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Biochim Biophys Acta Mol Cell Res. 2017 Oct;1864(10):1631-1641. doi: 10.1016/j.bbamcr.2017.06.018. Epub 2017 Jun 24.

T-type Ca2+ channels elicit pro-proliferative and anti-apoptotic responses through impaired PP2A/Akt1 signaling in PASMCs from patients with pulmonary arterial hypertension.

Author information

1
INSERM U999, Hôpital Marie Lannelongue, Le Plessis Robinson, France; Univ. Paris-Sud, Faculté de Médecine, Univ. Paris-Saclay, Le Kremlin Bicêtre, France.
2
PhyMedExp, Univ. Montpellier, Inserm U1046, cNRS UMR9214.34295 MINSERM U1046, Montpellier, France.
3
INSERM UMR-S1180, Univ. Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
4
National Pulmonary Hypertension Service, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.
5
INSERM U999, Hôpital Marie Lannelongue, Le Plessis Robinson, France; Univ. Paris-Sud, Faculté de Médecine, Univ. Paris-Saclay, Le Kremlin Bicêtre, France; AP-HP, Service de pneumologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
6
INSERM U999, Hôpital Marie Lannelongue, Le Plessis Robinson, France; Univ. Paris-Sud, Faculté de Médecine, Univ. Paris-Saclay, Le Kremlin Bicêtre, France. Electronic address: veronique.capuano@u-psud.fr.

Abstract

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 PASMCs from iPAH patients. Here we show that T-type channels Cav3.1 and Cav3.2 are present in the lung and PASMCs from iPAH patients and control subjects. The blockade of T-type channels by the specific blocker, TTA-A2, prevents cell cycle progression and PASMCs growth. In iPAH cells, T-type channel signaling fails to activate phosphatase PP2A, leading to an increase in ERK1/2, P38 activation. Moreover, T-type channel signaling is redirected towards the activation of the kinase Akt1, leading to increased expression of the anti-apoptotic protein survivin, and a decrease in the pro-apoptotic mediator FoxO3A. Finally, in iPAH cells, Akt1 is no longer able to regulate caspase 9 activation, whereas T-type channel overexpression reverses PP2A defect in iPAH cells but reinforces the deleterious effects of Akt1 activation. Altogether, these data highlight T-type channel signaling as a strong trigger of the pathological phenotype of PASMCs from iPAH patients (hyper-proliferation/cells survival and apoptosis resistance), suggesting that both T-type channels and PP2A may be promising therapeutic targets for pulmonary hypertension.

KEYWORDS:

Caspase; Cell cycle; FoxO3A; Lung; MAPkinase; Survivin

PMID:
28655554
DOI:
10.1016/j.bbamcr.2017.06.018
[Indexed for MEDLINE]
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