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Hypoxic Induction of Cox-2 Regulates Proliferation of Human Pulmonary Artery Smooth Muscle Cells

Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge; and Section on Clinical Pharmacology, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom

Address correspondence to: Dr. Nicholas W. Morrell, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Box 157, Hills Road, Cambridge CB2 2QQ, UK. E-mail: nwm23{at}cam.ac.uk

Chronic hypoxia-induced pulmonary hypertension results partly from proliferation of smooth muscle cells in small peripheral pulmonary arteries. Therefore, we examined the effect of hypoxia on growth of pulmonary artery smooth muscle cells (PASMCs) from human distal pulmonary arteries. Initial studies identified that serum-induced proliferation of explant-derived PASMCs was inhibited under hypoxic conditions (3–4 kPa in medium). However, selection of hypoxia-stimulated cells was achieved by culturing cells at low density under conditions of prolonged hypoxia (1–2 wk). In hypoxia-inhibited and -stimulated cells, Western blotting revealed hypoxic induction of cyclooxygenase (COX)-2, which was dependent on the activation of p38^MAPK, but not COX-1, inducible nitric oxide synthase (iNOS), or hemoxygenase-1 (HO-1). Hypoxic induction of COX-2 was also observed in the media of pulmonary arteries in lung organ culture. Hypoxia induced a 4- to 5-fold increase (P < 0.001) in prostaglandin (PG)E₂, PGD₂, PGF₂, and 6-keto-PGF₁ release from PASMCs. Hypoxic inhibition of proliferation was attenuated by incubation with indomethacin (10 µM), or the COX-2 antagonist, NS398 (10 µM), but not by the COX-1 antagonist, valeryl salicylate (0.5 mM). In conclusion, we have isolated cells from human peripheral pulmonary arteries that are either inhibited or stimulated by culture under hypoxic conditions. In both cell types hypoxia modulates cell proliferation by induction of COX-2 and production of antiproliferative prostaglandins. Induction of COX-2 may contribute to the inhibition of hypoxia-induced pulmonary vascular remodeling.

Abbreviations: carbon monoxide, CO • cyclooxygenase, COX • Dulbecco's modified Eagle's medium, DMEM • fetal bovine serum, FBS • heme oxygenase-1, HO-1 • interleukin, IL • inducible nitric oxide synthase, iNOS • nitric oxide, NO • pulmonary artery smooth muscle cells, PASMCs • prostaglandin, PG • S-Nitroso-N-acetylpenicillamine, SNAP • valeryl salicylate, VS

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