TY - JOUR
T1 - The COX-2/PGI2 receptor axis plays an obligatory role in mediating the cardioprotection conferred by the late phase of ischemic preconditioning
AU - Guo, Yiru
AU - Tukaye, Deepali Nivas
AU - Wu, Wen Jian
AU - Zhu, Xiaoping
AU - Book, Michael
AU - Tan, Wei
AU - Jones, Steven P.
AU - Rokosh, Gregg
AU - Narumiya, Shuh
AU - Li, Qianhong
AU - Bolli, Roberto
PY - 2012/7/23
Y1 - 2012/7/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84864206593&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0041178
DO - 10.1371/journal.pone.0041178
M3 - Article
C2 - 22844439
AN - SCOPUS:84864206593
SN - 1932-6203
VL - 7
JO - PloS one
JF - PloS one
IS - 7
M1 - e41178
ER -