Prostaglandin E2 mediates the late phase of ischemic preconditioning in the heart via its receptor subtype EP4

• Published in: Heart and vessels 2023-04, Vol.38 (4), p.606-613
• Main Authors: Kanno, Takayasu, Nakagawa, Naoki, Aonuma, Tatsuya, Kawabe, Jun-ichi, Yuhki, Koh-ichi, Takehara, Naofumi, Hasebe, Naoyuki, Ushikubi, Fumitaka
• Format: Article
• Language: English
• Subjects: AKT protein; Biomedical Engineering and Bioengineering; Biosynthesis; Cardiac Surgery; Cardiology; Cardiovascular diseases; Coronary artery; Cyclooxygenase-2; Heart; Heart diseases; Ischemia; Kinases; Medicine; Medicine & Public Health; mRNA; Occlusion; Original; Original Article; Preconditioning; Prostaglandin E2; Receptors; Reperfusion; Vascular Surgery
• ISSN: 0910-8327; 1615-2573
• DOI: 10.1007/s00380-022-02219-4

Ischemic preconditioning (IPC) describes a phenomenon wherein brief ischemia of the heart induces a potent cardioprotective mechanism against succeeding ischemic insult. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostanoid biosynthesis, is upregulated in the ischemic heart and contributes to IPC. Prostaglandin E 2 (PGE 2 ) protects the heart from ischemia–reperfusion (I/R) injury via its receptor subtype EP 4 . We sought to clarify the role of the PGE 2 /EP 4 system in the late phase of IPC. Mice were subjected to four IPC treatment cycles, consisting of 5 min of occlusion of the left anterior descending coronary artery (LAD). We found that COX-2 mRNA was significantly upregulated in wild-type hearts at 6 h after IPC treatment. Cardiac PGE 2 levels at 24 h after IPC treatment were significantly increased in both wild-type mice and mice lacking EP 4 (EP 4 –/– ). At 24 h after IPC treatment, I/R injury was induced by 30 min of LAD occlusion followed by 2 h of reperfusion and the cardiac infarct size was determined. The infarct size was significantly reduced by IPC treatment in wild-type mice; a reduction was not observed in EP 4 –/– mice. AE1-329, an EP 4 agonist, significantly reduced infarct size and significantly ameliorated deterioration of cardiac function in wild-type mice subjected to I/R without IPC treatment. Furthermore, AE1-329 significantly enhanced the I/R-induced activation of Akt, a pro-survival kinase. We demonstrated that the PGE 2 /EP 4 system in the heart plays a critical role in the late phase of IPC, partly by augmenting Akt-mediated signaling. These findings clarify the mechanism of IPC and may contribute to the development of therapeutic strategies for ischemic heart disease.