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Anesth Analg 2007; 105:1034-1041
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000278736.81133.26
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ANESTHETIC PHARMACOLOGY

The Antiproliferative Effect of Sildenafil on Pulmonary Artery Smooth Muscle Cells Is Mediated via Upregulation of Mitogen-Activated Protein Kinase Phosphatase-1 and Degradation of Extracellular Signal-Regulated Kinase 1/2 Phosphorylation

Bingbing Li, MD, PhD*, Lingchao Yang, MD{dagger}, Jianying Shen, MD, PhD{ddagger}, Chunshen Wang, MD§, and Zhen Jiang, MD*

From the *Department of Anesthesiology, Zhongshan Hospital affiliated Fudan University; {dagger}Department of Cardiology, School of Medicine, Xinhua Hospital affiliated Shanghai Jiaotong University; {ddagger}Departments of Cardiology; and §Cardiac Surgery, Zhongshan Hospital affiliated Fudan University, Shanghai, China.

BACKGROUND: Pulmonary hypertension is a group of diseases comprising vascular constriction and by obstructive changes of the pulmonary vasculature. Phosphodiesterase type 5 inhibitors, e.g., sildenafil, can alleviate vascular remodeling in the monocrotaline pulmonary hypertension model in rats, and inhibit the proliferation of pulmonary vascular smooth muscle cells in vitro. We examined the ability of sildenafil to inhibit platelet-derived growth factor (PDGF)-induced proliferation of porcine pulmonary artery smooth muscle cells.

METHODS: Pulmonary artery smooth muscle cell proliferation and cell cycle analysis were assessed by MTT assay and fluorescence-activated cell sorting. Western blotting was used to examine protein expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) and phosphorylation level of extracellular signal-regulated kinase (ERK1/2).

RESULTS: PDGF increased cell proliferation and the percentage of cells in S phase. These effects were inhibited by pretreatment with sildenafil in a dose-dependent manner. Sildenafil (96 µM) also caused a 67% decrease in PDGF-stimulated ERK1/2 phosphorylation. Sildenafil inhibition of ERK1/2 was accompanied by a rapid induction of MKP-1. Inhibition of the cGMP-dependent kinase I {alpha} (cGK I {alpha}) using Rp-8-BrcGMPS (25 µM) blocked sildenafil-induced MKP-1 expression. Either vanadate (12.5 µM), a phosphatase inhibitor, or Rp-8-BrcGMPS abolished the inhibitory effect of sildenafil on PDGF-stimulated phosphorylation of ERK1/2 and restored PDGF-induced cell proliferation.

CONCLUSION: This study indicates that sildenafil upregulates MKP-1 expression and promotes degradation of phosphorylation of ERK1/2, which suppresses the proliferation of pulmonary artery smooth muscle cells.






Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press
Copyright © 2007 by the International Anesthesia Research Society.