Divergent effects of BMP-2 on gene expression in pulmonary artery smooth muscle cells from normal subjects and patients with idiopathic pulmonary arterial hypertension.
Bone morphogenetic proteins (BMPs) inhibit proliferation and induce apoptosis in pulmonary artery smooth muscle cells (PASMCs) from normal subjects. Dysfunction of BMP signaling due to mutations in and/or down-regulation of BMP receptors has been implicated in idiopathic pulmonary arterial hypertension (IPAH). The authors examined whether BMP differentially regulates gene expression in PASMCs from normal subjects and IPAH patients using the Affymetrix microarray analysis. BMP-2 treatment (200 nM for 24 hours) altered expression levels of 6206 genes in normal and IPAH PASMCs. Of these genes, 1063 were regulated oppositely by BMP-2: 523 genes were down-regulated by BMP-2 in normal PASMCs but up-regulated in IPAH PASMCs, whereas 540 genes were up-regulated by BMP-2 in normal PASMCs but down-regulated in IPAH PASMCs. The divergent effects of BMP-2 on gene expression profiles indicate that PASMCs may undergo significant phenotypic changes in IPAH patients during development of the disease. The transition of the antiproliferative effect of BMP-2 in normal PASMCs to its proliferative effect in IPAH patients is attributed potentially to its differential effect on expression patterns of various genes that are involved in cell proliferation and apoptosis. Among the 6206 BMP-2-sensitive genes, there are more than 1800 genes whose expression levels were negatively (correlation coefficient, r, <-0.9) or positively (with r >+ 0.9) correlated with the pulmonary arterial pressure. These results suggest that BMP-mediated gene regulation is significantly altered in PASMCs from IPAH patients and mRNA expression changes in BMP-regulated genes may be involved in the development of IPAH.
Fantozzi
Ivana
I
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
Huang
Wei
W
Department of Bioengineering, School of Engineering, University of California, San Diego, La Jolla, CA 92093.
Zhang
Jifeng
J
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
Zhang
Shen
S
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
Platoshyn
Oleksandr
O
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
Remillard
Carmelle V
CV
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
Thistlethwaite
Patricia A
PA
Department of Surgery, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
Yuan
Jason X-J
JX
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011669:Pulmonary Wedge Pressure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta