Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells.
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.
Zhang
Shen
S
Dept. of Medicine, UCSD Medical Center, 200 West Arbor Dr., San Diego, CA 92103-8382, USA.
Fantozzi
Ivana
I
Tigno
Donna D
DD
Yi
Eunhee S
ES
Platoshyn
Oleksandr
O
Thistlethwaite
Patricia A
PA
Kriett
Jolene M
JM
Yung
Gordon
G
Rubin
Lewis J
LJ
Yuan
Jason X-J
JX
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D053222:Fas Ligand Protein; D015870:Gene Expression; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology; D008562:Membrane Glycoproteins / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology*; D017978:Receptors, Growth Factor / Q000235:genetics; D051785:Smad Proteins; D051898:Smad1 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
C525718:BMP2 protein, human; C525819:BMP7 protein, human; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017978:Receptors, Growth Factor; C497399:SMAD1 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D052004:Bone Morphogenetic Protein Receptors