Intravascular thrombosis after hypoxia-induced pulmonary hypertension - Regulation by cyclooxygenase-2

Article

关键词: SMOOTH-MUSCLE-CELLS;    ARTERIAL-HYPERTENSION;    PLATELET-AGGREGATION;    ENDOTHELIAL-CELLS;    PROSTACYCLIN;    INHIBITION;    A(2);    INDUCTION;    DISEASE;    PROLIFERATION;   

DOI  :  10.1161/01.CIR.0000145613.01188.0B

来源: SCIE

【 摘 要 】

Background-Pulmonary hypertension induced by chronic hypoxia is characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, and right-heart failure. Prostacyclin analogues reduce pulmonary pressures in this condition; raising the possibility that cycloxygenase-2 (COX-2) modulates the response of the pulmonary vasculature to hypoxia. Methods and Results-Sprague-Dawley rats in which pulmonary hypertension was induced by hypobaric hypoxia for 14 days were treated concurrently with the selective COX-2 inhibitor SC236 or vehicle. Mean pulmonary arterial pressure (mPAP) was elevated after hypoxia (28.1+/-3.2 versus 17.2+/-3.1 mm Hg; n=8, P<0.01), with thickening of small pulmonary arteries and increased COX-2 expression and prostacyclin formation. Selective inhibition of COX-2 aggravated the increase in mPAP (42.8&PLUSMN;5.9 mm Hg; n=8, P<0.05), an effect that was attenuated by the thromboxane (TX) A(2)/prostaglandin endoperoxide receptor antagonist ifetroban. Urinary TXB2 increased during hypoxia (5.9+/-0.9 versus 1.2+/-0.2 ng/mg creatinine; n=6, P<0.01) and was further increased by COX-2 inhibition (8.5&PLUSMN;0.7 ng/mg creatinine; n=6, P<0.05). In contrast, urinary excretion of the prostacyclin metabolite 6-ketoprostaglandin F-1alpha decreased with COX-2 inhibition (8.6+/-3.0 versus 27.0+/-4.8 ng/mg creatinine; n=6, P<0.05). Platelet activation was enhanced after chronic hypoxia. COX-2 inhibition further reduced the PFA-100 closure time and enhanced platelet deposition in the smaller pulmonary arteries, effects that were attenuated by ifetroban. Mice with targeted disruption of the COX-2 gene exposed to chronic hypoxia had exacerbated right ventricular end-systolic pressure, whereas targeted disruption of COX-1 had no effect. Conclusions-COX-2 expression is increased and regulates platelet activity and intravascular thrombosis in hypoxia-induced pulmonary hypertension.

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