Inhibition of cGMP phosphodiesterase 5 suppresses serotonin signalling in pulmonary artery smooth muscles cells.

Abstract

cGMP-specific phosphodiesterase 5 (PDE5) inhibition has been shown to be effective in improving pulmonary haemodynamics in both animal models and clinic patients with pulmonary hypertension. Here, we reveal a novel mechanism whereby PDE5 inhibition suppresses serotonin signalling and consequent cellular proliferation in primary cultured pulmonary artery smooth muscle cells (PASMCs). 1 microM serotonin induced 4.15-fold increases in DNA synthesis compared with control; this was accompanied by significant Ras homolog gene family member A (RhoA) activation and ERK1/2 MAP kinase phosphorylation/nucleus translocation. Furthermore, inhibition of Rho-associated kinase (ROCK) abolished serotonin-triggered DNA synthesis and ERK1/2 nucleus translocation without changing ERK1/2 phosphorylation, indicating that ERK1/2 phosphorylation and nucleus translocation are coupled to different upstream effectors. Pre-exposure of cells to sildenafil dose-dependently blocked the activation of these signalling pathways and elevated DNA synthesis. The inhibitive effects of sildenafil, however, were fully reversed by concomitant presence of PKG inhibitor in cells. These data suggest that RhoA and ERK1/2 pathways are partially cross-talked and concordantly mediate serotonin-stimulated PASMCs proliferation thereby vascular remodelling leading to the occurrence of pulmonary hypertension. Meanwhile, these two pathways are also separately modulated by enhanced cGMP-PKG signalling derived from inhibition of PDE5 with sildenafil to confer the overall roles of sildenafil against pulmonary hypertension.

• Authors: Manxiang Li, Xiuzhen Sun, Zongfang Li, Yun Liu
• Journal: Pharmacological research (Pharmacol Res) Vol. 59 Issue 5 Pg. 312-8 (May 2009) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 19416631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphodiesterase 5 Inhibitors
• Piperazines
• Purines
• Sulfones
• Serotonin
• DNA
• Sildenafil Citrate
• rho-Associated Kinases
• Cyclic GMP-Dependent Protein Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• rhoA GTP-Binding Protein

Topics

• Animals
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cyclic GMP-Dependent Protein Kinases (antagonists & inhibitors, physiology)
• DNA (biosynthesis)
• Enzyme Activation
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Muscle, Smooth, Vascular (cytology, drug effects, metabolism)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Phosphodiesterase 5 Inhibitors
• Phosphorylation
• Piperazines (pharmacology)
• Pulmonary Artery (cytology, drug effects, metabolism)
• Purines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Serotonin (pharmacology, physiology)
• Signal Transduction
• Sildenafil Citrate
• Sulfones (pharmacology)
• rho-Associated Kinases (antagonists & inhibitors)
• rhoA GTP-Binding Protein (antagonists & inhibitors, metabolism)