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Int J Mol Sci. 2019 Jul 22;20(14). pii: E3575. doi: 10.3390/ijms20143575.

Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous.

Author information

1
Université Paris-Sud, Faculté de Médecine, 94270 Kremlin-Bicêtre, France.
2
Assistance Publique-Hôpitaux de Paris (AP-HP), Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie et Réanimation Respiratoire, Hôpital de Bicêtre, 94270 Le Kremlin-Bicêtre, France.
3
Unité Mixte de Recherche 999, Institut National de la Santé et de la Recherche Médicale, Université Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, 92350 Le Plessis Robinson, France.
4
Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Montréal, QC G1V 4G5, Canada.
5
PhyMedExp, University of Montpellier, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, 34295 Montpellier, France.
6
Department of Anæsthesiology and Critical Care Medicine, Arnaud de Villeneuve Teaching Hospital, Montpellier University School of Medicine, 34295 Montpellier, France.
7
Department of Thoracic and Vascular Surgery, Marie Lannelongue Hospital, 92350 Le Plessis-Robinson, France.
8
Alfred Health, Monash University, VIC 3004 Melbourne, Australia.
9
Research Department, Marie Lannelongue Hospital, 92350 Le Plessis-Robinson, France.
10
Institut Curie, PSL Research University, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3244, Telomere and cancer lab, 75005 Paris, France.
11
PhyMedExp, University of Montpellier, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, 34295 Montpellier, France. saadia.eddahibi@inserm.fr.
12
Research Department, Marie Lannelongue Hospital, 92350 Le Plessis-Robinson, France. saadia.eddahibi@inserm.fr.

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a complex disease associated with vascular remodeling and a proliferative disorder in pulmonary artery smooth muscle cells (PASMCs) that has been variably described as having neoplastic features. To decode the phenotype of PASMCs in IPAH, PASMCs from explanted lungs of patients with IPAH (IPAH-PASMCs) and from controls (C-PASMCs) were cultured. The IPAH-PASMCs grew faster than the controls; however, both growth curves plateaued, suggesting contact inhibition in IPAH cells. No proliferation was seen without stimulation with exogenous growth factors, suggesting that IPAH cells are incapable of self-sufficient growth. IPAH-PASMCs were more resistant to apoptosis than C-PASMCs, consistent with the increase in the Bcl2/Bax ratio. As cell replication is governed by telomere length, these parameters were assessed jointly. Compared to C-PASMCs, IPAH-PASMCs had longer telomeres, but a limited replicative capacity. Additionally, it was noted that IPAH-PASMCs had a shift in energy production from mitochondrial oxidative phosphorylation to aerobic glycolysis. As DNA damage and genomic instability are strongly implicated in IPAH development a comparative genomic hybridization was performed on genomic DNA from PASMCs which showed multiple break-points unaffected by IPAH severity. Activation of DNA damage/repair factors (γH2AX, p53, and GADD45) in response to cisplatin was measured. All proteins showed lower phosphorylation in IPAH samples than in controls, suggesting that the cells were resistant to DNA damage. Despite the cancer-like processes that are associated with end-stage IPAH-PASMCs, we identified no evidence of self-sufficient proliferation in these cells-the defining feature of neoplasia.

KEYWORDS:

DNA damage.; energetic metabolism; idiopathic pulmonary artery hypertension; proliferation; pulmonary artery smooth muscle cells

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