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1 Department of Medicine, University of California, San Diego, San Diego, CA, USA
2 Department of Pathology, University of California, San Diego, San Diego, CA, USA
3 Department of Surgery, University of California, San Diego, San Diego, CA, USA
* To whom correspondence should be addressed. E-mail: xiyuan{at}ucsd.edu.
Pulmonary vascular medial hypertrophy in primary pulmonary hypertension (PPH) is mainly caused by increased proliferation and decreased apoptosis in pulmonary artery smooth muscle cells (PASMC). Mutations of the bone morphogenetic protein (BMP) receptor type II (BMP-RII) gene have been implicated in patients with familial and sporadic PPH. The objective of this study was to elucidate apoptotic effects of BMPs on normal human PASMC and to examine whether BMPinduced effect is altered in PASMC from PPH patients. Using RT-PCR, we detected 6 isoforms of BMPs, BMP1-6, and three subunits of BMP receptors, BMP-RIa, -RIb and -RII in PASMC. Treatment of normal PASMC with BMP2 or BMP7 (100-200 nM, 24-48 hrs) markedly increased percentage of the cells undergoing apoptosis. The BMP2-mediated apoptosis in normal PASMC was associated with a transient activation or phosphorylation of Smad1 and with a marked downregulation of Bcl-2, an antiapoptotic protein. In PASMC from PPH patients, the BMP2- or BMP7-induced apoptosis was significantly inhibited in comparison to PASMC from patients with secondary pulmonary hypertension. These results suggest that the antiproliferative effect of BMPs is partially due to induction of PASMC apoptosis, which serves as a critical mechanism to maintain normal cell number in the pulmonary vasculature. Inhibition of BMP-induced PASMC apoptosis in PPH patients may play an important role in the development of pulmonary vascular medial hypertrophy in these patients.
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