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Introduction
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April 2017 - present
September 2013 - April 2017
March 2011 - August 2013
Publications
Publications (136)
Rationale
Pulmonary arterial hypertension (PAH) has been described in patients treated with proteasome inhibitors (PI).
Objectives
To evaluate the association between PI and PAH.
Methods
Characteristics of incident PAH cases previously treated with Carfilzomib or Bortezomib were analyzed from the French PH Registry and the VIGIAPATH program from...
Pulmonary arterial hypertension (PAH) is severe cardiopulmonary disease that may be triggered by exposure to drugs such as dasatinib or facilitated by genetic predispositions. The incidence of dasatinib-associated PAH is estimated at 0.45%, suggesting individual predispositions. The mechanisms of dasatinib-associated PAH are still incomplete. We di...
Background
Bone morphogenetic proteins 9 and 10 (BMP9 and BMP10), encoded by GDF2 and BMP10 , play a pivotal role in pulmonary vascular regulation. GDF2 variants have been reported in pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). However, the phenotype of GDF2 and BMP10 carriers remains largely unexplored....
The ATP-sensitive potassium channels (K ATP ) and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH). Loss-of-function pathogenic variants in the ABCC8 gene, which encodes for SUR1, have been associated with heritable pulmonary arterial hypertension. Con...
Potassium channel subfamily K member 3 (KCNK3), encoded by the KCNK3 gene, is part of the two‐pore domain potassium channel family, constitutively active at resting membrane potentials in excitable cells, including smooth muscle and cardiac cells. Several physiological and pharmacological mediators, such as intracellular signalling pathways, extrac...
Pulmonary arterial hypertension (PAH) is due to progressive distal pulmonary artery (PA) obstruction leading to right ventricular hypertrophy and failure. Exacerbated store-operated Ca2+ entry (SOCE) contributes to PAH pathogenesis, mediating human PA smooth muscle cells (hPASMCs) abnormalities. The transient receptor potential canonical channels (...
Aims
We hypothesized that the ATP-sensitive K ⁺ channels (KATP) regulatory subunit (ABCC9) contributes to PAH pathogenesis. ABCC9 gene encodes for two regulatory subunits of KATP channels: the SUR2A and SUR2B proteins. In the KATP channel, the SUR2 subunits are associated with the K ⁺ channel Kir6.1. We investigated how the SUR2/Kir6.1 channel cont...
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH) occurring in a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2, general control nonderepressible 2) or in a sporadic form in older age (sPVOD), following exposure to chemotherapy or organic solvents. In contrast t...
Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca ²⁺ ) signaling contributes to abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance,...
Introduction: The ATP-sensitive K+ channels (KATP) regulatory subunit ABCC8 may be considered a new therapeutic target for pulmonary arterial hypertension (PAH).
Hypothesis: We hypothesised that the second KATP regulatory subunit (ABCC9) contributes to PAH pathogenesis. ABCC9 gene encodes for two regulatory subunits of KATP channels: the SUR2A and...
Right ventricular failure (RVF) is the most important prognostic factor for morbidity and mortality in pulmonary arterial hypertension (PAH) or pulmonary hypertension (PH) caused by left heart diseases. However, right ventricle (RV) remodeling is understudied and not targeted by specific therapies. This can be partly explained by the lack of basic...
Background
Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca ²⁺ ) signaling contributes to abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance,...
Pulmonary arterial hypertension (PAH) is an uncommon, progressive, and fatal disease [...]
Purpose
Impairment of left ventricular (LV) relaxation is associated with increased mortality after surgical treatment of pulmonary hypertension (PH). We sought to describe the pathophysiology of LV diastolic dysfunction in a porcine model of chronic thromboembolic pulmonary hypertension (CTEPH). The reversibility of LV diastolic dysfunction was in...
Endothelial dysfunction is a key player in advancing vascular pathology in pulmonary arterial hypertension (PAH), a disease essentially characterized by intense remodeling of the pulmonary vasculature, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, and thrombosis in situ. These vascular features culminate in an increase...
Mutations in ABCC8 have been identified in pulmonary arterial hypertension (PAH). ABCC8 encodes SUR1, a regulatory subunit of the ATP-sensitive-potassium channel Kir6.2. However, the pathophysiological role of the SUR1/Kir6.2 channel in PAH is unknown. We hypothesized that activation of SUR1 could be a novel potential target for PAH. We analysed th...
Background
The pathobiology of pulmonary arterial hypertension (PAH) involves pulmonary arterial smooth muscle cells (PASMCs) dysfunction leading to abnormal proliferation, apoptosis resistance and vasoconstriction. Store-operated Ca²⁺ entry (SOCE) strongly contributes to Ca²⁺ homeostasis in PASMCs, however, the role of SOCE archetype Orai1 Ca²⁺ ch...
Introduction
Leflunomide (LEF) is a immunomodulator indicated in various diseases including rheumatoid arthritis. Recently, a link between this drug and pulmonary arterial hypertension (PAH) has been suggested (Lacoste Palasset et al., 2021, Ann Am Thorac Soc). Our aim was to examine the effect of LEF on pulmonary artery (PA) tone, whose abnormalit...
Background
PAH is a severe cardiopulmonary disease which is defined by an elevation of the mPAP >25 mmHg. ABCC9 mutations are responsible of Cantu syndrome, a disease characterised by several cardiac disorders and for some case pulmonary hypertension. ABCC9 gene encodes for SUR2 protein, a regulatory subunit of KATP channels. We hypothesized that S...
Pulmonary arterial hypertension (PAH) is a rare disease characterised by pulmonary vascular remodelling and elevated pulmonary pressure, which eventually leads to right heart failure and death. Registries worldwide have noted a female predominance of the disease, spurring particular interest in hormonal involvement in the disease pathobiology. Seve...
Pulmonary arterial hypertension (PAH) is a severe and multifactorial disease. PAH pathogenesis mostly involves pulmonary arterial endothelial and pulmonary arterial smooth muscle cell (PASMC) dysfunction, leading to alterations in pulmonary arterial tone and distal pulmonary vessel obstruction and remodeling. Unfortunately, current PAH therapies ar...
Introduction: PAH is a severe and rare cardiopulmonary disease which is defined by an elevation of the mean pulmonary artery pressure >25mmHg. ABCC9 mutations are responsible of Cantu syndrome, a disease characterised by several cardiac disorders and for some case pulmonary hypertension (PH). ABCC9 gene encodes for SUR2 protein, a regulatory subuni...
Introduction: Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by a progressive obstruction of distal pulmonary artery (PA) leading to right ventricular hypertrophy and failure. Exacerbated intracellular Ca ²⁺ signalling contributes to functional abnormalities in pulmonary arterial smooth muscle cells (PASMCs), includin...
Introduction:
Over time and despite optimal medical management of patients with pulmonary hypertension (PH), the right ventricle (RV) function deteriorates from an adaptive to maladaptive phenotype, leading to RV failure (RVF). Although RV function is well recognized as a prognostic factor of PH, no predictive factor of RVF episodes has been eluci...
Introduction
Leflunomide (LEF) is an immunomodulator indicated in various diseases including rheumatoid arthritis. Recently, a link between this drug and pulmonary arterial hypertension (PAH) has been suggested (Lacoste-Palasset et al., 2021, Ann Am Thorac Soc).
Objective
Our aim was to document the effect of LEF on distal pulmonary arteries (PAs)...
Introduction
A reduction in pulmonary artery (PA) relaxation is a key event in pulmonary arterial hypertension (PAH) pathogenesis. CFTR dysfunction in airway epithelial cells plays a central role in cystic fibrosis (CF); CFTR is also expressed in PAs and has been shown to control endothelium-independent relaxation.
Aim and objectives
We aimed to d...
In Pulmonary arterial hypertension (PAH), a prototypic disease of the pulmonary circulation, the nature and the relevance of immune-related patho-mechanisms are highly debated. The presence of lung perivascular inflammatory cells and their frequent organization in bona fide tertiary lymphoid follicle-producing autoantibodies, the high concentration...
Aims
Pulmonary hypertension (PH) is a common complication of left heart disease (LHD, group 2 PH) leading to right ventricular (RV) failure and death. Several loss-of-function (LOF) mutations in KCNK3 were identified in pulmonary arterial hypertension (PAH, group 1 PH). Additionally, we found that KCNK3 dysfunction is a hallmark of PAH at pulmonary...
Since deregulation of intracellular Ca ²⁺ can lead to intracellular trypsin activation, and stromal interaction molecule-1 (STIM1) protein is the main regulator of Ca ²⁺ homeostasis in pancreatic acinar cells, we explored the Ca ²⁺ signaling in 37 STIM1 variants found in three pancreatitis patient cohorts. Extensive functional analysis of one parti...
The physiopathology of pulmonary arterial hypertension (PAH) is characterized by pulmonary artery smooth muscle cell (PASMC) and endothelial cell (PAEC) dysfunction, contributing to pulmonary arterial obstruction and PAH progression. KCNK3 loss of function mutations are responsible for the first channelopathy identified in PAH. Loss of KCNK3 functi...
Background
Recently mutations in ABBC8 have been identified in patients with pulmonary arterial hypertension (PAH). ABCC8 encodes SUR1 a regulatory subunit of the ATP-sensitive potassium channel Kir6.2. In 2018, Bohnen M et al., demonstrated that each identified ABCC8 mutation leads to a loss of ABCC8/Kir6.2 function. However, the role of SUR1/Kir6...
Background
Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca2+ entry (SOCE) in non-excitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear.
Methods
To test the role of these Orai1 channels in the cardiac pathophysi...
Introduction
Pulmonary veno-occlusive disease (PVOD) occurs in humans as heritable form due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2), or as a sporadic form. The pathobiology of this orphan fatal disease is currently unknown. However, the identification of EIF2AK4 as the major genetic cause of PVOD has clarified the nosology of...
Pulmonary arterial hypertension (PAH) is a rare and severe cardiopulmonary disease without curative treatments. PAH is a multifactorial disease that involves genetic predisposition, epigenetic factors, and environmental factors (drugs, toxins, viruses, hypoxia, and inflammation), which contribute to the initiation or development of irreversible rem...
Background:
The pathogenesis of pulmonary arterial hypertension (PAH) involves many signalling pathways. MicroRNAs are potential candidates involved in simultaneously coordinating multiple genes under such multifactorial conditions.
Methods and results:
MiR-138-5p is overexpressed in pulmonary arterial smooth muscle cells (PASMCs) from PAH patie...
Pulmonary veno-occlusive disease (PVOD) occurs in humans either as a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2) or as a sporadic form in older age (sPVOD). The chemotherapeutic agent mitomycin C (MMC) is a potent inducer of PVOD in humans and in rats (MMC-PVOD). Here, we compared human hPVOD and sPVOD,...
Since deregulation of intracellular Ca ²⁺ can lead to intracellular trypsin activation and STIM1 (stromal interaction molecule-1) protein is the main regulator of Ca ²⁺ homeostasis in pancreatic acinar cells, we explored the Ca ²⁺ signaling in 37 STIM1 variants found in three pancreatitis patient cohorts. Extensive functional analysis of one partic...
Background:
Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear.
Methods:
To test the role of these Orai1 channels in the cardiac pathoph...
Pulmonary arterial hypertension is a progressive and lethal cardiopulmonary disease. The rise in right ventricular afterload leads to right ventricular hypertrophy and failure. Right ventricular failure is the most important prognostic factor for morbidity and mortality in pulmonary arterial hypertension or pulmonary hypertension caused by left hea...
Background
Early detection of left ventricular (LV) failure is crucial to improve prognosis of patients with right ventricular (RV) overload.
Objectives
We aim to assess whether LV function is precociously affected in 2 surgical porcine models of moderate (Fallot repaired) and severe RV dysfunction (progressive pulmonary hypertension HP) at in viv...
Background
Early and easy to do detection of left ventricular (LV) failure is crucial to improve following and outcomes of patients with right ventricular (RV) overload in congenital heart diseases. Electrical cardiometry (Osypka medical) is easy handling, even in medical office or in pre-hospital condition, and can provide cardiac output, and a ne...
Whereas cardiac TRPC (transient receptor potential canonical) channels and the associated store-operated Ca2+ entry (SOCE) are abnormally elevated during cardiac hypertrophy and heart failure, the mechanism of this upregulation is not fully elucidated but might be related to the activation of the mineralocorticoid pathway. Using a combination of bi...
Rationale:
Pulmonary arterial hypertension (PAH) is a severe lethal cardio-pulmonary disease. Loss of function mutations in KCNK3 gene, which encodes an outward rectifier K+ channel, have been identified in PAH patients.
Objective:
We have demonstrated that KCNK3 dysfunction is common to heritable and non-heritable PAH and to experimental pulmon...
Background
Early and easy to do detection of left ventricular (LV) failure is crucial to improve following and outcomes of patients with right ventricular (RV) overload in congenital heart diseases. Electrical cardiometry (Osypka medical) is easy handling, even in medical office or in pre-hospital condition, and can provide cardiac output, and a ne...
Background
Early detection of left ventricular (LV) failure is crucial to improve prognosis of patients with right ventricular (RV) overload.
Objectives
We aim to assess whether LV function is precociously affected in 2 surgical porcine models of moderate (Fallot repaired) and severe RV dysfunction (progressive pulmonary hypertension HP) at in viv...
Potassium (K+) ion channels are the main determinant of vascular tone by regulating cell resting membrane potential (Em). Systemic arterial tone as well as pulmonary arterial tone is mainly controlled by the Em of systemic vascular smooth muscle cells (SVSMC) or pulmonary arterial smooth muscle cells (PASMC), and via endothelial cell (EC) functions...
We read with interest the article “Pulmonary arterial hypertension in patient treated for multiple sclerosis with 4‐aminopyridine” by Baptista et al. [1]. The authors reported the case of a 64‐year‐old woman treated for multiple sclerosis with 4‐aminopyridine (4‐AP) who developed severe pulmonary arterial hypertension (PAH) confirmed by right heart...
The bromodomain and extra-terminal domain family inhibitors (BETi) are a promising new class of anticancer agents. Since numerous anticancer drugs have been correlated to cardiomyopathy, and since BETi can affect non-cancerous tissues, we aimed to investigate in healthy animals any ultrastructural BETi-induced alterations of the heart as compared t...
In this study, we explored the complex interactions between platelet-derived growth factor (PDGF) and N-methyl-d-aspartate receptor (NMDAR) and their effect on the excessive proliferation and migration of smooth muscle cells leading to obstructed arteries in pulmonary arterial hypertension (PAH). We report lower expression of glutamate receptor NMD...
Pulmonary arterial hypertension (PAH) is a multifactorial and severe disease without curative therapies. PAH pathobiology involves altered pulmonary arterial tone, endothelial dysfunction, distal pulmonary vessel remodeling, and inflammation, which could all depend on ion channel activities (K+, Ca2+, Na+ and Cl−). This review focuses on ion channe...
Background:
Monoallelic mutations in the gene encoding bone morphogenetic protein receptor 2 ( Bmpr2) are the main genetic risk factor for heritable pulmonary arterial hypertension (PAH) with incomplete penetrance. Several Bmpr2 transgenic mice have been reported to develop mild spontaneous PAH. In this study, we examined whether rats with the Bmp...
Background:
Right ventricular (RV) function is the most important prognostic factor for pulmonary arterial hypertension (PAH) patients. The progressive increase of pulmonary vascular resistance induces RV hypertrophy (RVH) and at term RV failure (RVF). However, the molecular mechanisms of RVH and RVF remain understudied. In this study, we gained i...
Background
-Excessive proliferation and apoptosis resistance in pulmonary vascular cells underlie vascular remodeling in pulmonary arterial hypertension (PAH). Specific treatments for PAH exist, mostly targeting endothelial dysfunction, but high pulmonary arterial pressure still causes heart failure and death. Pulmonary vascular remodeling may be...
Aims:
Mutations in the KCNK3 gene, which encodes for an outward-rectifier K+ channel, have been identified in patients suffering from pulmonary arterial hypertension (PAH), and constitute the first described channelopathy in PAH. In human PAH and experimental pulmonary hypertension (PH), we demonstrated that KCNK3 expression and function are sever...
TWIK-related acid-sensitive potassium channel 1 (TASK-1 encoded by KCNK3) belongs to the family of two-pore domain potassium channels. This gene subfamily is constitutively active at physiological resting membrane potentials in excitable cells, including smooth muscle cells, and has been particularly linked to the human pulmonary circulation. TASK-...
Background
Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the EIF2AK4 gene, leading to a loss of GCN2. The role of GCN2-expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histological and biological features in heritable PVOD.
Methods
Clinical data and lung histology of 24 PVOD-...
Idiopathic pulmonary arterial hypertension (iPAH) is characterized by obstructive hyperproliferation and apoptosis resistance of distal pulmonary artery smooth muscle cells (PASMCs). T-type Ca2 + channel blockers have been shown to reduce experimental pulmonary hypertension, although the impact of T-type channel inhibition remains unexplored in PAS...
Pulmonary arterial hypertension (PAH) is a severe and incurable pulmonary vascular disease. One of the primary origins of PAH is pulmonary endothelial dysfunction leading to vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Our objective was to study the...
Contrasting with the major attention that left heart failure has received, right heart failure remains understudied both at the preclinical and clinical levels. However, right ventricle failure is a major predictor of outcomes in patients with precapillary pulmonary hypertension because of pulmonary arterial hypertension, and in patients with postc...
Cystic Fibrosis (CF) is the most frequent fatal genetic disease in Caucasian populations. Mutations in the chloride channel CF Transmembrane Conductance Regulator (CFTR) gene are responsible for functional defects of the protein and multiple associated dysregulations. The most common mutation in patients with CF, F508del-CFTR, causes defective CFTR...
STIM1 and Orai1 are essential players of store-operated Ca2 + entry (SOCE) in human skeletal muscle cells and are required for adult muscle differentiation. Besides these two proteins, TRPC (transient receptor potential canonical) channels and STIM1L (a longer STIM1 isoform) are also present on muscle cells. In the present study, we assessed the ro...
Simple CLEM method to asses rare pulmonary vascular remodeling
Péchoux C ¹ ; Antigny F ² ; Hautefort A ² ; Ranchoux B ² ; Gouadon E ² ; Humbert M ² ; Perros F ² ; Rücker‐Martin C ²
1‐ GABI, Inra, AgroparisTech, Université Paris‐Saclay, MIMA2, 78350 Jouy‐en‐Josas, France
2‐ Centre Chirurgical Marie Lannelongue, Inserm UMR‐S999, Le Plessis‐Robinson,...
Rationale: BMPR2 mutations are the main genetic risk factor for heritable pulmonary arterial hypertension (hPAH) with an incomplete penetrance of 20%. Transgenic mice have been created but develop no or mild PAH.
Aim: To create Bmpr2 mutated rats and to characterize their phenotype.
Methods: Rats with heterozygous mutations in Bmpr2 were obtained u...
Background: Inactivating mutations in the KCNK3 gene (K+ channel) have been identified in heritable forms of pulmonary arterial hypertension (PAH). We discovered that KCNK3 dysfunction contributes actually to the development of both heritable and non-heritable PAH, and to experimental pulmonary hypertension (PH) ( Antigny et al. Circulation 2016 )....
The Store-Operated Ca2+ Entry (SOCE) has emerged as an important mechanism in cardiac pathology. However, the signals that upregulate SOCE in the heart remain unexplored. Clinical trials have emphasized the beneficial role of mineralocorticoid receptor (MR) signaling blockade in heart failure and associated arrhythmias. Accumulated evidences sugges...
We thank Dr Belge and colleagues for their interest in our study reporting mitomycin-C–induced pulmonary veno-occlusive disease (PVOD) in patients displaying anal cancer and our preclinical model of PVOD in rats.1 Interestingly, they report 2 additional cases of PVOD in patients with anal cancer treated with mitomycin-C and 5-fluorouracil, initiall...
Background
Mutations in the KCNK3 gene have been identified in some patients suffering from heritable pulmonary arterial hypertension (PAH). KCNK3 encodes for an outward rectifier K+ channel, and each identified mutations lead to a loss of function. However, the pathophysiological role of KCNK3 in PAH remains to be elucidated. We hypothesized that...
Background:
-Mutations in the KCNK3 gene have been identified in some patients suffering from heritable pulmonary arterial hypertension (PAH). KCNK3 encodes an outward rectifier K(+) channel, and each identified mutation leads to a loss of function. However, the pathophysiological role of KCNK3 in PAH is unclear. We hypothesized that loss of funct...
Introduction: Pulmonary arterial hypertension (PAH) is a severe occlusive vascular disease of the lungs. One of the primary origin of PAH is pulmonary endothelial dysfunction driving vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Interestingly, endoth...
Background: Pulmonary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. We recently showed that the DNA damage activated PARP-1 was overexpressed...
Background: Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable due to biallelic mutations of the EIF2AK4 gene. Isolated case reports suggest that chemotherapy may be a risk factor for PV...
5-Ethynyl-2′-deoxyuridine (EdU) incorporation is becoming the gold standard method for
in vitro
and
in vivo
visualization of proliferating cells. The small size of the fluorescent azides used for detection results in a high degree of specimen penetration. It can be used to easily detect DNA replication in large tissue samples or organ explants with...
TRPC6 plays important human physiological functions, notably in artery and arterioles constriction, in regulation of vascular volume and in bronchial muscle constriction. It is implicated in pulmonary hypertension, cardiovascular disease, and focal segmental glomerulosclerosis and seems to play a role in cancer development. Previously, we identifie...
