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

Autor:	Pierre Sentenac, Saadia Eddahibi, Elie Fadel, Tom Kotsimbos, Grégoire Manaud, Olaf Mercier, David Boulate, Florence Lecerf, Lilia Lamrani, Frédéric Perros, Arturo Londoño-Vallejo, Marc Humbert
Přispěvatelé:	Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Montréal, QC G1V 4G5, Canada, Hôpital de Bicêtre, 94270 Le Kremlin-Bicêtre, France, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Marie-Lannelongue, Alfred Health, Centre Chirurgical Marie Lannelongue (CCML), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Curie, MORNET, Dominique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre chirurgical Marie Lannelongue, Marie Lannelongue Hospital, Marie Lannelongue Hospital, 92350 Le Plessis-Robinson, France, Centre chirurgical Marie Lannelongue, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)
Rok vydání:	2019
Předmět:	0301 basic medicine [SDV]Life Sciences [q-bio] Apoptosis Cell Communication 030204 cardiovascular system & hematology Muscle Smooth Vascular lcsh:Chemistry 0302 clinical medicine Familial Primary Pulmonary Hypertension lcsh:QH301-705.5 Cells Cultured Spectroscopy Contact Inhibition Gadd45 General Medicine Cell cycle Mitochondria 3. Good health Computer Science Applications [SDV] Life Sciences [q-bio] medicine.drug energetic metabolism DNA damage proliferation Idiopathic Pulmonary Hypertension Myocytes Smooth Muscle Biology Article Genomic Instability Catalysis Inorganic Chemistry 03 medical and health sciences medicine Humans Physical and Theoretical Chemistry Molecular Biology Cell Proliferation Cisplatin Organic Chemistry Telomere Homeostasis Contact inhibition Muscle Smooth idiopathic pulmonary artery hypertension Telomere 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 Anaerobic glycolysis Cancer research Energy Metabolism pulmonary artery smooth muscle cells DNA Damage
Zdroj:	International Journal of Molecular Sciences International Journal of Molecular Sciences, 2019, 20 (14), pp.3575. ⟨10.3390/ijms20143575⟩ Volume 20 Issue 14 International Journal of Molecular Sciences, MDPI, 2019, 20 (14), pp.3575. ⟨10.3390/ijms20143575⟩ International Journal of Molecular Sciences, Vol 20, Iss 14, p 3575 (2019)
ISSN:	1422-0067 1661-6596
DOI:	10.3390/ijms20143575
Popis:	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 (&gamma H2AX, 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&mdash the defining feature of neoplasia.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1da15b8b1bb8b8658265848730d1c0b4 https://doi.org/10.3390/ijms20143575 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.