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

https://doi.org/10.1016/j.bbamcr.2017.06.018Get rights and content
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Highlights

  • T-type Ca2 + channels are involved in Ca2 + homeostasis in human PASMCs.

  • In PASMCs from patients with pulmonary arterial hypertension (PAH), T-type Ca2 + channels signaling fail to activate PP2A and overactivate Akt1

  • Altered T-type Ca2 + channels signaling dysregulate activation of MAP kinases, survivin expression and FoxO3A stability in PAH PASMCs

  • T-type Ca2 + channels signaling participate in the proliferative/apoptosis resistance phenotype of PASMCs from PAH patients

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.

Abbreviations

CDK4/6
cyclin-dependent kinase 4 and 6
CTL
control
CycD1
cyclin D1
FoxO3A
forkhead transcription factor
ICaT
T-type Ca2 + current
OA
okadaïc acid
PAH
pulmonary arterial hypertension
iPAH
idiopathic PAH
PASMC
pulmonary arterial smooth cell
PFA
paraformaldehyde
PP2A
protein phosphatase 2A
RCaG
vector overexpressing Cav3.1
RC
empty vector

Keywords

Lung
Cell cycle
MAPkinase
FoxO3A
Caspase
Survivin

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