Hyperoxia, despite its vasodilatory actions in the pulmonary circulation, significantly worsened the PAH phenotype (elevated right ventricular systolic pressure, decreased cardiac output, and increased pulmonary vascular occlusion) in Bmpr2 mutant animals.
Our findings, taken in context with the observed prevalence of pulmonary arterial hypertension associated with BMPR2 mutations, define converging molecular pathways that lead to the development of pulmonary hypertension, through either genetic or epigenetic loss of function of components of the BMP signaling pathway.
GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [BMPR2] mutation carriers, 21 non-carriers), and 3 experimental pulmonary hypertension models.
Pulmonary arterial hypertension (PAH) occurs more frequently in women with mutations in bone morphogenetic protein receptor type 2 (BMPR2) and dysfunctional BMPR2 signalling underpinning heritable PAH.
In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in BMPR2 lead to upregulation of miR-145 in mice and PAH patients.
The first case of BMPR2 mutation found in Japan is reported here in a 19-year-old woman with a clinical diagnosis of PPH and no identifiable family history of pulmonary hypertension.
We analysed individual participant data of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight cohorts that had been systematically tested for BMPR2 mutations.
290 idiopathic (I)PAH patients and 15 heritable (H)PAH were screened to determine the spectrum and rate of BMPR2 mutations in a large Chinese patient group.
Although <i>Bone Morphogenetic Protein Receptor Type 2</i> gene (<i>BMPR2)</i> mutations are related with idiopathic and heritable PAH, the low penetrance and variable expressivity in PAH suggest the existence of other genetic and/or environmental factors.
We have previously demonstrated that low-dose lipopolysaccharide (LPS) is a potent stimulus for the development of PAH in the context of a genetic PAH mouse model of BMPR2 dysfunction.
These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation through dampening Smad signaling, and suggest that augmented Smad signaling and fibroblast hyper-proliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1c.474delA mutation.
Pulmonary arterial hypertension is related to mutations in the bone morphogenetic protein receptor type 2, pulmonary vascular dysfunction and is increasingly recognized as a systemic disease.
These findings identify defects in caveolae that may serve as contributing factors to the development of PAH and CGL and broaden our knowledge of CAV1 mutations associated with human disease.
We performed genetic testing of the bone morphogenic protein receptor 2 (BMPR2) gene, which mutated in 70% of patients with familial PAH and approximately 25% of patients with idiopathic PAH.
Using a targeted in vivo gene delivery approach, we assessed the impact of BMPR2 gene delivery in a transgenic mouse model in which PAH was first induced by doxycycline driven expression of a dominant negative BMPR2 mutant (R899X).
The failure to find BMPR2 mutations in all families with familial PPH and in all patients with sporadic PPH suggests that other genes remain to be identified.
We tested the hypothesis that relatives of idiopathic/familial PAH patients display an enhanced frequency of hypertensive TRV response to stress and that this response is associated with mutations in the bone morphogenetic protein receptor II (BMPR2) gene.
These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1c.474delA mutation.
Sequence variants in BMPR2 and genes involved in the serotonin and nitric oxide pathways in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: relation to clinical parameters and comparison with left heart disease.
Heritable and idiopathic pulmonary arterial hypertension (PAH) are phenotypically identical and associated with mutations in several genes related to transforming growth factor (TGF) beta signaling, including bone morphogenetic protein receptor type 2, activin receptor-like kinase 1, endoglin, and mothers against decapentaplegic 9.