T-type Ca 2+ channels elicit pro-proliferative and anti-apoptotic responses through impaired PP2A/Akt1 signaling in PASMCs from patients with pulmonary arterial hypertension

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Benzeneacetamides / pharmacology
  • Calcium Channels, T-Type / genetics*
  • Cell Proliferation / genetics
  • Familial Primary Pulmonary Hypertension / genetics
  • Familial Primary Pulmonary Hypertension / metabolism*
  • Familial Primary Pulmonary Hypertension / pathology
  • Forkhead Box Protein O3 / genetics
  • Gene Expression Regulation / drug effects
  • Humans
  • Myocytes, Smooth Muscle / metabolism
  • Protein Phosphatase 2 / genetics*
  • Protein Phosphatase 2 / metabolism
  • Proto-Oncogene Proteins c-akt / genetics*
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / pathology
  • Pyridines / pharmacology
  • Signal Transduction / drug effects

Substances

  • 2-(4-cyclopropylphenyl)-N-(1-(5-((2,2,2-trifluoroethyl)oxo)pyridin-2-yl)ethyl)acetamide
  • Benzeneacetamides
  • CACNA1G protein, human
  • CACNA1H protein, human
  • Calcium Channels, T-Type
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Pyridines
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • PPP2CA protein, human
  • Protein Phosphatase 2