COX-1(+/-)COX-2(-/-) Genotype in Mice is Associated with Shortened Time to Carotid Artery Occlusion Through Increased PAI-1

Overview

Journal J Thromb Haemost

Publisher Elsevier

Specialty Hematology

Date 2010 Dec 9

PMID 21138526

Citations 1

Authors

T E Riehl

L He

L Zheng

S Greco

D M Tollefsen

W F Stenson

Affiliations

Soon will be listed here.

Abstract

Background: We found a high incidence of thrombotic deaths in COX-1(+/-)COX-2(-/-) mice and sought to define the mechanism of these events. The cyclooxygenase products thromboxane A(2) and prostacyclin are important in the regulation of coagulation but their role in fibrinolysis is largely unexplored. PAI-1 blocks fibrinolysis by inhibiting plasminogen activator.

Aim: Our objective was to explain the mechanism of increased thrombosis associated with the COX-1(+/-)COX-2(-/-) genotype.

Methods: Carotid artery occlusion times were measured after photochemical injury. PAI-1 levels were measured in the plasma by ELISA. PAI-1 levels in the aorta were measured by RT-PCR and Western blotting. Urinary metabolites of Thromboxane A(2) and prostacyclin were measured by ELISA.

Results: The COX-1(+/-)COX-2(-/-) genotype is associated with a decreased time to occlusion in the carotid artery thrombosis model (30 ± 5 minutes vs 60 ± minutes in wild type, p<.001). The COX-1(-/-)COX-2(+/+), COX-1(+/-)COX-2(+/-) and COX-1(+/-)COX-2(+/+) all had occlusion times similar to wild type. COX-1(+/+)COX-2(-/-) had a prolonged occlusion time. COX-1(+/-)COX-2(-/-) had increased PAI-1 levels in the plasma and aorta and with a prolonged euglobulin lysis time (37.4 ± 10.2 hours vs 15.6 ± 9.8 hours in wild type, p<.004). The decreased time to occlusion in the COX-1(+/-)COX2(-/-) mice was normalized by an inhibitory antibody to PAI-1 whereas the antibody had no effect on the time to occlusion in wild type mice.

Conclusion: The COX-1(+/-)COX-2(-/-) genotype is associated with a shortened time to occlusion in the carotid thrombosis model and the shortened time to occlusion is mediated through increased PAI-1 levels resulting in decreased fibrinolysis.

Citing Articles

Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2-/- mice by increasing NO and prostacyclin to reduce platelet spreading and glycoprotein VI activation.

Fang C, Stavrou E, Schmaier A, Grobe N, Morris M, Chen A Blood. 2013; 121(15):3023-32.

PMID: 23386129 PMC: 3624945. DOI: 10.1182/blood-2012-09-459156.

References

Baenziger N, Becherer P, MAJERUS P . Characterization of prostacyclin synthesis in cultured human arterial smooth muscle cells, venous endothelial cells and skin fibroblasts. Cell. 1979; 16(4):967-74. DOI: 10.1016/0092-8674(79)90111-9. View

Cheng Y, Wang M, Yu Y, Lawson J, Funk C, FitzGerald G . Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function. J Clin Invest. 2006; 116(5):1391-9. PMC: 1435722. DOI: 10.1172/JCI27540. View

Morham S, Langenbach R, Loftin C, Tiano H, Vouloumanos N, Jennette J . Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell. 1995; 83(3):473-82. DOI: 10.1016/0092-8674(95)90125-6. View

Creminon C, Habib A, Maclouf J, Pradelles P, Grassi J, Frobert Y . Differential measurement of constitutive (COX-1) and inducible (COX-2) cyclooxygenase expression in human umbilical vein endothelial cells using specific immunometric enzyme immunoassays. Biochim Biophys Acta. 1995; 1254(3):341-8. DOI: 10.1016/0005-2760(94)00197-7. View

Kohler H, Grant P . Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med. 2000; 342(24):1792-801. DOI: 10.1056/NEJM200006153422406. View

Dupont D, Blouse G, Hansen M, Mathiasen L, Kjelgaard S, Jensen J . Evidence for a pre-latent form of the serpin plasminogen activator inhibitor-1 with a detached beta-strand 1C. J Biol Chem. 2006; 281(47):36071-81. DOI: 10.1074/jbc.M606851200. View

Carmeliet P, Stassen J, Schoonjans L, Ream B, van den Oord J, de Mol M . Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest. 1993; 92(6):2756-60. PMC: 288474. DOI: 10.1172/JCI116893. View

Kurien B, Scofield R . Mouse urine collection using clear plastic wrap. Lab Anim. 2000; 33(1):83-6. DOI: 10.1258/002367799780578525. View

Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C . Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987; 2(8549):3-9. DOI: 10.1016/s0140-6736(87)93050-9. View

10.

A Smith A, Jacobson L, Miller B, Hathaway W, Manco-Johnson M . A new euglobulin clot lysis assay for global fibrinolysis. Thromb Res. 2004; 112(5-6):329-37. DOI: 10.1016/j.thromres.2004.01.001. View

11.

Solomon S, Wittes J, Finn P, Fowler R, Viner J, Bertagnolli M . Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation. 2008; 117(16):2104-13. PMC: 2965408. DOI: 10.1161/CIRCULATIONAHA.108.764530. View

12.

Davis B, Lennard D, Lee C, Tiano H, Morham S, Wetsel W . Anovulation in cyclooxygenase-2-deficient mice is restored by prostaglandin E2 and interleukin-1beta. Endocrinology. 1999; 140(6):2685-95. DOI: 10.1210/endo.140.6.6715. View

13.

Dinchuk J, Car B, Focht R, Johnston J, Jaffee B, Covington M . Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature. 1995; 378(6555):406-9. DOI: 10.1038/378406a0. View

14.

NEEDLEMAN P, Moncada S, Bunting S, Vane J, Hamberg M, Samuelsson B . Identification of an enzyme in platelet microsomes which generates thromboxane A2 from prostaglandin endoperoxides. Nature. 1976; 261(5561):558-60. DOI: 10.1038/261558a0. View

15.

James M, Walsh J . Inter-relationships between vascular thromboxane and prostacyclin synthesis. Prostaglandins Leukot Essent Fatty Acids. 1988; 31(2):91-5. DOI: 10.1016/0952-3278(88)90081-6. View

16.

Moncada S, Gryglewski R, Bunting S, Vane J . An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976; 263(5579):663-5. DOI: 10.1038/263663a0. View

17.

Westrick R, Winn M, Eitzman D . Murine models of vascular thrombosis (Eitzman series). Arterioscler Thromb Vasc Biol. 2007; 27(10):2079-93. DOI: 10.1161/ATVBAHA.107.142810. View

18.

Atsuta H, Uchiyama T, Kanai H, Iso T, Tanaka T, Suga T . Effects of a stable prostacyclin analogue beraprost sodium on VEGF and PAI-1 gene expression in vascular smooth muscle cells. Int J Cardiol. 2008; 132(3):411-8. DOI: 10.1016/j.ijcard.2007.12.119. View

19.

Fosbol E, Gislason G, Jacobsen S, Folke F, Hansen M, Schramm T . Risk of myocardial infarction and death associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther. 2008; 85(2):190-7. DOI: 10.1038/clpt.2008.204. View

20.

Cozzolino D, Coppola L, Masi S, Salvatore T, Sasso F, De Lucia D . Short- and long-term treatments with iloprost in diabetic patients with peripheral vascular disease: effects on the cardiovascular risk factor plasminogen activator inhibitor type-1. Eur J Clin Pharmacol. 1999; 55(7):491-7. DOI: 10.1007/s002280050662. View