Targeting the TGF-β signaling pathway for resolution of pulmonary arterial hypertension

Sharmin, Nahid; Nganwuchu, Chinyere Chioma; Nasim, Talat

doi:10.1016/j.tips.2021.04.002

Cited by 19 publications

(10 citation statements)

References 20 publications

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“…In accordance with our results, previous studies have shown TβRI receptor expression in the pulmonary vasculature, particularly in PASMC and PAEC [ 43 , 44 ], and the ability of these cells to express and secrete TGF-β1 [ 45 , 46 , 47 ]. TGF-β1 is a growth factor involved in PH pathophysiology [ 31 , 32 , 33 , 34 ], whose expression is also increased in this disease [ 28 , 29 , 30 ]. In addition, alterations in TGF-β1-dependent canonical (involving Smad3) and non-canonical (involving p38) signaling pathways have been observed in PH [ 31 , 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…Human PASMC or PAEC were treated with either IL-1β or H 2 O 2 , and we then evaluated NGF secretion by these cells. We also investigated the mechanism involved in the NGF increased secretion we observed and focused on the role of the transforming growth factor-β1 (TGF-β1), another growth factor whose expression is also increased in PH [ 28 , 29 , 30 ], and which also plays a pathophysiological role in this disease [ 31 , 32 , 33 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

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Inflammation and Oxidative Stress Induce NGF Secretion by Pulmonary Arterial Cells through a TGF-β1-Dependent Mechanism

Bouchet

Cardouat

Douard

et al. 2022

Cells

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Expression of the nerve growth factor NGF is increased in pulmonary hypertension (PH). We have here studied whether oxidative stress and inflammation, two pathological conditions associated with transforming growth factor-β1 (TGF-β1) in PH, may trigger NGF secretion by pulmonary arterial (PA) cells. Effects of hydrogen peroxide (H2O2) and interleukin-1β (IL-1β) were investigated ex vivo on rat pulmonary arteries, as well as in vitro on human PA smooth muscle (hPASMC) or endothelial cells (hPAEC). TβRI expression was assessed by Western blotting. NGF PA secretion was assessed by ELISA after TGF-β1 blockade (anti-TGF-β1 siRNA, TGF-β1 blocking antibodies, TβRI kinase, p38 or Smad3 inhibitors). TβRI PA expression was evidenced by Western blotting both ex vivo and in vitro. H2O2 or IL-1β significantly increased NGF secretion by hPASMC and hPAEC, and this effect was significantly reduced when blocking TGF-β1 expression, binding to TβRI, TβRI activity, or signaling pathways. In conclusion, oxidative stress and inflammation may trigger TGF-β1 secretion by hPASMC and hPAEC. TGF-β1 may then act as an autocrine factor on these cells, increasing NGF secretion via TβRI activation. Since NGF and TGF-β1 are relevant growth factors involved in PA remodeling, such mechanisms may therefore be relevant to PH pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inflammation and Oxidative Stress Induce NGF Secretion by Pulmonary Arterial Cells through a TGF-β1-Dependent Mechanism

Bouchet

Cardouat

Douard

et al. 2022

Cells

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“…Among the 45 study subjects, 3 of them had family aggregate of heritable PAH (Table 2). Patient (A256) with BMPR2 BMPR2 genetic variants will lead to receptor protein deficiency and result in abnormal overactivation of the TGF-β1 signaling pathway (3). The TGF-β pathway over-activation leads to proliferation of vascular smooth muscle cells and increase of PVR in pulmonary circulation in primary PAH (3,46).…”

Section: Family History Of Pah In the Study Cohortmentioning

confidence: 99%

“…Patient (A256) with BMPR2 BMPR2 genetic variants will lead to receptor protein deficiency and result in abnormal overactivation of the TGF-β1 signaling pathway (3). The TGF-β pathway over-activation leads to proliferation of vascular smooth muscle cells and increase of PVR in pulmonary circulation in primary PAH (3,46). Asian cohort from Korea reported that the prevalence of BMPR2 variants in Korean primary PAH patients was 22% (19).…”

Section: Family History Of Pah In the Study Cohortmentioning

confidence: 99%

“…It is now well established that around 70–80% of heritable pulmonary arterial hypertension (PAH) and 10–20% of idiopathic PAH cases are related with genetic variants in bone morphogenetic protein receptor type-2 ( BMPR2 ) ( 1 , 2 ). BMPR2 deficiency leads to an abnormal over-activation of the transforming growth factor β (TGF-β) signaling pathway, resulting in over-proliferation of vascular smooth muscle cells at pulmonary arteriole ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

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Whole Exome Sequencing of Patients With Heritable and Idiopathic Pulmonary Arterial Hypertension in Central Taiwan

Liang

Chang

Chen

et al. 2022

Front. Cardiovasc. Med.

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BackgroundGenetic variants could be identified in subjects with idiopathic and heritable pulmonary arterial hypertension (PAH). The 6th World Symposium on Pulmonary Hypertension (WSPH) provided a list of genes with evidence of association with PAH. However, reports using whole exome sequencing (WES) from southeastern Asian PAH cohorts were scarce.MethodsSubjects with idiopathic and heritable PAH (N = 45) from two medical centers in central Taiwan were screened for PAH related gene variants. The genomic DNA was prepared from peripheral blood lymphocytes. We performed WES for all patients enrolled in this study. All identified gene variants were validated by polymerase-chain reaction and Sanger sequencing. The clinical and hemodynamic data were compared between bone morphogenetic protein receptor type-2 (BMPR2) gene variants carriers vs. non-carriers.ResultsEight patients (8/45 = 17.8%) was identified carrying BMPR2 gene variants and 8 patients (8/45 = 17.8%) had other WSPH-listed PAH-related gene variants (1 with ACVRL1, 1 with ENG, 1 with SMAD9, 1 with SMAD1, 1 with ATP13A3 and 3 with AQP1). In addition, a total of 14 non-WSPH-listed PAH-related genetic variant sites (ABCC8, NOTCH1, NOTCH2, NOTCH3, JAG1, BMP10, GGCX, FBLN2, ABCA3 and PTGIS) were found in this PAH cohort. Subjects carrying BMPR2 gene variant (N = 8) were younger at diagnosis of PAH (30 ± 11 vs 49 ± 13 years, p = 0.001) than the non-carrier group (N = 37). BMPR2 variant carriers had a trend toward having higher mean pulmonary arterial pressure (PAP) (61 ± 19 vs. 51 ± 13 mmHg, p = 0.076) than the non-carriers upon initial diagnosis. Pulmonary vascular resistance, right atrial pressure, cardiac output, as well as functional class were similar between BMPR2 variant carriers and non-carriers at initial diagnosis.ConclusionsWe identified 17.8% of patients with BMPR2 gene variants and 17.8% subjects with other 6th WSPH-listed PAH-related gene variants in a Taiwanese idiopathic and heritable PAH cohort. PAH patients carrying BMPR2 variants presented at a younger age with a trend toward having higher mean PAP at initial diagnosis.

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Large‐ and medium‐sized arterial aneurysms in two patients with SMAD4‐related juvenile polyposis syndrome

van Weelden,

Bleeker,

van Stijn

et al. 2024

American J of Med Genetics Pt A

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Germline SMAD4 pathogenic variants (PVs) cause juvenile polyposis syndrome (JPS), which is known for an increased risk of gastrointestinal juvenile polyps and gastrointestinal cancer. Many patients with SMAD4 PV also show signs of hereditary hemorrhagic telangiectasia (HHT) and some patients have aneurysms and dissections of the thoracic aorta. Here we describe two patients with a germline SMAD4 PV and a remarkable clinical presentation including multiple medium‐sized arterial aneurysms. More data are needed to confirm whether the more extensive vascular phenotype and the other described features in our patients are indeed part of a broader JPS spectrum.

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Targeting the TGF-β signaling pathway for resolution of pulmonary arterial hypertension

Cited by 19 publications

References 20 publications

Inflammation and Oxidative Stress Induce NGF Secretion by Pulmonary Arterial Cells through a TGF-β1-Dependent Mechanism

Inflammation and Oxidative Stress Induce NGF Secretion by Pulmonary Arterial Cells through a TGF-β1-Dependent Mechanism

Whole Exome Sequencing of Patients With Heritable and Idiopathic Pulmonary Arterial Hypertension in Central Taiwan

Large‐ and medium‐sized arterial aneurysms in two patients with SMAD4‐related juvenile polyposis syndrome

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