Sildenafil inhibits calcineurin/NFATc2-mediated cyclin A expression in pulmonary artery smooth muscle cells

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Utilizing the Precision-Cut Lung Slice to Study the Contractile Regulation of Airway and Intrapulmonary Arterial Smooth Muscle
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Utilizing the Precision-Cut Lung Slice to Study the Contractile Regulation of Airway and Intrapulmonary Arterial Smooth Muscle

Published on: May 5, 2022

Manxiang Li1, Yuan Liu, Xiuzhen Sun

  • 1Respiratory Diseases Research Center, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, PR China. manxiangli@hootmail.com

Life Sciences
|August 20, 2011
PubMed
Abstract

Insights

The calcineurin/NFAT pathway drives pulmonary artery smooth muscle cell proliferation. Sildenafil inhibits this pathway, reducing cell proliferation and offering potential for pulmonary hypertension treatment.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Cellular Signaling

Background:

  • Pulmonary artery smooth muscle cell (PASMC) proliferation is a key factor in pulmonary hypertension.
  • The calcineurin/nuclear factor of activated T-cells (NFAT) signaling pathway is implicated in cell growth and proliferation.

Purpose of the Study:

  • To investigate the role of the calcineurin/NFAT pathway in PASMC proliferation.
  • To determine if the phosphodiesterase-5 (PDE5) inhibitor sildenafil impacts this pathway and subsequent cell proliferation.

Main Methods:

  • Assessed cell proliferation using [(3)H]thymidine incorporation.
  • Measured cyclin A, NFATc2, cyclin-dependent kinase 2 (CDK2) activity, calcineurin, and NFAT activity via Western blot and specific assay kits.
  • Utilized chemical inhibitors and siRNA to modulate calcineurin/NFAT signaling.

Main Results:

  • Serotonin increased PASMC proliferation, cyclin A expression, and CDK2 activity, correlating with calcineurin/NFAT activation.
  • Inhibiting calcineurin or NFATc2 blocked serotonin-induced proliferation.
  • Sildenafil suppressed serotonin-induced calcineurin/NFAT activation and PASMC proliferation, an effect reversed by a protein kinase G (PKG) inhibitor.

Conclusions:

  • The calcineurin/NFAT pathway mediates PASMC proliferation through cyclin A and CDK2.
  • Sildenafil's beneficial effects in pulmonary hypertension may involve suppressing this pathway via enhanced PKG activity.

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