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PMID:17600318

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Citation

Yang, X, Lee, PJ, Long, L, Trembath, RC and Morrell, NW (2007) BMP4 induces HO-1 via a Smad-independent, p38MAPK-dependent pathway in pulmonary artery myocytes. Am. J. Respir. Cell Mol. Biol. 37:598-605

Abstract

Bone morphogenetic proteins (BMPs) are multifunctional cytokines, which play a key role in vascular development and remodeling. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, has been shown to be protective against vascular and lung injury. In a microarray study, we identified HO-1 as a major target of BMP4 signaling in human pulmonary artery smooth muscle cells (PASMCs), and confirmed the induction of HO-1 mRNA and protein by RT-PCR and Western blotting, respectively. Immunoblotting demonstrated that incubation of PASMCs with BMP4 rapidly phosphorylated Smad1/5 and activated the mitogen-activated protein kinases, p38(MAPK) and ERK1/2, in PASMCs, but not JNK. Using pathway selective inhibitors, the induction of HO-1 mRNA and protein was shown to be dependent on activation of p38(MAPK). Induction was independent of Smad1/5 signaling, since HO-1 mRNA and protein induction was intact in PASMCs harboring mutations in the kinase domain of BMP type II receptor, with disrupted Smad signaling. In addition, adenoviral transfection of kinase-deficient BMPR-II also failed to inhibit BMP4-induced HO-1 expression. In functional studies, the HO-1 inhibitor, ZnPP-IX, partly reversed the growth-inhibitory effects of BMP4, and overexpression of HO-1 in PASMCs inhibited serum-stimulated [3H]-thymidine incorporation. Taken together, these findings show that HO-1 is an important Smad-independent target of BMP signaling in vascular smooth muscle. Inhibition of HO-1 function or expression will further increase the proproliferative capacity of BMPR-II-deficient PASMCs and may thus represent a potential "second hit" necessary for disease manifestation.

Links

PubMed Online version:10.1165/rcmb.2006-0360OC

Keywords

Animals; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins/physiology; Cattle; Cell Proliferation; Cells, Cultured; Enzyme Induction/physiology; Heme Oxygenase-1/biosynthesis; Humans; Myocytes, Smooth Muscle/enzymology; Pulmonary Artery/cytology; Rabbits; Signal Transduction/physiology; Smad Proteins/physiology; p38 Mitogen-Activated Protein Kinases/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:HMOX1

involved_in

GO:0048662: negative regulation of smooth muscle cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HMOX1

involved_in

GO:0048661: positive regulation of smooth muscle cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0048661: positive regulation of smooth muscle cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0000186: activation of MAPKK activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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