Diagnosis and Management of Pulmonary Hypertension in the Modern Era: Insights from the 6th World Symposium

Thomas, Christopher; Anderson, Ryan J.; Condon, David; Perez, Vinicio A. de Jesus

doi:10.1007/s41030-019-00105-5

Cited by 38 publications

(30 citation statements)

References 67 publications

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“…Samples were obtained from the Spanish PAH registries (REHAP and REHIPED), and the ethical committee approved the project of scientific research of the Hospital Universitario La Paz, Madrid (PI-1210, PI-3996). PAH was confirmed in all patients by right heart catheterization (RHC) following the recommendations of the 6th World Symposium and the European Society of Cardiology (1,2,22). Screening of family members was carried out by performing a family pedigree of all individual index cases of PAH.…”

Section: Patient Studiesmentioning

confidence: 99%

Novel TNIP2 and TRAF2 Variants Are Implicated in the Pathogenesis of Pulmonary Arterial Hypertension

et al. 2021

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Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling and right heart failure. Specific genetic variants increase the incidence of PAH in carriers with a family history of PAH, those who suffer from certain medical conditions, and even those with no apparent risk factors. Inflammation and immune dysregulation are related to vascular remodeling in PAH, but whether genetic susceptibility modifies the PAH immune response is unclear. TNIP2 and TRAF2 encode for immunomodulatory proteins that regulate NF-κB activation, a transcription factor complex associated with inflammation and vascular remodeling in PAH.Methods: Two unrelated families with PAH cases underwent whole-exome sequencing (WES). A custom pipeline for variant prioritization was carried out to obtain candidate variants. To determine the impact of TNIP2 and TRAF2 in cell proliferation, we performed an MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay on healthy lung pericytes transfected with siRNA specific for each gene. To measure the effect of loss of TNIP2 and TRAF2 on NF-kappa-beta (NF-κB) activity, we measured levels of Phospho-p65-NF-κB in siRNA-transfected pericytes using western immunoblotting.Results: We discovered a novel missense variant in the TNIP2 gene in two affected individuals from the same family. The two patients had a complex form of PAH with interatrial communication and scleroderma. In the second family, WES of the proband with PAH and primary biliary cirrhosis revealed a de novo protein-truncating variant in the TRAF2. The knockdown of TNIP2 and TRAF2 increased NF-κB activity in healthy lung pericytes, which correlated with a significant increase in proliferation over 24 h.Conclusions: We have identified two rare novel variants in TNIP2 and TRAF2 using WES. We speculate that loss of function in these genes promotes pulmonary vascular remodeling by allowing overactivation of the NF-κB signaling activity. Our findings support a role for WES in helping identify novel genetic variants associated with dysfunctional immune response in PAH.

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Section: Patient Studiesmentioning

confidence: 99%

Novel TNIP2 and TRAF2 Variants Are Implicated in the Pathogenesis of Pulmonary Arterial Hypertension

et al. 2021

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“…ст.) [1]. Следует отметить, что в 2009 году было показано, что у здоровых лиц сДЛА составляет 14,0±3,3 мм рт.…”

Section: гемодинамическое определение лагunclassified

“…За последние два десятилетия произошли значимые изменения в подходах к ведению пациентов с легочной артериальной гипертензией (ЛАГ). С 1973 года, когда прошел Первый Всемирный Симпозиум по легочной гипертензии (ЛГ), появились новые диагностические возможности и новые препараты, которые позволили улучшить качество жизни и выживаемость пациентов [1].…”

Section: Introductionunclassified

Pulmonary Arterial Hypertension: Regional Health Care Opportunities

Филиппов

2021

Evrazijskij kardiologičeskij žurnal

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“…Pulmonary hypertension (PH) is a rare vascular disorder, now defined clinically as a mean pulmonary artery pressure (mPAP) over 25 mmHg at rest or over 30 mmHg during activity. Pulmonary vascular remodeling plays an important role in PH pathology, which is mainly characterized by endothelial cell injury, smooth muscle cell proliferation, fibroblast muscularization, extracellular matrix increase, in situ thrombosis, varying degree inflammation, and plexiform arterial changes [ 1 , 2 ]. In these pathological changes, the proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the most important cause of pulmonary vascular remodeling in PH.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-137 Inhibited Hypoxia-Induced Proliferation of Pulmonary Artery Smooth Muscle Cells by Targeting Calpain-2

Zhu

Yao

et al. 2021

BioMed Research International

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The proliferation of pulmonary artery smooth muscle cells (PASMCs) is an important cause of pulmonary vascular remodeling in pulmonary hypertension (PH). It has been reported that miR-137 inhibits the proliferation of tumor cells. However, whether miR-137 is involved in PH remains unclear. In this study, male Sprague-Dawley rats were subjected to 10% O2 for 3 weeks to establish PH, and rat primary PASMCs were treated with hypoxia (3% O2) for 48 h to induce cell proliferation. The effect of miR-137 on PASMC proliferation and calpain-2 expression was assessed by transfecting miR-137 mimic and inhibitor. The effect of calpain-2 on PASMC proliferation was assessed by transfecting calpain-2 siRNA. The present study found for the first time that miR-137 was downregulated in pulmonary arteries of hypoxic PH rats and in hypoxia-treated PASMCs. miR-137 mimic inhibited hypoxia-induced PASMC proliferation and upregulation of calpain-2 expression in PASMCs. Furthermore, miR-137 inhibitor induced the proliferation of PASMCs under normoxia, and knockdown of calpain-2 mRNA by siRNA significantly inhibited hypoxia-induced proliferation of PASMCs. Our study demonstrated that hypoxia-induced downregulation of miR-137 expression promoted the proliferation of PASMCs by targeting calpain-2, thereby potentially resulting in pulmonary vascular remodeling in hypoxic PH.

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Diagnosis and Management of Pulmonary Hypertension in the Modern Era: Insights from the 6th World Symposium

Cited by 38 publications

References 67 publications

Novel TNIP2 and TRAF2 Variants Are Implicated in the Pathogenesis of Pulmonary Arterial Hypertension

Novel TNIP2 and TRAF2 Variants Are Implicated in the Pathogenesis of Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension: Regional Health Care Opportunities

MicroRNA-137 Inhibited Hypoxia-Induced Proliferation of Pulmonary Artery Smooth Muscle Cells by Targeting Calpain-2

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