Cyclooxygenase isozyme expression and intimal hyperplasia in a rat model of balloon angioplasty.
Prostaglandin formation is enhanced in vascular disease, in part through induction of cyclooxygenase (COX-2) in vascular smooth muscle cells. Because COX regulates cell growth and migration, we examined whether the COX expression plays a role in the development of intimal hyperplasia after vascular injury. Rats undergoing balloon angioplasty of the carotid artery were randomized to receive a selective COX-2 inhibitor (SC-236), a selective COX-1 inhibitor (SC-560) or a combination of the two. Normal, uninjured vessels showed COX-1, but no COX-2 expression. Fourteen days after balloon injury, both COX-1 and COX-2 were expressed in the neointima. Balloon angioplasty resulted in a marked increase in the urinary excretion of prostaglandin (PG) E(2,) PGF(2alpha), and thromboxane (TX) B(2). Both the COX-1 inhibitor SC-560 and the COX-2 inhibitor SC-236 suppressed the generation of PGE(2) and PGF(2alpha), particularly when combined, suggesting a role for both isozymes in the generation of prostaglandins in this model. In contrast, TXA(2) was markedly suppressed by the COX-1 inhibitor SC-560. COX-2 inhibition with SC-236 had no effect on intimal hyperplasia at day 14 (0 versus 8.5%; n = 7 in controls). In contrast, intimal hyperplasia was reduced by SC-560 when administered alone (by 42%; n = 7, p < 0.05) or in combination with SC-236 (by 40%; n = 7, p < 0.05). COX-1 may play a role in the development of intimal hyperplasia, potentially through the inhibition of platelet TXA(2). Despite being expressed in the neointima, COX-2 does not play a role in the development of intimal hyperplasia after vascular injury.
Connolly
Elizabeth
E
Department of Clinical Pharmacology and Surgery, and Institute of Biopharmaceutical Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
Bouchier-Hayes
David J
DJ
Kaye
Elaine
E
Leahy
Austin
A
Fitzgerald
Desmond
D
Belton
Orina
O
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D002339:Carotid Arteries / Q000201:enzymology; D051545:Cyclooxygenase 1; D017931:DNA Primers; D015237:Dinoprost / Q000097:blood; D015777:Eicosanoids / Q000652:urine; D006083:Graft Occlusion, Vascular / Q000201:enzymology; D006965:Hyperplasia / Q000201:enzymology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013929:Thromboxane B2 / Q000097:blood; D017539:Tunica Intima / Q000201:enzymology* / Q000473:pathology*
D017931:DNA Primers; D015777:Eicosanoids; D007527:Isoenzymes; D008565:Membrane Proteins; D013929:Thromboxane B2; D015237:Dinoprost; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat