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1 AND BMP4 ON THE HYPOXIC INDUCTION OF CYCLOOXYGENASE-2 IN HUMAN PULMONARY ARTERY SMOOTH MUSCLE CELLS
1 Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, Cambridgeshire, United Kingdom
* To whom correspondence should be addressed. 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. Previously we demonstrated
that hypoxia modulates the proliferation of human peripheral pulmonary artery smooth muscle cells (PASMCs) by induction of cyclooxygenase-2 (COX-2) and production of
antiproliferative prostaglandins. The TGF-
superfamily plays a critical role in the regulation of pulmonary vascular remodeling, though to date an interaction with hypoxia has not been examined. We therefore investigated the pathways involved in the hypoxic
induction of COX-2 in peripheral PASMCs and the contribution of TGF-1 and BMP4 in
this response. In the present study we demonstrate that hypoxia induces activation of p38MAPK, ERK1/2 and Akt in PASMCs and that these pathways are involved in the hypoxic regulation of COX-2. Whereas inhibition of p38MAPK or ERK1/2 activity suppressed hypoxic induction of COX-2, inhibition of the phosphoinositide-3-kinase pathway enhanced hypoxic induction of COX-2. Furthermore, exogenous TGF-1 induced COX-2 mRNA and protein expression, and our findings demonstrate that release of TGF-1 by PASMCs during hypoxia contributes to the hypoxic induction of COX-2
via the p38MAPK pathway. In contrast, BMP4 inhibited the hypoxic-induction of COX-2 by a MAPK- independent pathway. Taken together, these findings suggest that the TGF- superfamily are part of an autocrine/paracrine system involved in the regulation of
COX-2 expression in the distal pulmonary circulation and this modulates hypoxiainduced pulmonary vascular cell proliferation.
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