title: Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells.
abstract: Bone morphogenetic protein type II receptor (BMPR-II) mutations are responsible for over 70% of cases of heritable pulmonary arterial hypertension (PAH). Loss of BMP signaling promotes pulmonary vascular remodeling via modulation of pulmonary artery smooth muscle cell (PASMC) proliferation. Id proteins (Id1-4) are major downstream transcriptional targets of BMP signaling. However, the impact of BMPR-II mutation on the expression of the range of Id proteins and the contribution of individual Id proteins to abnormal PASMC function remain unclear. Human PASMCs were used to determine the expression of Id proteins (Id1-4) by real-time PCR and immunoblotting. The BMP responses in control cells were compared with PASMCs harboring BMPR-II mutations and cells in which BMPR-II was knocked down by siRNA transfection. Id3 expression in pulmonary vessels was also investigated in BMPR-II mutant mice and in patients with heritable PAH. BMP4 and BMP6, but not BMP9, induced mRNA expression of Id1, Id2, and Id3. The BMP-stimulated induction of Id1 and Id3 was markedly reduced in BMPR-II mutant PASMCs and in control PASMCs following siRNA silencing of BMPR-II. Pulmonary arteries in BMPR-II mutant mice and patients with heritable PAH demonstrated reduced levels of Id3 compared with control subjects. Lentiviral overexpression of Id3 reduced cell cycle progression and inhibited proliferation of PASMCs. Lipopolysaccharide further reduced Id3 expression in mutant PASMCs. In conclusion, Id proteins, and particularly Id1 and Id3, are critical downstream effectors of BMP signaling in PASMCs. Loss of BMPR-II function reduces the induction of Id genes in PASMCs, Id1, and Id3 regulate the proliferation of PASMCs via cell cycle inhibition, an effect that may be exacerbated by inflammatory stimuli.
authors.affiliation: Dept. of Medicine, Level 5, Box 157 Addenbrooke's Hospitals, Hills Rd., Cambridge, CB2 0QQ, UK.. nwm23@cam.ac.uk.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.forename: Lingying
authors.initials: L
authors.lastname: Ye
authors.forename: Lu
authors.initials: L
authors.lastname: Long
authors.forename: Rafia S
authors.initials: RS
authors.lastname: Al-Lamki
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
mesh_terms: D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000172:deficiency / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D065627:Familial Primary Pulmonary Hypertension; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000473:pathology; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011651:Pulmonary Artery / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D019485:Bone Morphogenetic Proteins; D051796:Inhibitor of Differentiation Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: Id; bone morphogenetic protein type II receptor; cell cycle; pulmonary arterial smooth muscle cell; pulmonary hypertension