title: Simvastatin enhances bone morphogenetic protein receptor type II expression.
abstract: Statins confer therapeutic benefits in systemic and pulmonary vascular diseases. Bone morphogenetic protein (BMP) receptors serve essential signaling functions in cardiovascular development and skeletal morphogenesis. Mutations in BMP receptor type II (BMPR2) are associated with human familial and idiopathic pulmonary arterial hypertension, and pathologic neointimal proliferation of vascular endothelial and smooth muscle cells within small pulmonary arteries. In severe experimental pulmonary hypertension, simvastatin reversed disease and conferred a 100% survival advantage. Here, modulation of BMPR2 gene expression by simvastatin is characterized in human embryonic kidney (HEK) 293T, pulmonary artery smooth muscle, and lung microvascular endothelial cells (HLMVECs). A 1.4kb BMPR2 promoter containing Egr-1 binding sites confers reporter gene activation in 293T cells which is partially inhibited by simvastatin. Simvastatin enhances steady-state BMPR2 mRNA and protein expression in HLMVEC, through posttranscriptional mRNA stabilization. Simvastatin induction of BMPR2 expression may improve BMP-BMPR2 signaling thereby enhancing endothelial differentiation and function.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305-5236, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Hu
authors.forename: Arthur
authors.initials: A
authors.lastname: Sung
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhao
authors.forename: Lingfang
authors.initials: L
authors.lastname: Shi
authors.forename: Daoming
authors.initials: D
authors.lastname: Qiu
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nishimura
authors.forename: Peter N
authors.initials: PN
authors.lastname: Kao
mesh_terms: D001483:Base Sequence; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012323:RNA Processing, Post-Transcriptional; D019821:Simvastatin / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II