Cyclooxygenase-2-linked attenuation of hypoxia-induced pulmonary hypertension and intravascular thrombosis

Cathcart, Mary Clare, Tamosiuniene, Rasa, Cheng, Gang, Neilan, Tomas G., Bradford, Aidan, O'Byrne, Kenneth J., Fitzgerald, Desmond J., & Pidgeon, Graham P. (2008) Cyclooxygenase-2-linked attenuation of hypoxia-induced pulmonary hypertension and intravascular thrombosis. Journal of Pharmacology and Experimental Therapeutics, 326(1), pp. 51-58.

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Abstract

Exogenous prostacyclin is effective in reducing pulmonary vascular resistance in some forms of human pulmonary hypertension (PH). To explore whether endogenous prostaglandins played a similar role in pulmonary hypertension, we examined the effect of deleting cyclooxygenase (COX)-gene isoforms in a chronic hypoxia model of PH. Pulmonary hypertension, examined by direct measurement of right ventricular end systolic pressure (RVESP), right ventricular hypertrophy (n = 8), and hematocrit (n = 3), was induced by 3 weeks of hypobarichypoxia in wild-type and COX-knockout (KO) mice. RVESP was increased in wild-type hypoxic mice compared with normoxic controls (24.4 ± 1.4 versus 13.8 ± 1.9 mm Hg; n = 8; p < 0.05). COX-2 KO mice showed a greater increase in RVESP following hypoxia (36.8 ± 2.7 mm Hg; p < 0.05). Urinary thromboxane (TX)B2 excretion increased following hypoxia (44.6 ± 11.1 versus 14.7 ± 1.8 ng/ml; n = 6; p < 0.05), an effect that was exacerbated by COX-2 gene disruption (54.5 ± 10.8 ng/ml; n = 6). In contrast, the increase in 6-keto-prostacyclin1α excretion following hypoxia was reduced by COX-2 gene disruption (29 ± 3 versus 52 ± 4.6 ng/ml; p < 0.01). Tail cut bleed times were lower following hypoxia, and there was evidence of intravascular thrombosis in lung vessels that was exacerbated by disruption of COX-2 and reduced by deletion of COX-1. The TXA2/endoperoxide receptor antagonist ifetroban (50 mg/kg/day) offset the effect of deleting the COX-2 gene, attenuating the hypoxia-induced rise in RVESP and intravascular thrombosis. COX-2 gene deletion exacerbates pulmonary hypertension, enhances sensitivity to TXA2, and induces intravascular thrombosis in response to hypoxia. The data provide evidence that endogenous prostaglandins modulate the pulmonary response to hypoxia. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.

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ID Code: 64856
Item Type: Journal Article
Refereed: Yes
Additional Information: All articles after 12 months back to 1 Jan 1997.
Additional URLs:
Keywords: 6 ketoprostacyclin, cyclooxygenase 1, cyclooxygenase 2, endoperoxide receptor antagonist, ifetroban, prostacyclin, receptor blocking agent, thromboxane A2, thromboxane A2 receptor blocking agent, thromboxane B2, animal experiment, animal model, animal tissue, article, comparative study, controlled study, disease exacerbation, female, gene deletion, gene disruption, heart right ventricle end systolic pressure, heart right ventricle hypertrophy, heart right ventricle pressure, hematocrit, hypoxia, knockout mouse, lung blood vessel, measurement, mouse, nonhuman, priority journal, pulmonary hypertension, thrombosis, urinary excretion, wild type, Animals, Anoxia, Hypertension, Pulmonary, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Venous Thrombosis
DOI: 10.1124/jpet.107.134221
ISSN: 0022-3565
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2008 American Society for Pharmacology and Experimental Therapeutics
Deposited On: 27 Nov 2013 07:50
Last Modified: 02 Feb 2015 03:23

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