Targeting BMP signalling in cardiovascular disease and anaemia

Morrell, Nicholas W.; Bloch, Donald B.; Dijke, Peter ten; Goumans, Marie–José; Hata, Akiko; Smith, Jim; Yu, Paul B.; Bloch, Kenneth D.

doi:10.1038/nrcardio.2015.156

Cited by 195 publications

(208 citation statements)

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“…ALK2 is also found in the endothelium and is reported to modulate ALK1 expression in response to BMP stimuli [224]. Type II BMP receptors BMPR2 and ACTR2A are expressed in mesenchyme-derived tissues, while BMPR2 is expressed at high levels in the endothelium [137]. ALK2, ALK3, BMPR2, and ACTR2A are also found in pulmonary artery smooth muscle cells (PASMCs) and cardiomyocytes [154,218,226].…”

Section: Bmp Ligands and Receptors In The Cardiopulmonary Systemmentioning

confidence: 98%

“…The functional roles of these components have been investigated individually by direct application of recombinant ligand or antagonist proteins of interest or by the transgenic overexpression of wild-type or constitutively active mutant receptor proteins [16], whereas the consequences of their removal have been studied by genetic ablation [137], neutralizing antibodies, ligand traps, and small molecule inhibitors [24,47,124]. The most relevant BMP ligands in the cardiopulmonary system are likely to be BMP9, BMP10, and BMP6 as they are secreted into the circulation at functionally relevant concentrations [40,82,108,209].…”

Section: Bmp Ligands and Receptors In The Cardiopulmonary Systemmentioning

confidence: 99%

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Bone Morphogenetic Protein Signaling in Pulmonary Arterial Hypertension

Yang

2017

Bone Morphogenetic Proteins: Systems Biology Regulators

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A wealth of evidence from human genetics, developmental and cell biology, and translational science has implicated members of the bone morphogenetic protein (BMP) and transforming growth factor-β (TGF-β ) signaling family in the pathogenesis of pulmonary arterial hypertension (PAH). The discovery of loss-offunction germline mutations in BMPR2 and in functionally related BMP/TGF-β signal transduction molecules as causes of heritable PAH and several overlapping congenital vascular syndromes has catalyzed work to elucidate how BMP signals critically regulate vascular development, vascular homeostasis, inflammation, metabolism and pathogenic remodeling. This work in vascular biology and experimental medicine has in turn led to a more nuanced understanding by which the structurally diverse family of BMP ligands and receptors achieve their tissue-specific and context-dependent functions. Recently this work has shed light on promising new strategies by which dysregulated BMP/TGF-β might be modulated for therapeutic benefit in PAH and related conditions. BMP Signaling in the Cardiopulmonary SystemBMP signaling plays a fundamental role in the development and homeostasis of the heart and the systemic and pulmonary circulation. Spatiotemporal specificity of BMP signaling in the cardiopulmonary system is achieved by selective expression

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Section: Bmp Ligands and Receptors In The Cardiopulmonary Systemmentioning

confidence: 98%

Section: Bmp Ligands and Receptors In The Cardiopulmonary Systemmentioning

confidence: 99%

Bone Morphogenetic Protein Signaling in Pulmonary Arterial Hypertension

Yang

2017

Bone Morphogenetic Proteins: Systems Biology Regulators

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“…Inflammation is an important contributor to the pathogenesis of systemic and pulmonary hypertension (39). Since proinflammatory cytokine TNF-␣ is involved in the acute phase reaction and IL-6 evokes late phase reaction, we determined TNF-␣ and IL-6 expression in the arteries/pulmonary artery smooth muscle cells exposed to 20-HETE.…”

Section: -Hete-induced Expression Of Tnf-␣ By Pulmonary Arteries Ismentioning

confidence: 99%

20-HETE-induced mitochondrial superoxide production and inflammatory phenotype in vascular smooth muscle is prevented by glucose-6-phosphate dehydrogenase inhibition

Lakhkar

Dhagia

Joshi

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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. 20-HETE-induced mitochondrial superoxide production and inflammatory phenotype in vascular smooth muscle is prevented by glucose-6-phosphate dehydrogenase inhibition. Am J Physiol Heart Circ Physiol 310: H1107-H1117, 2016. First published February 26, 2016 doi:10.1152/ajpheart.00961.2015 produced by cytochrome P-450 monooxygenases in NA-DPH-dependent manner is proinflammatory, and it contributes to the pathogenesis of systemic and pulmonary hypertension. In this study, we tested the hypothesis that inhibition of glucose-6-phosphate dehydrogenase (G6PD), a major source of NADPH in the cell, prevents 20-HETE synthesis and 20-HETE-induced proinflammatory signaling that promotes secretory phenotype of vascular smooth muscle cells. Lipidomic analysis indicated that G6PD inhibition and knockdown decreased 20-HETE levels in pulmonary arteries as well as 20-HETEinduced 1) mitochondrial superoxide production, 2) activation of mitogen-activated protein kinase 1 and 3, 3) phosphorylation of ETS domain-containing protein Elk-1 that activate transcription of tumor necrosis factor-␣ gene (Tnfa), and 4) expression of tumor necrosis factor-␣ (TNF-␣). Moreover, inhibition of G6PD increased protein kinase G1␣ activity, which, at least partially, mitigated superoxide production and Elk-1 and TNF-␣ expression. Additionally, we report here for the first time that 20-HETE repressed miR-143, which suppresses Elk-1 expression, and miR-133a, which is known to suppress synthetic/secretory phenotype of vascular smooth muscle cells. In summary, our findings indicate that 20-HETE elicited mitochondrial superoxide production and promoted secretory phenotype of vascular smooth muscle cells by activating MAPK1-Elk-1, all of which are blocked by inhibition of G6PD.20-HETE; TNF-␣; elk-1; mitogen-activated protein kinase 1 and 3; extracellular signal regulated kinase 2 and 1; protein kinase G; miRs 20-HYDROXYEICOSATETRAEONIC acid (20-HETE), the -hydroxylation metabolite of arachidonic acid (AA), is produced by cytochrome P-450 monooxygenases of the (CYP4A and CYP4F gene) families in an NADPH-dependent manner (49). 20-HETE is proinflammatory and it regulates vascular and renal function (49). It also plays a critical role in the pathogenesis of systemic hypertension, renal stenosis, and atherosclerosis (27,63,65). 20-HETE increased by hypoxia inhibits hypoxia-induced pulmonary artery constriction (69). However, its role in the hypoxia-induced inflammation of pulmonary arteries or lungs is yet unclear. NEWS & NOTEWORTHY 20-Hydroxyeicosatetraeonic acid (20-HETE) plays a criticalRecently, our laboratory also found that 20-HETE is involved in promoting prolonged hypoxia-induced pulmonary vasoconstriction and that glucose-6-phosphate dehydrogenase (G6PD), which is a major producer of NADPH in the cell, and cytochrome P-450 monooxygenase enzymes are functionally coupled in vascular smooth muscle tissue (unpublished observations). G6PD inhibition relaxes pulmonary arteries by decreasing intracellular calcium (20), prevents switching of vascular smooth ...

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Section: @Erspublicationsmentioning

confidence: 99%

“…The presence of a known causal mutation in a PAH gene is classified as heritable PAH. Understanding the role played by BMPR-II in PAH pathobiology has led to several preclinical approaches to treating this disease [5][6][7] that are now being translated into experimental medicine studies in patients [8].Although mutations in BMPR2 are the commonest genetic cause of PAH, they do not explain all cases, especially the sporadic cases. Over the past 15 years mutations have been identified in additional genes (reviewed in [9]).…”

mentioning

confidence: 99%

Towards a molecular classification of pulmonary arterial hypertension

Gräf

Morrell

2016

Eur Respir J

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@ERSpublicationsThis editorial discusses recent advances in understanding the genetic basis of pulmonary arterial hypertension http://ow.ly/mmfi303fvCuPulmonary arterial hypertension (PAH), although rare, remains a serious and life-limiting condition despite the availability of existing therapies [1]. In particular, the diagnosis of idiopathic PAH (in the absence of known disease gene associations) carries a 3 year survival of 60-70% in most registries [2]. The survival is even poorer for patients with familial PAH, who have at least one affected relative [3]. It is likely that the key to finding better treatments for patients with rare and severe forms of PAH is an improved understanding of the cellular and molecular basis of this disease, since knowledge of the genetics provides important clues to the major pathways to be targeted. For many rare diseases, rare high impact mutations in single genes play a major role in their pathobiology. Indeed, we now know that in families with PAH over 80% of cases are caused by heterozygous germline mutations in the gene (BMPR2) encoding the bone morphogenetic protein type II receptor (BMPR-II), a receptor for the transforming growth factor-β family of ligands [3]. In sporadic cases of idiopathic PAH, mutations in BMPR2 are found in 15-20% of cases [3]. These latter cases appear to be sporadic, rather than familial, because the mutations in BMPR2 exhibit low penetrance (less than 50% of carriers are affected, with females more susceptible than males), while some sporadic cases present with de novo mutations in the gene [4]. The presence of a known causal mutation in a PAH gene is classified as heritable PAH. Understanding the role played by BMPR-II in PAH pathobiology has led to several preclinical approaches to treating this disease [5][6][7] that are now being translated into experimental medicine studies in patients [8].Although mutations in BMPR2 are the commonest genetic cause of PAH, they do not explain all cases, especially the sporadic cases. Over the past 15 years mutations have been identified in additional genes (reviewed in [9]). Interestingly, several of these are within the bone morphogenetic protein (BMP) and transforming growth factor-β signalling pathways, for example ACVRL1 (encoding activin-receptor-like kinase 1 (ALK1)) [10] and ENG (encoding endoglin) [11]. Mutations in these genes are usually found in families with hereditary haemorrhagic telangiectasia (HHT), but occasionally these individuals present with severe PAH. The link appears to be that both ALK1 and endoglin are essential for BMP signalling in pulmonary artery endothelial cells. In addition, mutations in the genes encoding the downstream signalling intermediaries for BMP receptors, the Smad proteins ( particularly SMAD1 and SMAD9) have been reported in some patients [9]. Further mutations have been reported in genes not immediately associated with BMP signalling, including CAV1 (encoding caveolin-1) [12] and KCNK3 (encoding a potassium channel) [13]. There have also been reports of autosomal...

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Targeting BMP signalling in cardiovascular disease and anaemia

Cited by 195 publications

References 216 publications

Bone Morphogenetic Protein Signaling in Pulmonary Arterial Hypertension

Bone Morphogenetic Protein Signaling in Pulmonary Arterial Hypertension

20-HETE-induced mitochondrial superoxide production and inflammatory phenotype in vascular smooth muscle is prevented by glucose-6-phosphate dehydrogenase inhibition

Towards a molecular classification of pulmonary arterial hypertension

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