S97 BMPR2 R899X knock-in mice developed age-related pulmonary hypertension
Identifieur interne : 001486 ( Main/Exploration ); précédent : 001485; suivant : 001487S97 BMPR2 R899X knock-in mice developed age-related pulmonary hypertension
Auteurs : L. Long [Royaume-Uni] ; X. Yang [Royaume-Uni] ; N W Morrell [Royaume-Uni] ; M. Southwood [Royaume-Uni]Source :
- Thorax [ 0040-6376 ] ; 2011-12.
English descriptors
- Teeft :
- 1university, 2papworth, 2papworth hospital, Additional loss, Arterial hypertension, Bmpr2, Bmpr2 mutation, Bmps, Body weight, Cambridge university, Cell proliferation, Central role, Chloroquine, Coculture, Conclusions survival, Copd, Cytokine, Cytokine expression, Cytokine levels, Cytokine release, Cytokine response, Cytoplasmic, Cytoplasmic tail, December, Dunmore, Elisa, Encoding, Gene encoding, Genetic mutations, Germline, Germline mutations, Growth factor, Growth receptorb superfamily, Gure, Haemodynamic, Haemodynamics, Harbouring, Heritable, Higher mortality rate, Higher right, Homologue, Hpah, Human disease, Human pasmc, Hyperproliferative, Hypertension, Idiopathic, Immunohistochemistry, Increases cell surface expression, Knockin, Knockout, Knockout mice, Littermate, Littermate controls, Littermates, Liver weight, Lysosomal, Lysosomal inhibitor, Main results, Mansoni, Mansoni eggs, Mimic, Morphometric, Morphometric data, Morphometry, Morrell, Mouse, Mouse harbouring, Mouse homologue, Mouse model, Muscle cells, Mutant, Mutant mice, Mutation, Mutation causes, Ndings, Nonsense mutation, Pasmc, Pasmc proliferation, Pathway, Pathway increases, Percutaneously, Postinfection, Protein receptor, Protein receptor type, Protein type, Pulmonary artery, Pulmonary haemodynamics, Pulmonary hypertension, Qpcr, Receptor, Receptor superfamily, Receptorb, Remodelling, Rvsp, Schistosomiasis, Schistosomiasiseinduced, Sessions years, Smad, Southwood, Stratifying, Superfamily, Suppl, Systolic, Systolic pressure, Systolic pressures, Thirdworld, Thorax, Thorax december, Unanticipated, Variable proportion, Vascular morphometry, Weeks postinfection right, Western world, Wildtypes.
Abstract
Background Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR2) underlie the majority (>70%) of cases of heritable pulmonary arterial hypertension (hPAH) and a variable proportion of idiopathic PAH (15%–40%). There are also reports of PAH in patients with mutations in the downstream Smad signalling proteins. However, to date there is no mouse model that mimics the genetic mutations in human disease. Methods We developed a knock-in mouse harbouring a heterozygous (±) human disease causing mutation in BMPR-II: a nonsense mutation in the cytoplasmic tail (R899X) to determine the in vivo physiologic consequences of this BMPR2 mutation. In addition, we crossed this animal with Smad1± knockout mice to determine the effect of additional loss of signalling via this pathway. Haemodynamic, and morphometric data were collected at 3 months and 6 months of age. Results At 3 months of age pulmonary haemodynamics and vascular morphometry of R899X± and Smad1± mice were similar to wild-type littermate controls. In contrast, at 6 months of age R899X± and Smad1± mice developed mild pulmonary hypertension with pulmonary vascular remodelling compared with wild-types. Pulmonary artery smooth muscle cells from R899X± mice were hyperproliferative in serum and exhibited defects in Smad signalling in response to BMPs. When R899X± mice were crossed with Smad1± animals, double heterozygous mice had significantly higher right ventricular systolic pressures than single heterozygous mice. Conclusion These findings demonstrate that knockin of a human disease causing BMPR-II mutation causes age-related pulmonary hypertension in mice. In addition, we show that the accumulation of defects in the BMP/Smad signalling pathway increases the susceptibility to pulmonary hypertension, highlighting the central role of this pathway in disease.
Url:
DOI: 10.1136/thoraxjnl-2011-201054b.97
Affiliations:
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<front><div type="abstract">Background Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR2) underlie the majority (>70%) of cases of heritable pulmonary arterial hypertension (hPAH) and a variable proportion of idiopathic PAH (15%–40%). There are also reports of PAH in patients with mutations in the downstream Smad signalling proteins. However, to date there is no mouse model that mimics the genetic mutations in human disease. Methods We developed a knock-in mouse harbouring a heterozygous (±) human disease causing mutation in BMPR-II: a nonsense mutation in the cytoplasmic tail (R899X) to determine the in vivo physiologic consequences of this BMPR2 mutation. In addition, we crossed this animal with Smad1± knockout mice to determine the effect of additional loss of signalling via this pathway. Haemodynamic, and morphometric data were collected at 3 months and 6 months of age. Results At 3 months of age pulmonary haemodynamics and vascular morphometry of R899X± and Smad1± mice were similar to wild-type littermate controls. In contrast, at 6 months of age R899X± and Smad1± mice developed mild pulmonary hypertension with pulmonary vascular remodelling compared with wild-types. Pulmonary artery smooth muscle cells from R899X± mice were hyperproliferative in serum and exhibited defects in Smad signalling in response to BMPs. When R899X± mice were crossed with Smad1± animals, double heterozygous mice had significantly higher right ventricular systolic pressures than single heterozygous mice. Conclusion These findings demonstrate that knockin of a human disease causing BMPR-II mutation causes age-related pulmonary hypertension in mice. In addition, we show that the accumulation of defects in the BMP/Smad signalling pathway increases the susceptibility to pulmonary hypertension, highlighting the central role of this pathway in disease.</div>
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