Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous - Archive ouverte HAL
Article Dans Une Revue International Journal of Molecular Sciences Année : 2019

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

Tom Kotsimbos
  • Fonction : Auteur

Résumé

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.
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Dates et versions

hal-02194334 , version 1 (08-05-2020)

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Frédéric Perros, Pierre Sentenac, David Boulate, Grégoire Manaud, Tom Kotsimbos, et al.. Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous. International Journal of Molecular Sciences, 2019, 20 (14), pp.3575. ⟨10.3390/ijms20143575⟩. ⟨hal-02194334⟩
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