Document Detail

Cyclooxygenase-2-linked attenuation of hypoxia-induced pulmonary hypertension and intravascular thrombosis.
MedLine Citation:
PMID:  18375790     Owner:  NLM     Status:  MEDLINE    
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 hypobaric-hypoxia 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)B(2) 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-prostacyclin(1alpha) 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 TXA(2)/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 TXA(2), and induces intravascular thrombosis in response to hypoxia. The data provide evidence that endogenous prostaglandins modulate the pulmonary response to hypoxia.
Mary-Clare Cathcart; Rasa Tamosiuniene; Gang Chen; Tomas G Neilan; Aidan Bradford; Kenneth J O'Byrne; Desmond J Fitzgerald; Graham P Pidgeon
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-03-28
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  326     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-06-19     Completed Date:  2008-07-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  51-8     Citation Subset:  IM    
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons Ireland, Dublin, Ireland.
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MeSH Terms
Anoxia / complications,  enzymology*,  genetics
Cyclooxygenase 2 / genetics,  physiology*
Hypertension, Pulmonary / enzymology*,  etiology,  genetics
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Knockout
Venous Thrombosis / enzymology*,  etiology,  genetics
Reg. No./Substance:
EC 1.14.99.-/Ptgs2 protein, mouse; EC 2

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