Heritable pulmonary hypertension: from bench to bedside

Girerd, Barbara; Weatherald, Jason; Montani, David; Humbert, Marc

doi:10.1183/16000617.0037-2017

Cited by 30 publications

(20 citation statements)

References 68 publications

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“…The group of conditions that can be associated with PVOD/PCH also includes interstitial lung diseases -PLCH [7] and sarcoidosis [8,9], autoimmunological diseases such as Hashimoto's thyroiditis [21], haematopoetic stem cells transplantation [4] and other haematologic malignancies (polycythemia vera) [22].…”

Section: Occupational Dependence Of Pvod/pchmentioning

confidence: 99%

Pulmonary Veno-Occlusive Disease: Pathogenesis, Risk Factors, Clinical Features and Diagnostic Algorithm—State of the Art

Szturmowicz¹,

Kacprzak²,

Szołkowska³

et al. 2018

Advances in Respiratory Medicine

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Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH) are rare disorders, with the estimated prevalence of less than 1 case per million inhabitants. The vascular pathology in PVOD/PCH involves pre-septal and septal veins, alveolar capillaries and small pulmonary arteries. According to the ERS/ESC classification of pulmonary hypertension (PH) from 2015, PVOD/PCH have been included in the subgroup 1' of pulmonary arterial hypertension (PAH). Recent data indicate, however, the possibility of PVOD/PCH pathology in the patients diagnosed in the group 1. The problem may concern PAH associated with scleroderma, drug-induced PAH, PAH due to HIV infection and up to 10% of patients with idiopathic PAH (IPAH). Recently, bi-allelic EIF2AK4 mutations were found in the cases with heritable form of PVOD/PCH and in about 9% of sporadic cases. Moreover, an association between occupational exposure to organic solvents and PVOD/PCH was proved. The present review is an attempt to summarise the current data on pathogenesis, risk factors, clinical features and diagnostic algorithm for PVOD/PCH.

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Section: Occupational Dependence Of Pvod/pchmentioning

confidence: 99%

Pulmonary Veno-Occlusive Disease: Pathogenesis, Risk Factors, Clinical Features and Diagnostic Algorithm—State of the Art

Szturmowicz¹,

Kacprzak²,

Szołkowska³

et al. 2018

Advances in Respiratory Medicine

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“…Haploinsufficient loss-of-function mutations in the bone morphogenetic protein type 2 receptor ( BMPR2 ) gene, a member of the transforming growth factor-beta (TGF-β) superfamily, account for over 80% of hereditary PAH cases and approximately 20% of idiopathic PAH cases [4]. Several mutations in other genes have been reported, accounting for at least a portion of the remainder of PAH heritability.…”

Section: Introductionmentioning

confidence: 99%

Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130/301-Vascular Matrix Feedback Loop

Bertero

Handen

Chan

2018

IJMS

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Pulmonary arterial hypertension (PAH) is characterized by occlusion of lung arterioles, leading to marked increases in pulmonary vascular resistance. Although heritable forms of PAH are known to be driven by genetic mutations that share some commonality of function, the extent to which these effectors converge to regulate shared processes in this disease is unknown. We have causally connected extracellular matrix (ECM) remodeling and mechanotransduction to the miR-130/301 family in a feedback loop that drives vascular activation and downstream PAH. However, the molecular interconnections between factors genetically associated with PAH and this mechano-driven feedback loop remain undefined. We performed systematic manipulation of matrix stiffness, the miR-130/301 family, and factors genetically associated with PAH in primary human pulmonary arterial cells and assessed downstream and reciprocal consequences on their expression. We found that a network of factors linked to heritable PAH converges upon the matrix stiffening-miR-130/301-PPARγ-LRP8 axis in order to remodel the ECM. Furthermore, we leveraged a computational network biology approach to predict a number of additional molecular circuits functionally linking this axis to the ECM. These results demonstrate that multiple genes associated with heritable PAH converge to control the miR-130/301 circuit, triggering a self-amplifying feedback process central to pulmonary vascular stiffening and disease.

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“…The role of genetics in PAH, both the risk of developing the disease and the progression of pulmonary vascular lesions, has been proven (9)(10)(11)(12)(13)(14). The human multidrug resistance gene (MDR1) (or ABCB1) encodes an integrated membrane protein, P-glycoprotein (Pgp), which plays an important role in the bioavailability of some drug agents and also in the protection of cells against toxic substances and metabolites by acting ATP-dependent cellular efflux mechanism (15).…”

Section: Introductionmentioning

confidence: 99%

“…The human multidrug resistance gene (MDR1) (or ABCB1) encodes an integrated membrane protein, P-glycoprotein (Pgp), which plays an important role in the bioavailability of some drug agents and also in the protection of cells against toxic substances and metabolites by acting ATP-dependent cellular efflux mechanism (15). P-glycoprotein is expressed in the epithelial cells of different organs, including the lungs, where it facilitates transmembrane intracellular transport of various toxins, decreasing the intracellular concentration of toxic compounds (12,16). MDR1 polymorphism is associated with the decrease synthesis and function alteration of P-gp.…”

Section: Introductionmentioning

confidence: 99%

Association between MDR1 gene polymorphism and clinical course of pediatric pulmonary arterial hypertension

Muntean

Şuteu

Togănel

et al. 2018

Revista Romana De Medicina De Laborator

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Pulmonary arterial hypertension (PAH) is a progressive disease with a complex pathogenesis. The polymorphism of the gene of multidrug resistance-1 (MDR1) has been associated with many diseases including PAH. Objective. In this study we aimed to investigate the relevance of the MDR1 polymorphism to pediatric PAH clinical course. Methods. A total of 40 pediatric patients with PAH (secondary to congenital heart defects or idiopathic) and 40 control subjects were enrolled. Patients with PAH were divided into 2 groups, according to their evolution: 28 patients who remained clinically stable at 12-months (non-worsening group) and 12 patients who presented clinical worsening at 12-months (worsening group). Genomic DNA was genotyped for MDR1 gene polymorphisms as follows: C1236T, G2677T and C3435T. Results. There were no significant differences between PAH children groups (clinical worsening and non-worsening) nor between PAH children and controls in terms of frequency distribution of the three studied genotypes or alleles. Conclusions. The MDR1 polymorphism could not be correlated with the clinical evolution of pediatric PAH patients in our study.

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Heritable pulmonary hypertension: from bench to bedside

Cited by 30 publications

References 68 publications

Pulmonary Veno-Occlusive Disease: Pathogenesis, Risk Factors, Clinical Features and Diagnostic Algorithm—State of the Art

Pulmonary Veno-Occlusive Disease: Pathogenesis, Risk Factors, Clinical Features and Diagnostic Algorithm—State of the Art

Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130/301-Vascular Matrix Feedback Loop

Association between MDR1 gene polymorphism and clinical course of pediatric pulmonary arterial hypertension

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