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BMP4 Induces HO-1 via a Smad-Independent, p38^MAPK-Dependent Pathway in Pulmonary Artery Myocytes

¹ Department of Medicine, University of Cambridge, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom; ² Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut; and ³ Division of Molecular Medicine and Genetics, Kings College London, London, United Kingdom

Correspondence and requests for reprints should be addressed to Dr. Nicholas W. Morrell, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Box 157, Hills Road, Cambridge CB2 2QQ, UK. E-mail: nwm23{at}cam.ac.uk

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.

Key Words: pulmonary hypertension • vascular remodelling • bone morphogenetic protein type II receptor • Smads • signal transduction

CLINICAL RELEVANCE We identify heme oxygenase-1 as an important functional target of bone morphogenetic protein signaling in human pulmonary artery smooth muscle cells. These findings have important implications for our understanding of the pathogenesis of familial pulmonary hypertension.