The Prodomain-bound Form of Bone Morphogenetic Protein 10 Is Biologically Active on Endothelial Cells.

BMP10 is highly expressed in the developing heart and plays essential roles in cardiogenesis. BMP10 deletion in mice results in embryonic lethality because of impaired cardiac development. In adults, BMP10 expression is restricted to the right atrium, though ventricular hypertrophy is accompanied by increased BMP10 expression in a rat hypertension model. However, reports of BMP10 activity in the circulation are inconclusive. In particular, it is not known whether in vivo secreted BMP10 is active or whether additional factors are required to achieve its bioactivity. It has been shown that high-affinity binding of the BMP10 prodomain to the mature ligand inhibits BMP10 signaling activity in C2C12 cells, and it was proposed that prodomain-bound BMP10 (pBMP10) complex is latent. In this study, we demonstrated that the BMP10 prodomain did not inhibit BMP10 signaling activity in multiple endothelial cells, and that recombinant human pBMP10 complex, expressed in mammalian cells and purified under native conditions, was fully active. In addition, both BMP10 in human plasma and BMP10 secreted from the mouse right atrium were fully active. Finally, we confirmed that active BMP10 secreted from mouse right atrium was in the prodomain-bound form. Our data suggest that circulating BMP10 in adults is fully active and that the reported vascular quiescence function of BMP10 in vivo is due to the direct activity of pBMP10 and does not require an additional activation step. Moreover, being an active ligand, recombinant pBMP10 may have therapeutic potential as an endothelial-selective BMP ligand, in conditions characterized by loss of BMP9/10 signaling.This work was supported by British Heart Foundation Grants PG/12/54/29734 (to W. L., P. D. U., and N. W. M.) and CH/09/001/25945 (to N. W. M.). He Jiang was supported by the Cambridge Wellcome Trust 4-year Ph.D Programme in Metabolic and Cardiovascular Disease.This is the final version of the article. It first appeared from the American Society for Biochemistry and Molecular Biology via http://dx.doi.org/10.1074/jbc.M115.68329

Which circulating antioxidant vitamins are confounded by socioeconomic deprivation? The MIDSPAN family study

<p><b>Background:</b> Antioxidant vitamins are often described as having “independent” associations with risk of cancer, cardiovascular disease (CVD) and mortality. We aimed to compare to what extent a range of antioxidant vitamins and carotenoids are associated with adulthood and childhood markers of socioeconomic deprivation and to adverse lifestyle factors.</p> <p><b>Methods and Findings:</b> Socioeconomic and lifestyle measures were available in 1040 men and 1298 women from the MIDSPAN Family Study (30–59 years at baseline) together with circulating levels of vitamins A, C, E, and carotenoids (α-carotene, β-carotene, lutein and lycopene). Markers of socioeconomic deprivation in adulthood were consistently as strongly associated with lower vitamin C and carotenoid levels as markers of adverse lifestyle; the inverse association with overcrowding was particularly consistent (vitamin C and carotenoids range from 19.1% [95% CI 30.3–6.0] to 38.8% [49.9–25.3] lower among those in overcrowded residencies). These associations were consistent after adjusting for month, classical CVD risk factors, body mass index, physical activity, vitamin supplements, dietary fat and fibre intake. Similar, but weaker, associations were seen for childhood markers of deprivation. The association of vitamin A or E were strikingly different; several adult adverse lifestyle factors associated with higher levels of vitamin A and E, including high alcohol intake for vitamin A (9.5% [5.7–13.5]) and waist hip ratio for vitamin E (9.5% [4.8–14.4]), with the latter associations partially explained by classical risk factors, particularly cholesterol levels.</p> <p><b>Conclusions:</b> Plasma vitamin C and carotenoids have strong inverse associations with adulthood markers of social deprivation, whereas vitamin A and E appear positively related to specific adverse lifestyle factors. These findings should help researchers better contextualize blood antioxidant vitamin levels by illustrating the potential limitations associated with making causal inferences without consideration of social deprivation.</p&gt

BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production.

BACKGROUND: Bone morphogenetic proteins (BMPs) and their receptors, such as bone morphogenetic protein receptor (BMPR) II, have been implicated in a wide variety of disorders including pulmonary arterial hypertension (PAH). Similarly, endothelin-1 (ET-1), a mitogen and vasoconstrictor, is upregulated in PAH and endothelin receptor antagonists are used in its treatment. We sought to determine whether there is crosstalk between BMP signalling and the ET-1 axis in human pulmonary artery endothelial cells (HPAECs), possible mechanisms involved in such crosstalk and functional consequences thereof. METHODOLOGY/PRINCIPAL FINDING: Using western blot, real time RT-PCR, ELISA and small RNA interference methods we provide evidence that in HPAECs BMP-9, but not BMP-2, -4 and -6 significantly stimulated ET-1 release under physiological concentrations. This release is mediated by both Smad1 and p38 MAPK and is independent of the canonical Smad4 pathway. Moreover, knocking down the ALK1 receptor or BMPR II attenuates BMP-9 stimulated ET-1 release, whilst causing a significant increase in prepro ET-1 mRNA transcription and mature peptide release. Finally, BMP-9 induced ET-1 release is involved in both inhibition of endothelial cell migration and promotion of tubule formation. CONCLUSIONS/SIGNIFICANCE: Although our data does not support an important role for BMP-9 as a source of increased endothelial ET-1 production seen in human PAH, BMP-9 stimulated ET-1 production is likely to be important in angiogenesis and vascular stability. However, increased ET-1 production by endothelial cells as a consequence of BMPR II dysfunction may be clinically relevant in the pathogenesis of PAH

The promise of recombinant BMP ligands and other approaches targeting BMPR-II in the treatment of pulmonary arterial hypertension.

Human genetic discoveries offer a powerful method to implicate pathways of major importance to disease pathobiology and hence provide targets for pharmacological intervention. The genetics of pulmonary arterial hypertension (PAH) strongly implicates loss-of-function of the bone morphogenetic protein type II receptor (BMPR-II) signalling pathway and moreover implicates the endothelial cell as a central cell type involved in disease initiation. We and others have described several approaches to restore BMPR-II function in genetic and non-genetic forms of PAH. Of these, supplementation of endothelial BMP9/10 signalling with exogenous recombinant ligand has been shown to hold considerable promise as a novel large molecule biopharmaceutical therapy. Here, we describe the mechanism of action and discuss potential additional effects of BMP ligand therapy

Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension.

Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH

Health-related quality of life of children with attention-deficit/hyperactivity disorder versus children with diabetes and healthy controls

The impact of attention-deficit/hyperactivity disorder (ADHD) on health-related quality of life (HRQoL) is reported to be similar to that of other mental health and physical disorders. In this cross-sectional study, we hypothesized that children with ADHD and children with type 1 diabetes mellitus (T1DM) would have significantly worse HRQoL compared with healthy children, and that better clinical status in ADHD and T1DM would be associated with better HRQoL. Children were recruited from three outpatient services in Scotland. Responses to two frequently used validated HRQoL instruments, the Paediatric Quality of Life Inventory (PedsQL) and Child Health and Illness Profile-child edition (CHIP-CE), were obtained from parents/carers and children (6–16 years) with/without ADHD or T1DM. Child and parent/carer-completed HRQoL measurements were evaluated for 213 children with ADHD, 58 children with T1DM and 117 healthy children (control group). Significantly lower self and parent/carer ratings were observed across most PedsQL (P < 0.001) and CHIP-CE (P < 0.05) domains (indicating reduced HRQoL) for the ADHD group compared with the T1DM and control groups. Parent/carer and child ratings were significantly correlated for both measures of HRQoL (PedsQL total score: P < 0.001; CHIP-CE all domains: P < 0.001), but only with low-to-moderate strength. Correlation between ADHD severity and HRQoL was significant with both PedsQL and CHIP-CE for all parent/carer (P < 0.01) and most child (P < 0.05) ratings; more ADHD symptoms were associated with poorer HRQoL. These data demonstrate that ADHD has a significant impact on HRQoL (as observed in both parent/carer and child ratings), which seems to be greater than that for children with T1DM