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Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells
Shen Zhang1, Ivana Fantozzi, Donna D Tigno
1Dept. of Medicine, UCSD Medical Center, 200 West Arbor Dr., San Diego, CA 92103-8382, USA.
Abstract:
Pulmonary vascular medial hypertrophy in primary pulmonary hypertension (PPH) is mainly caused by increased proliferation and decreased apoptosis in pulmonary artery smooth muscle cells (PASMCs). 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 the apoptotic effects of BMPs on normal human PASMCs and to examine whether BMP-induced effects are altered in PASMCs from PPH patients. Using RT-PCR, we detected six isoforms of BMPs (BMP-1 through -6) and three subunits of BMP receptors (BMP-RIa, -RIb, and -RII) in PASMCs. Treatment of normal PASMCs with BMP-2 or -7 (100-200 nM, 24-48 h) markedly increased the percentage of cells undergoing apoptosis. The BMP-2-mediated apoptosis in normal PASMCs was associated with a transient activation or phosphorylation of Smad1 and a marked downregulation of the antiapoptotic protein Bcl-2. In PASMCs from PPH patients, the BMP-2- or BMP-7-induced apoptosis was significantly inhibited compared with PASMCs 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.
Insights
Bone morphogenetic proteins (BMPs) induce apoptosis in normal pulmonary artery smooth muscle cells (PASMCs). This BMP-induced apoptosis is inhibited in PASMCs from primary pulmonary hypertension (PPH) patients, contributing to vascular disease.
Area of Science:
- Cardiovascular Biology
- Cell Biology
- Molecular Medicine
Background:
- Pulmonary vascular medial hypertrophy in primary pulmonary hypertension (PPH) is linked to increased proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs).
- Mutations in the bone morphogenetic protein (BMP) receptor type II (BMP-RII) gene are associated with familial and sporadic PPH.
- Understanding BMP signaling in PASMCs is crucial for PPH pathogenesis.
Purpose of the Study:
- To investigate the apoptotic effects of BMPs on normal human PASMCs.
- To determine if BMP-induced apoptosis is altered in PASMCs from PPH patients compared to other pulmonary hypertension types.
Main Methods:
- RT-PCR was used to detect BMP isoforms and BMP receptor subunits in PASMCs.
- Normal and PPH-derived PASMCs were treated with BMP-2 or BMP-7.
- Apoptosis levels, Smad1 phosphorylation, and Bcl-2 expression were analyzed.
Main Results:
- BMP-2 and BMP-7 treatment significantly increased apoptosis in normal PASMCs.
- BMP-2 induced apoptosis involved Smad1 activation and Bcl-2 downregulation.
- BMP-2 and BMP-7 induced apoptosis was significantly inhibited in PASMCs from PPH patients compared to secondary pulmonary hypertension patients.
Conclusions:
- BMPs induce PASMC apoptosis, a key mechanism for regulating pulmonary vascular cell numbers.
- Inhibition of BMP-induced PASMC apoptosis may contribute to pulmonary vascular medial hypertrophy in PPH.
- Targeting BMP signaling could offer therapeutic strategies for PPH.