect of cPGI2 and ONO-AE-248 was completely abrogated by pretreatment with 5-hydroxydecanoate or glibenclamide. In the second series of experiments, the mitochondrial ATP-sensitive K+ (KATP) channel opener diazoxide (Dx) reversibly oxidized flavoproteins in control myocytes. Exposure to prostanoid analogs alone had no effect on flavoprotein fluorescence. A second application of Dx in the presence of cPGI2 or ONO-AE-248 significantly increased flavoprotein fluorescence compared with Dx alone, but IP-selective agonists did not. This study demonstrates that PGI 2 analogs protect cardiac myocytes from oxidative stress mainly via activation of EP3. The data also indicate that activation of EP 3 receptors primes the opening of mitochondrial KATP channels and that this mechanism is essential for EP3-dependent protection.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume288
Issue number5 57-5
DOIs
Publication statusPublished - 2005 May

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Epoprostenol
Diazoxide
Flavoproteins
Muscle Cells
Prostaglandins E
Prostaglandins
Cell Survival
Receptor Cross-Talk
Fluorescence
Myocardial Reperfusion Injury
KATP Channels
Trypan Blue
Glyburide
Reperfusion Injury
Cardiac Myocytes
Myocardial Ischemia
Oxidative Stress
Adenosine Triphosphate
mitochondrial K(ATP) channel
ONO AE 248

Keywords

  • Flavoprotein fluorescence
  • IP receptor
  • Oxidative stress
  • Prostaglandin

ASJC Scopus subject areas

  • Physiology

Cite this

Prostacyclin attenuates oxidative damage of myocytes by opening mitochondrial ATP-sensitive K+ channels via the EP3 receptor. / Shinmura, Ken; Tamaki, Kayoko; Sato, Toshiaki; Ishida, Hideyuki; Bolli, Roberto.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 288, No. 5 57-5, 05.2005.

Research output: Contribution to journalArticle

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