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1 Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan; Division of Respiratory Medicine, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
2 Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan
3 Division of Biomedical Imaging Research, Biomedical Research Center, Juntendo University School of Medicine, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: htakahashi{at}tmgh.metro.tokyo.jp.
Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR-II) and dysfunction of BMPR-II have been implicated in patients with primary pulmonary hypertension (PH). To clarify the possible involvement of bone morphogenetic protein (BMP) and BMPR-II in the development of hypoxic PH, the expression of BMP-2, BMPR-II and their downstream signals was investigated in rat lung under normal and hypoxic conditions by RT-PCR, immunoblot, and immunohistochemical methods. In rats under normal conditions, BMP-2 is localized in the endothelium of the pulmonary artery while BMPR-II is abundantly expressed in the endothelium, smooth muscle cells and adventitial fibroblasts. After 0.5 and 3 days of exposure to hypoxia, up-regulation of BMP-2 was observed in the intra-pulmonary arteries. The change was accompanied with activation of its downstream signaling, p38 mitogen-activated protein kinase (MAPK), Erk 1/2 MAPK and apoptotic process measured by caspase-3 activity and TUNEL positive cells. In contrast, a significant decrease in the expression of BMPR-II and inactivation of p38 MAPK and caspase-3 were observed in the pulmonary vasculature after 7 to 21 days of exposure to hypoxia. Since BMP-2 is known to inhibit proliferation of vascular smooth muscle cells and promote cellular apoptosis, disruption of BMP signaling pathway through down-regulation of BMPR-II in chronic hypoxia may result in pulmonary vascular remodeling due to the failure of critical anti-proliferative/ differentiation programs in the pulmonary vasculature. These results suggest abrogation of BMP signaling may be a common molecular pathogenesis in the development of PH with various pathophysiological events, including primary and hypoxic PH.
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