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Smad Signaling in the Rat Model of Monocrotaline Pulmonary Hypertension

¹ Departments of Pathology, Immunology, and Microbiology and
² Molecular BioSciences, School of Veterinary Medicine, University of California, Davis, Davis, California, USA

Correspondence: Address correspondence to: Dennis Wilson, DVM, PhD, DACVP, School of Veterinary Medicine, Pathology, Immunology, Microbiology, One Shields Avenue, 1044 Haring Hall, Davis, CA 95616-8617; e-mail: dwwilson{at}ucdavis.edu.

Mutations in the bone morphogenetic protein receptor type II (BMPrII) gene have been implicated in the development of familial pulmonary artery hypertension (PAH). The function of BMP signal transduction within the pulmonary vasculature and the role BMPrII mutations have in the development of PAH are incompletely understood. We used the monocrotaline (MCT) model of PAH to examine alterations in Smad signal transduction pathways in vivo. Lungs harvested from Sprague-Dawley rats treated with a single 60-mg/kg intraperitoneal (IP) injection of MCT were compared to saline-treated controls 2 weeks following treatment. Smad 4 was localized by immunohistochemistry to endothelial nuclei of the intra-acinar vessels undergoing remodeling. Smad 4, common to both BMP and transforming growth factor β (TGFβ) signaling, and BMP-specific Smad 1 were significantly decreased in western blot from whole lungs of treated animals, while no change was found for TGFβ-specific Smad 2. MCT-treated rats also had increased expression of phosphorylated Smad 1 (P-Smad 1) but not phosphorylated Smad 2 (P-Smad 2). There was a decrease in the expression of the full BMPrII protein but not its short form variant in MCT-treated rat lungs. The type I receptor Alk1 had increased expression. Collectively, our data indicate that vascular remodeling in the MCT model is associated with alterations in BMP receptors and persistent endothelial Smad 1 signaling.

Key Words: BMP receptors • Smad signal transduction • pulmonary hypertension • monocrotaline

Abbreviations: BM, bone morphogenetic protein • BMPrII, bone morphogenetic protein type II receptor • BSA TBS, bovine serum albumin Tris buffered saline • DAPI, 4’-6-diamidino-2-phenylindole • DMEM, Dulbecco’s modified eagle medium • DMF, N,N-dimethyl formamide • ECL, enhanced chemiluminescence • FBS, fetal bovine serum • HPAECs, human pulmonary artery endothelial cells • HRP-DAB, horseradish peroxidase-diaminobenzidine • IFC, immunofluorescent chemistry • IHC, immunohistochemistry • IP, intraperitoneal • IPAH, idiopathic pulmonary arterial hypertension • MCT, monocrotaline • MCTP, monocrotaline pyrrole • PAH, pulmonary artery hypertension • PASMCs, pulmonary artery smooth muscle cells • PH, pulmonary hypertension • PPH, primary pulmonary hypertension • PVDF, polyvinylidene fluoride • P-Smad 1, P Smad 2, phosphorylated Smad 1 or Smad 2 • RIPA, radioimmunoprecipitation assay • SDS, sodium dodecyl sulfate • TGFβ, transforming growth factor β

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