title: The COX-2/PGI2 receptor axis plays an obligatory role in mediating the cardioprotection conferred by the late phase of ischemic preconditioning.
abstract: 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.
authors: Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, United States of America.
authors: Yiru
authors: Y
authors: Guo
authors: Deepali Nivas
authors: DN
authors: Tukaye
authors: Wen-Jian
authors: WJ
authors: Wu
authors: Xiaoping
authors: X
authors: Zhu
authors: Michael
authors: M
authors: Book
authors: Wei
authors: W
authors: Tan
authors: Steven P
authors: SP
authors: Jones
authors: Gregg
authors: G
authors: Rokosh
authors: Shuh
authors: S
authors: Narumiya
authors: Qianhong
authors: Q
authors: Li
authors: Roberto
authors: R
authors: Bolli
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006339:Heart Rate / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010865:Pilot Projects; D011422:Propionates / Q000494:pharmacology; D044006:Receptors, Epoprostenol / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013696:Temperature; D013997:Time Factors
chemical_list: D001572:Benzofurans; D011422:Propionates; C515593:RO3244794; D044006:Receptors, Epoprostenol; D051546:Cyclooxygenase 2