BACKGROUND: Mutations in the bmpr2 gene, encoding the type II bone morphogenetic protein (BMP) receptor, have been identified in patients with pulmonary arterial hypertension (PAH), implicating BMP signaling in PAH. The aim of this study was to assess BMP signaling and its physiological effects in a monocrotaline (MCT) model of PAH. METHODS AND RESULTS: Expression of BMP receptors Ib and II, and Smads 4, 5, 6, and 8, was downregulated in lungs but not kidneys of MCT-treated rats. Smad1 phosphorylation and expression of BMP/Smad target genes id1 and id3 was also reduced, although ERK1/2 and p38(MAPK) phosphorylation remained unaffected. BMP receptor and Smad expression, Smad1 phosphorylation, and induction of the BMP/Smad-responsive element of the id1 promoter were reduced in pulmonary artery smooth muscle cells (PASMCs) from MCT-treated rats. As a consequence of impaired BMP/Smad signaling, PASMCs from MCT-treated rats were resistant to apoptosis induced by BMP-4 and BMP-7, and were also resistant to BMP-4 antagonism of proliferation induced by platelet-derived growth factor. CONCLUSION: BMP signaling and BMP-regulated physiological phenomena are perturbed in MCT-treated rats, lending solid support to the proposed roles for BMP signaling in the pathogenesis of human PAH.
BACKGROUND: Mutations in the bmpr2 gene, encoding the type II bone morphogenetic protein (BMP) receptor, have been identified in patients with pulmonary arterial hypertension (PAH), implicating BMP signaling in PAH. The aim of this study was to assess BMP signaling and its physiological effects in a monocrotaline (MCT) model of PAH. METHODS AND RESULTS: Expression of BMP receptors Ib and II, and Smads 4, 5, 6, and 8, was downregulated in lungs but not kidneys of MCT-treated rats. Smad1 phosphorylation and expression of BMP/Smad target genes id1 and id3 was also reduced, although ERK1/2 and p38(MAPK) phosphorylation remained unaffected. BMP receptor and Smad expression, Smad1 phosphorylation, and induction of the BMP/Smad-responsive element of the id1 promoter were reduced in pulmonary artery smooth muscle cells (PASMCs) from MCT-treated rats. As a consequence of impaired BMP/Smad signaling, PASMCs from MCT-treated rats were resistant to apoptosis induced by BMP-4 and BMP-7, and were also resistant to BMP-4 antagonism of proliferation induced by platelet-derived growth factor. CONCLUSION:BMP signaling and BMP-regulated physiological phenomena are perturbed in MCT-treated rats, lending solid support to the proposed roles for BMP signaling in the pathogenesis of human PAH.
Authors: Lei Wang; Li-Juan Guo; Jie Liu; Wang Wang; Jason X-J Yuan; Lan Zhao; Jun Wang; Chen Wang Journal: Pulm Circ Date: 2013-12-05 Impact factor: 3.017
Authors: Raphaela Schwappacher; Ana Kilic; Baktybek Kojonazarov; Michaela Lang; Thuan Diep; Shunhui Zhuang; Thomas Gawlowski; Ralph T Schermuly; Alexander Pfeifer; Gerry R Boss; Renate B Pilz Journal: J Biol Chem Date: 2013-04-23 Impact factor: 5.157
Authors: Edda Spiekerkoetter; Xuefei Tian; Jie Cai; Rachel K Hopper; Deepti Sudheendra; Caiyun G Li; Nesrine El-Bizri; Hirofumi Sawada; Roxanna Haghighat; Roshelle Chan; Leila Haghighat; Vinicio de Jesus Perez; Lingli Wang; Sushma Reddy; Mingming Zhao; Daniel Bernstein; David E Solow-Cordero; Philip A Beachy; Thomas J Wandless; Peter Ten Dijke; Marlene Rabinovitch Journal: J Clin Invest Date: 2013-07-15 Impact factor: 14.808
Authors: Jarrod W Barnes; Elif T Kucera; Liping Tian; Noël E Mellor; Nina Dvorina; William W Baldwin; Micheala A Aldred; Carol F Farver; Suzy A A Comhair; Metin Aytekin; Raed A Dweik Journal: Am J Respir Cell Mol Biol Date: 2016-10 Impact factor: 6.914