Characterization of <i>GDF2</i> Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension

Hodgson, Joshua; Swietlik, Emilia M.; Salmon, Richard M.; Hadinnapola, Charaka; Nikolić, Ivana; Wharton, John; Guo, Jingxu; Liley, James; Haimel, Matthias; Bleda, Marta; Southgate, Laura; Machado, Rajiv D.; Martin, Jennifer; Treacy, Carmen; Yates, Katherine; Daugherty, Louise C.; Shamardina, Olga; Whitehorn, Deborah; Holden, Simon; Bogaard, Harm Jan; Church, Colin; Coghlan, Gerry; Condliffe, Robin; Corris, Paul A.; Danesino, Cesare; Eyries, Mélanie; Gall, Henning; Ghio, Stefano; Ghofrani, Hossein Ardeschir; Gibbs, J. Simon R.; Girerd, Barbara; Houweling, Arjan C.; Howard, Luke; Humbert, Marc; Kiely, David G.; Kovàcs, Gabór; Lawrie, Allan; Ross, Robert V.Mac Kenzie; Moledina, Shahin; Montani, David; Olschewski, Andrea; Olschewski, Horst; Ouwehand, Willem H.; Peacock, Andrew J.; Pepke‐Zaba, Joanna; Prokopenko, Inga; Rhodes, Christopher J.; Scelsi, Laura; Seeger, Werner; Soubrier, Florent; Suntharalingam, Jay; Toshner, Mark; Trembath, Richard; Vonk‐Noordegraaf, Anton; Wort, Stephen J.; Wilkins, Martin R.; Yu, Paul B.; Li, Wei; Gräf, Stefan; Upton, Paul D.; Morrell, Nicholas W.

doi:10.1164/rccm.201906-1141oc

Cited by 93 publications

(156 citation statements)

References 30 publications

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“…Although overall BMP9 and BMP10 levels did not differ between PAH patients and controls, a subset of PAH patients had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations. These findings support therapeutic strategies to enhance BMP9 or BMP10 signalling in PAH 41 .…”

Section: State Of the Artsupporting

confidence: 71%

The role of genomics and genetics in pulmonary arterial hypertension

Swietlik¹,

Gräf²,

Morrell³

2020

gcsp

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[No abstract. Showing first paragraph of article]Although pulmonary hypertension (PH) had been recognised for centuries, it was not until the invention of cardiac catheterisation in the 1950s that enabled an accurate gene encoding bone morphogenetic protein receptor type 2, in patients with familial and clinical diagnosis. The discovery of heterozygous germline mutations in BMPR2, the idiopathic forms of pulmonary arterial hypertension (PAH) was another breakthrough in understanding the disease and initiated a new era in care of patients with this condition.

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Section: State Of the Artsupporting

confidence: 71%

The role of genomics and genetics in pulmonary arterial hypertension

Swietlik¹,

Gräf²,

Morrell³

2020

gcsp

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“…In this study, we show that BMP9 represses basal CCL2 expression at concentrations as low as 0.1 ng/ml. As plasma BMP9 concentrations are reported to be less than 0.5 ng/ml by ELISA ( Kienast et al, 2016 ; Bidart et al, 2012 ; Nikolic et al, 2019 ; Hodgson et al, 2020 ), we suggest that circulating BMP9 and BMP10 serve to reduce monocyte recruitment under normal homeostatic conditions.…”

Section: Discussionmentioning

confidence: 75%

Endothelial protective factors BMP9 and BMP10 inhibit CCL2 release by human vascular endothelial cells

Upton

Park

Souza

et al. 2020

Journal of Cell Science

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Bone morphogenetic protein 9 (BMP9) and BMP10 are circulating ligands that mediate endothelial cell (EC) protection via complexes of the type I receptor ALK1 and the type II receptors activin type-IIA receptor (ACTR-IIA) and bone morphogenetic type II receptor (BMPR-II). We previously demonstrated that BMP9 induces the expression of interleukin-6, interleukin-8 and E-selectin in ECs and might influence their interactions with monocytes and neutrophils. We asked whether BMP9 and BMP10 regulate the expression of chemokine (C-C motif) ligand 2 (CCL2), a key chemokine involved in monocyte–macrophage chemoattraction. Here, we show that BMP9 and BMP10 repress basal CCL2 expression and release from human pulmonary artery ECs and aortic ECs. The repression was dependent on ALK1 and co-dependent on ACTR-IIA and BMPR-II. Assessment of canonical Smad signalling indicated a reliance of this response on Smad4. Of note, Smad1/5 signalling contributed only at BMP9 concentrations similar to those in the circulation. In the context of inflammation, BMP9 did not alter the induction of CCL2 by TNF-α. As CCL2 promotes monocyte/macrophage chemotaxis and endothelial permeability, these data support the concept that BMP9 preserves basal endothelial integrity.

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“…This revealed Cd207, Bmp10, Cxcl13, Myoc, Vsig4, A930005H10Rik, and Mrap as the top 7 genes with differentially increased expression in left atrium of Pitx2c +/mice. Bmp10 was selected for further quantification due to its restriction to cardiac tissue and based on its known biology as a secreted protein (22). Bmp10 mRNA, quantified by qPCR, was expressed at 32-fold-increased levels in the left atria of Pitx2c +/mice compared with their WT littermates (WT 0.03 [0.01, 0.04], Pitx2c +/-3.20 [2.86, 3.60], P = 0.002; Figure 5B) and at low to undetectable levels in left ventricular tissue of either genotype (WT 0.05 [0.01, 0.09], Pitx2c +/-0.01 [0.01, 0.02], P = 0.060; Figure 5B).…”

Section: I N I C a L M E D I C I N Ementioning

confidence: 99%

“…These findings suggest that BMP10 is repressed by PITX2 in the adult left atrium. Importantly, unlike markers such as N-terminal pro-B-type natriuretic peptide (NTproBNP), plasma concentrations of BMP10 appear relatively unaffected by other cardiovascular conditions such as heart failure (22). Hence, elevated plasma BMP10 concentrations were used as a surrogate for reduced atrial PITX2.…”

Section: I N I C a L M E D I C I N Ementioning

confidence: 99%

Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation

Reyat¹,

Chua²,

Cardoso³

et al. 2020

JCI Insight

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Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension

Abstract: provides new genetic evidence for the association of GDF2 mutations with PAH and confirms that these mutations cause impaired BMP9 function

Cited by 93 publications

References 30 publications

The role of genomics and genetics in pulmonary arterial hypertension

The role of genomics and genetics in pulmonary arterial hypertension

Endothelial protective factors BMP9 and BMP10 inhibit CCL2 release by human vascular endothelial cells

Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation

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