ALK2 and BMPR2 knockdown and endothelin-1 production by pulmonary microvascular endothelial cells

Star, Gregory P.; Giovinazzo, Michele; Langleben, David

doi:10.1016/j.mvr.2012.10.012

Cited by 24 publications

(14 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutations associated with the genes in the TGFβ signaling pathway, such as ALK2 ( ACVR1 ), ALK1 ( ACVRL1) , and CAV1 , are also very important. ALK1 and ALK2 function to activate other proteins and genes in the TGFβ and BMPR2 pathways [ 42 ]. CAV1 has been extensively reported with many confirmed mutations specific for PAH [ 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

A systematic review of genetic mutations in pulmonary arterial hypertension

et al. 2017

View full text Add to dashboard Cite

BackgroundPulmonary arterial hypertension (PAH) is a group of vascular diseases that produce right ventricular dysfunction, heart failure syndrome, and death. Although the majority of patients appear idiopathic, accumulated research work combined with current sequencing technology show that many gene variants could be an important component of the disease. However, current guidelines, clinical practices, and available gene panels focus the diagnosis of PAH on a relatively low number of genes and variants associated with the bone morphogenic proteins and transforming Growth Factor-β pathways, such as the BMPR2, ACVRL1, CAV1, ENG, and SMAD9.MethodsTo provide an expanded view of the genes and variants associated with PAH, we performed a systematic literature review. Facilitated by a web tool, we classified, curated, and annotated most of the genes and PubMed abstracts related to PAH, in which many of the mutations and variants were not annotated in public databases such as ClinVar from NCBI. The gene list generated was compared with other available tests.ResultsOur results reveal that there is genetic evidence for at least 30 genes, of which 21 genes shown specific mutations. Most of the genes are not covered by current available genetic panels. Many of these variants were not annotated in the ClinVar database and a mapping of these mutations suggest that next generation sequencing is needed to cover all mutations found in PAH or related diseases. A pathway analysis of these genes indicated that, in addition to the BMP and TGFβ pathways, there was connections with the nitric oxide, prostaglandin, and calcium homeostasis signalling, which may be important components in PAH.ConclusionOur systematic review proposes an expanded gene panel for more accurate characterization of the genetic incidence and risk in PAH. Their usage would increase the knowledge of PAH in terms of genetic counseling, early diagnosis, and potential prognosis of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0440-5) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

A systematic review of genetic mutations in pulmonary arterial hypertension

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In contrast, no effects of mutants Tyr67Cys, Thr268fs, and Gln433X on levels of ET -1 in HLMVE cells were found. As many previous studies have demonstrated that TGF-β stimulates production of ET-1 in endothelial cells [10], the question is raised as to whether the Ser863Asp mutant increases ET-1 levels itself or stimulates TGF-β signaling, which would indirectly increase ET-1 levels. The increased levels of ET-1 associated with the Ser863Asp mutant and the decreased levels of NO in all four mutants we identified may represent a mechanism that explains how BMPR2 mutations are associated with the development of PAH.…”

Section: Discussionmentioning

confidence: 99%

“…Bone morphogenic proteins (BMPs) may modulate a number of pathophysiological processes, not only in the vascular smooth muscle (VSM) but also in the endothelium, which may contribute to the development of PAH. Within the endothelium, BMP has been shown to modulate the formation of the key transmitters, NO [9] and ET [10], and to regulate endothelial cell migration [11], as well as survival and proliferation [12].…”

Section: Introductionmentioning

confidence: 99%

Functional Changes in Pulmonary Arterial Endothelial Cells Associated with BMPR2 Mutations

Wang

Meng

et al. 2014

PLoS ONE

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by abnormal remodeling of small, peripheral pulmonary arteries. Germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene are a major risk factor for developing PAH. At present, the correlation between the BMPR2 mutation and the patient's prognosis remains controversial despite several investigations. In this study, we explored the functional effects of four BMPR2 mutations to dissect the functional significance of the BMPR2 gene defect. Cellular immunofluorescence assay of four mutants (Tyr67Cys, Thr268fs, Ser863Asn, and Gln433X) revealed that the BMPR2 protein containing Thr268fs, Ser863Asn, or Gln433X exhibited abnormal subcellular localization. The BrdU incorporation and TUNEL assay suggested that any of the BMPR2 mutations Thr268fs, Ser863Asn, or Gln433X could improve endothelial cell apoptosis and decrease cell proliferation. All of the four mutants could inhibit nitric oxide (NO) synthesis in HLMVE cells, and ET-1 levels increased in the cells transfected with mutant Ser863Asn. Our results will improve the understanding of the genotype-phenotype correlations and mechanisms associated with BMPR2 mutations.

show abstract

“…A role for TGF-β is suggested since that increase was prevented by ALK2 knockdown. Thus, increased ET-1 production by endothelial cells as a consequence of BMPR II dysfunction may be clinically relevant in the pathogenesis of the vasculopathy in PAH and SSc [28, 29]. The loss of small precapillary arteries is a prominent feature of PAH and SSc vasculopathy that is thought to be as a result of enhanced susceptibility of ECs both to apoptosis and to failure of angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic repression of bone morphogenetic protein receptor II expression in scleroderma

Wang

Kahaleh

2013

J Cellular Molecular Medi

View full text Add to dashboard Cite

Germline mutations in the bone morphogenetic protein type II receptor (BMPRII) gene play an essential role in the pathogenesis of familial pulmonary arterial hypertension (FPAH). In view of the histological similarities between scleroderma (SSc) and FPAH arterial lesion, we examined the expression levels of BMPRII in SSc microvascular endothelial cells (MVEC). Oxidative stress and serum starvation were used to examine apoptotic responses of MVECs. BMPRII expression levels were determined by RT-PCR and by Western blot. Epigenetic regulation of BMPRII expression was examined by the addition of epigenetic inhibitors to MVECs cultures, by methylation-specific PCR, and by sequence analysis of DNA methylation pattern of the BMPRII promotor region. SSc-MVECs were more sensitive to apoptotic signals than were normal-MVECs. A significant decrease in BMPRII expression levels in SSc-MVECs was noted, whereas no significant differences in the expression levels of BMPRIA and BMPRIB were observed. Similar reduction in expression levels was noted in SSc skin biopsies. The expression level of BMPRII in SSc-MVECs was normalized by the addition of 2-deoxy-5-azacytidine and trichostatin A to cell cultures. Extensive CpG sites methylation in the BMPRII promoter region was noted in SSc-MVECs with no detectable site methylation in control-MVECs. SSc-MVECs are more sensitive to apoptotic triggers than are control-MVECs. The enhanced apoptosis may be related to epigenetic repression of BMPRII expression as apoptosis of control-MVECs can be augmented by knocking down BMPRII expression. The role of BMPRII underexpression in the pathogenesis of SSc vasculopathy is suggested and should be investigated further.

show abstract

ALK2 and BMPR2 knockdown and endothelin-1 production by pulmonary microvascular endothelial cells

Cited by 24 publications

References 43 publications

A systematic review of genetic mutations in pulmonary arterial hypertension

A systematic review of genetic mutations in pulmonary arterial hypertension

Functional Changes in Pulmonary Arterial Endothelial Cells Associated with BMPR2 Mutations

Epigenetic repression of bone morphogenetic protein receptor II expression in scleroderma

Contact Info

Product

Resources

About