Role of prostacyclin in the cardiovascular response to thromboxane A2.
Thromboxane (Tx) A2 is a vasoconstrictor and platelet agonist. Aspirin affords cardioprotection through inhibition of TxA2 formation by platelet cyclooxygenase (COX-1). Prostacyclin (PGI2) is a vasodilator that inhibits platelet function. Here we show that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI2 receptor (IP) but are depressed in mice genetically deficient in the TxA2 receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TxA2. This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PGI2 but not TxA2.
Cheng
Yan
Y
Center for Experimental Therapeutics, 153 Johnson Pavilion, 3620 Hamilton Walk, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA.
Austin
Sandra C
SC
Rocca
Bianca
B
Koller
Beverly H
BH
Coffman
Thomas M
TM
Grosser
Tilo
T
Lawson
John A
JA
FitzGerald
Garret A
GA
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D020212:Carotid Artery Injuries / Q000473:pathology; D017536:Carotid Artery, Common / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002455:Cell Division; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011464:Epoprostenol / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007783:Lactones / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011422:Propionates; D011451:Prostaglandin-Endoperoxide Synthases; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000502:physiology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D013450:Sulfones; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013928:Thromboxane A2 / Q000502:physiology*; D017539:Tunica Intima / Q000166:cytology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D009281:Naphthalenes; D011422:Propionates; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013450:Sulfones; D013764:Tetrahydronaphthalenes; C116926:rofecoxib; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C501362:terutroban; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases