The COX-2/PGI2 receptor axis plays an obligatory role in mediating the cardioprotection conferred by the late phase of ischemic preconditioning

PLoS One. 2012;7(7):e41178. doi: 10.1371/journal.pone.0041178. Epub 2012 Jul 23.


Background: Pharmacologic studies with cyclooxygenase-2 (COX-2) inhibitors suggest that the late phase of ischemic preconditioning (PC) is mediated by COX-2. However, nonspecific effects of COX-2 inhibitors cannot be ruled out, and the selectivity of these inhibitors for COX-2 vs. COX-1 is only relative. Furthermore, the specific prostaglandin (PG) receptors responsible for the salubrious actions of COX-2-derived prostanoids remain unclear.

Objective: To determine the role of COX-2 and prostacyclin receptor (IP) in late PC by gene deletion.

Methods: COX-2 knockout (KO) mice (COX-2(-/-)), prostacyclin receptor KO (IP(-/-)) mice, and respective wildtype (WT, COX-2(+/+) and IP(+/+)) mice underwent sham surgery or PC with six 4-min coronary occlusion (O)/4-min R cycles 24 h before a 30-min O/24 h R.

Results: There were no significant differences in infarct size (IS) between non-preconditioned (non-PC) COX-2(+/+), COX-2(-/-), IP(+/+), and IP(-/-) mice, indicating that neither COX-2 nor IP modulates IS in the absence of PC. When COX-2(-/-) or IP(-/-) mice were preconditioned, IS was not reduced, indicating that the protection of late PC was completely abrogated by deletion of either the COX-2 or the IP gene. Administration of the IP selective antagonist, RO3244794 to C57BL6/J (B6) mice 30 min prior to the 30-min O had no effect on IS. When B6 mice were preconditioned 24 h prior to the 30-min O, IS was markedly reduced; however, the protection of late PC was completely abrogated by pretreatment of RO3244794.

Conclusions: This is the first study to demonstrate that targeted disruption of the COX-2 gene completely abrogates the infarct-sparing effect of late PC, and that the IP, downstream of the COX-2/prostanoid pathway, is a key mediator of the late PC. These results provide unequivocal molecular genetic evidence for an essential role of the COX-2/PGI2 receptor axis in the cardioprotection afforded by the late PC.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzofurans / pharmacology
  • Cyclooxygenase 2 / deficiency
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Gene Knockout Techniques
  • Heart Rate / drug effects
  • Ischemic Preconditioning, Myocardial*
  • Liver / drug effects
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Mice
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / prevention & control
  • Myocardium / enzymology
  • Myocardium / metabolism*
  • Pilot Projects
  • Propionates / pharmacology
  • Receptors, Epoprostenol / antagonists & inhibitors
  • Receptors, Epoprostenol / deficiency
  • Receptors, Epoprostenol / genetics
  • Receptors, Epoprostenol / metabolism*
  • Temperature
  • Time Factors


  • Benzofurans
  • Propionates
  • RO3244794
  • Receptors, Epoprostenol
  • Cyclooxygenase 2