Sheares Karen K K, Jeffery Trina K, Long Lu, Yang Xudong, Morrell Nicholas W
Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge CB2 2QQ, United Kingdom.
Am J Physiol Lung Cell Mol Physiol. 2004 Nov;287(5):L919-27. doi: 10.1152/ajplung.00012.2004. Epub 2004 Jun 25.
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 transforming growth factor (TGF)-beta superfamily plays a critical role in the regulation of pulmonary vascular remodeling, although 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-beta1 and bone morphogenetic protein (BMP)-4 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 p38(MAPK) 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-beta1 induced COX-2 mRNA and protein expression, and our findings demonstrate that release of TGF-beta1 by PASMCs during hypoxia contributes to the hypoxic induction of COX-2 via the p38MAPK pathway. In contrast, BMP-4 inhibited the hypoxic induction of COX-2 by an MAPK-independent pathway. Together, these findings suggest that the TGF-beta superfamily is part of an autocrine/paracrine system involved in the regulation of COX-2 expression in the distal pulmonary circulation, and this modulates hypoxia-induced pulmonary vascular cell proliferation.
慢性缺氧诱导的肺动脉高压部分源于外周小肺动脉平滑肌细胞的增殖。此前，我们证明缺氧通过诱导环氧化酶-2（COX-2）和产生抗增殖前列腺素，调节人外周肺动脉平滑肌细胞（PASMCs）的增殖。转化生长因子（TGF）-β超家族在肺血管重塑的调节中起关键作用，尽管迄今为止尚未研究其与缺氧的相互作用。因此，我们研究了外周PASMCs中COX-2缺氧诱导所涉及的信号通路，以及TGF-β1和骨形态发生蛋白（BMP）-4在此反应中的作用。在本研究中，我们证明缺氧可诱导PASMCs中p38MAPK、ERK1/2和Akt的激活，并且这些信号通路参与了COX-2的缺氧调节。抑制p38（MAPK）或ERK1/2活性可抑制COX-2的缺氧诱导，而抑制磷酸肌醇3激酶通路则增强COX-2的缺氧诱导。此外，外源性TGF-β1可诱导COX-2 mRNA和蛋白表达，我们的研究结果表明，缺氧期间PASMCs释放的TGF-β1通过p38MAPK信号通路促进COX-2的缺氧诱导。相反，BMP-4通过一条不依赖MAPK的信号通路抑制COX-2的缺氧诱导。总之，这些发现表明，TGF-β超家族是远端肺循环中参与调节COX-2表达的自分泌/旁分泌系统的一部分，这调节了缺氧诱导的肺血管细胞增殖。
