Esther J Nossent1, Fabrice Antigny2, David Montani3, Harm Jan Bogaard4, Maria Rosa Ghigna5, Mélanie Lambert6, Vincent Thomas de Montpréville7, Barbara Girerd3, Xavier Jaïs3, Laurent Savale3, Olaf Mercier8, Elie Fadel8, Florent Soubrier9, Olivier Sitbon3, Gérald Simonneau3, Anton Vonk Noordegraaf4, Marc Humbert3, Frédéric Perros6, Peter Dorfmüller10. 1. Department of Pulmonary Diseases, Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, The Netherlands; Institut National de la Santé et de la Recherche Unités Mixtes de Recherche_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France. 2. Institut National de la Santé et de la Recherche Unités Mixtes de Recherche_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France. 3. Institut National de la Santé et de la Recherche Unités Mixtes de Recherche_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France; Faculty of Medicine, Paris-South University, Kremlin-Bicêtre, Paris, France; National Reference Center of Pulmonary Hypertension, Department of Pulmonology and Intensive Care Unit for Respiratory Diseases, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Kremlin-Bicêtre, Paris, France. 4. Department of Pulmonary Diseases, Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, The Netherlands. 5. Institut National de la Santé et de la Recherche Unités Mixtes de Recherche_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France; Faculty of Medicine, Paris-South University, Kremlin-Bicêtre, Paris, France; Department of Pathology, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France. 6. Institut National de la Santé et de la Recherche Unités Mixtes de Recherche_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France; Faculty of Medicine, Paris-South University, Kremlin-Bicêtre, Paris, France. 7. Department of Pathology, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France. 8. Faculty of Medicine, Paris-South University, Kremlin-Bicêtre, Paris, France; Department of Thoracic and Vascular Surgery, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France. 9. Department of Clinical Genetics, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris and Unités Mixtes de Recherche_S 1166-ICAN, Institut National De La Santé Et De La Recherche Unités Mixtes De Recherche, Université Pierre et Marie Curie Sorbonne Universités, Paris, France. 10. Institut National de la Santé et de la Recherche Unités Mixtes de Recherche_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France; Faculty of Medicine, Paris-South University, Kremlin-Bicêtre, Paris, France; Department of Pathology, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France. Electronic address: peter.dorfmuller@u-psud.fr.
Abstract
BACKGROUND: Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) gene, leading to a loss of general control nonderepressible 2 (GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD. METHODS: Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry. GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [BMPR2] mutation carriers, 21 non-carriers), and 3 experimental pulmonary hypertension models. RESULTS: PVOD patients showed a significant decrease of pulmonary arterial patency (p < 0.0001) compared with healthy controls. Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis (p = 0.001), less severe medial hypertrophy (p = 0.001), and (2) stronger muscular hyperplasia of interlobular septal veins (p = 0.002). GCN2 expression was abolished in heritable PVOD (p < 0.0001), but also importantly decreased in sporadic PVOD (p = 0.03) as well as in heritable (p = 0.002) and idiopathic PAH (p = 0.003); moreover, GCN2 was abolished in 2 experimental pulmonary hypertension models and importantly decreased in 1 model (p < 0.0001 for all models). CONCLUSIONS: Pulmonary arterial remodeling in PVOD is present to an important extent. A significant decrease of GCN2 expression is a common denominator of all tested groups of PVOD and PAH, including their respective experimental models. Our results underline specific morphologic and biologic similarities between PAH and PVOD and let us consider both conditions rather in one large spectrum of disease than as two distinct and clear-cut entities.
BACKGROUND: Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) gene, leading to a loss of general control nonderepressible 2 (GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD. METHODS: Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry. GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [BMPR2] mutation carriers, 21 non-carriers), and 3 experimental pulmonary hypertension models. RESULTS: PVOD patients showed a significant decrease of pulmonary arterial patency (p < 0.0001) compared with healthy controls. Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis (p = 0.001), less severe medial hypertrophy (p = 0.001), and (2) stronger muscular hyperplasia of interlobular septal veins (p = 0.002). GCN2 expression was abolished in heritable PVOD (p < 0.0001), but also importantly decreased in sporadic PVOD (p = 0.03) as well as in heritable (p = 0.002) and idiopathic PAH (p = 0.003); moreover, GCN2 was abolished in 2 experimental pulmonary hypertension models and importantly decreased in 1 model (p < 0.0001 for all models). CONCLUSIONS: Pulmonary arterial remodeling in PVOD is present to an important extent. A significant decrease of GCN2 expression is a common denominator of all tested groups of PVOD and PAH, including their respective experimental models. Our results underline specific morphologic and biologic similarities between PAH and PVOD and let us consider both conditions rather in one large spectrum of disease than as two distinct and clear-cut entities.
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