A novel BMPR2 mutation in a patient with heritable pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia

Ye, Fanhao; Jiang, Wenbing; Lin, Wei; Wang, Yi; Chen, Hao; He, Zou; Huang, Shi‐Wei; Zhu, Ning; Han, Sisi

doi:10.1097/md.0000000000021342

Cited by 6 publications

(9 citation statements)

References 14 publications

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“…The mutational spectrum of HTT includes the ENG and activin receptor-like kinase type 1 ( ALK1 ) gene, distinctive for the HHT type 1 and 2, respectively [ 47 , 48 ]. The decapentaplegic homolog 4 (SMAD4) and BMP gene were also identified in HHT patients [ 47 , 48 , 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Brain AVMs-Related microRNAs: Machine Learning Algorithm for Expression Profiles of Target Genes

Lucifero

Luzzi

2022

Brain Sciences

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Introduction: microRNAs (miRNAs) are a class of non-coding RNAs playing a myriad of important roles in regulating gene expression. Of note, recent work demonstrated a critical role of miRNAs in the genesis and progression of brain arteriovenous malformations (bAVMs). Accordingly, here we examine miRNA signatures related to bAVMs and associated gene expression. In so doing we expound on the potential prognostic, diagnostic, and therapeutic significance of miRNAs in the clinical management of bAVMs. Methods: A PRISMA-based literature review was performed using PubMed/Medline database with the following search terms: “brain arteriovenous malformations”, “cerebral arteriovenous malformations”, “microRNA”, and “miRNA”. All preclinical and clinical studies written in English, regardless of date, were selected. For our bioinformatic analyses, miRWalk and miRTarBase machine learning algorithms were employed; the Kyoto Encyclopedia of Genes and Genomes (KEGG) database was quired for associated pathways/functions. Results: four studies were ultimately included in the final analyses. Sequencing data consistently revealed the decreased expression of miR-18a in bAVM-endothelial cells, resulting in increased levels of vascular endodermal growth factor (VEGF), Id-1, matrix metalloproteinase, and growth signals. Our analyses also suggest that the downregulation of miR-137 and miR-195* within vascular smooth muscle cells (VSMCs) may foster the activation of inflammation, aberrant angiogenesis, and phenotypic switching. In the peripheral blood, the overexpression of miR-7-5p, miR-629-5p, miR-199a-5p, miR-200b-3p, and let-7b-5p may contribute to endothelial proliferation and nidus development. The machine learning algorithms employed confirmed associations between miRNA-related target networks, vascular rearrangement, and bAVM progression. Conclusion: miRNAs expression appears to be critical in managing bAVMs’ post-transcriptional signals. Targets of microRNAs regulate canonical vascular proliferation and reshaping. Although additional scientific evidence is needed, the identification of bAVM miRNA signatures may facilitate the development of novel prognostic/diagnostic tools and molecular therapies for bAVMs.

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Section: Discussionmentioning

confidence: 99%

Brain AVMs-Related microRNAs: Machine Learning Algorithm for Expression Profiles of Target Genes

Lucifero

Luzzi

2022

Brain Sciences

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“…Rarely, PAH has been identified in patients with HHT and mutations in GDF2 and BMPR2. 22,75 Alternative causes of PAH, including pulmonary capillary hemangiomatosis and portal hypertension, have also been observed in patients with HHT. 76,77 Clinically, patients with PAH will present with progressive exertional dyspnea and decreased exercise tolerance.…”

Section: Pathophysiology and Presentationmentioning

confidence: 99%

“…Therefore, patients with HHT1 exhibiting precapillary PH should be thoroughly evaluated to exclude other etiologies (e.g., CTEPH and congenital heart disease). Rarely, PAH has been identified in patients with HHT and mutations in GDF2 and BMPR2 22,75 . Alternative causes of PAH, including pulmonary capillary hemangiomatosis and portal hypertension, have also been observed in patients with HHT 76,77 …”

Section: Pulmonary Arterial Hypertensionmentioning

confidence: 99%

Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review

Mathavan,

Reddy

et al. 2023

Pulm. circ.

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Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant hereditary disorder characterized by recurrent spontaneous epistaxis, mucocutaneous telangiectasias, and solid organ arteriovenous malformations (AVMs). Pulmonary hypertension (PH) is an increasingly recognized complication in patients with HHT, most often precipitated by high‐output heart failure in the presence of hepatic AVMs as well as pulmonary arterial hypertension in the form of a proliferative vasculopathy. The presence of PH in patients with HHT is associated with significant elevations in rates of morbidity and mortality. Additionally, there is growing recognition of a thromboembolic propensity in this population that increases the risk of chronic thromboembolic PH, posing unique clinical considerations regarding the use of anticoagulation. Patients with HHT are also at risk of PH due to disorders commonly seen in the general population, including left‐sided heart and lung disease. The etiology of PH in HHT is multifaceted and complex; the diagnostic approach and treatment strategies must consider the underlying pathophysiology of HHT. This comprehensive review summarizes current knowledge of PH in HHT, detailing the pathogenesis of known etiologies, diagnostic evaluation, and suggested treatment modalities as well as emerging therapies that may be of future interest.

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“…BMPR2 mutations are associated with the development of pulmonary hypertension (PAH), 9 chronic obstructive pulmonary disease (COPD), 12 hemorrhagic telangiectasia (HHT), tumors, and obesity. 13 In pulmonary hypertension, BMPR2 deficiency inhibits the proliferation and differentiation of vascular smooth muscle cells and endothelial cells, and modulation of BMPR2 expression changes the processes of proliferation and apoptosis. 9 In recent years, noncoding RNAs (ncRNAs) have become of interest in various fields.…”

Section: Introductionmentioning

confidence: 99%

The MEG3 lncRNA promotes trophoblastic cell growth and invasiveness in preeclampsia by acting as a sponge for miR-21, which regulates BMPR2 levels

Liu

Zhang

et al. 2021

Eur J Histochem

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Preeclampsia (PE) is one of the leading causes of maternal morbidity and mortality in pregnant women. This study aimed to investigate the potential impact and regulatory mechanisms of bone morphogenetic protein receptor 2 (BMPR2) on the progression of PE. We obtained placental tissues from pregnant women with PE and normal pregnant women, and the results showed that BMPR2 was expressed at low levels in the tissue from PE women. Genetic knockdown of BMPR2 increased the proliferation and invasion of cultured trophoblast cells, whereas its overexpression reduced these characteristics. Bioinformatics analysis and luciferase reporter gene assays confirmed that BMPR2 is a direct target of miR-21. Overexpression of a miR-21 inhibitor promoted the growth and invasiveness of trophoblast cells, whereas the opposite results were observed for the miR-21 mimic. Furthermore, miR-21 was sponged by the lncRNA MEG3, and shRNA inhibition of MEG3 reduced trophoblast cell growth and invasiveness. miR-21 was upregulated in the tissues from PE women, whereas MEG3 was downregulated, and the two were negatively correlated. Collectively, this study demonstrates that the lncRNA MEG3 acts as a sponge for miR-21, which regulates BMPR2 expression and promotes trophoblast cell proliferation and invasiveness, thereby preventing the development of PE. These findings provide novel insight into a targeted therapy that could be used to treat or prevent the development of PE.

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A novel BMPR2 mutation in a patient with heritable pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia

Cited by 6 publications

References 14 publications

Brain AVMs-Related microRNAs: Machine Learning Algorithm for Expression Profiles of Target Genes

Brain AVMs-Related microRNAs: Machine Learning Algorithm for Expression Profiles of Target Genes

Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review

The MEG3 lncRNA promotes trophoblastic cell growth and invasiveness in preeclampsia by acting as a sponge for miR-21, which regulates BMPR2 levels

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