Abstract
Decreased pulmonary artery smooth muscle cell (PASMC) apoptosis play a key role in pulmonary artery remodeling during pulmonary artery hypertension (PAH), but the mechanisms involved are unclear. Serotonin (5-HT) inhibits apoptosis in many pathologic processes by activating the 5-HT2A receptor. Therefore, we hypothesized that 5-HT may be the promoter of decreased apoptosis in PAH through the 5-HT2A receptor. We found that inhibition of the 5-HT2A receptor prevented the increase in pulmonary artery pressure and pulmonary artery remodeling in rats stimulated by monocrotaline. This effect was accompanied by increased apoptosis in the pulmonary artery. Cultured PASMCs stimulated with 5-HT showed a decrease in apoptosis with increased phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), pyruvate dehydrogenase kinase (PDK), and mitochondrial transmembrane potential. These effects were markedly prevented by a 5-HT2A receptor inhibitor, an ERK1/2 activation inhibitor peptide I, or a PDK inhibitor. In conclusion, 5-HT inhibited PASMC apoptosis by activating the 5-HT2A receptor through the pERK1/2 and PDK pathways.5-HT decreasing apoptosis through 5-HT2A receptor is involved, at least in part, in pulmonary artery remolding.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Cell Proliferation / drug effects
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Cells, Cultured
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Disease Models, Animal
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Familial Primary Pulmonary Hypertension
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Humans
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Hypertension, Pulmonary / drug therapy
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Hypertension, Pulmonary / pathology*
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Hypertension, Pulmonary / physiopathology
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Hypertrophy, Right Ventricular / drug therapy
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Hypertrophy, Right Ventricular / pathology
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Hypertrophy, Right Ventricular / physiopathology
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Ketanserin / pharmacology
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Male
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Membrane Potential, Mitochondrial / drug effects
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Membrane Potential, Mitochondrial / physiology
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Pulmonary Artery / cytology*
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Pulmonary Artery / drug effects
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Random Allocation
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Rats
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Rats, Sprague-Dawley
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Receptor, Serotonin, 5-HT2A / physiology*
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Serotonin / pharmacology
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Serotonin / physiology*
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Serotonin 5-HT2 Receptor Antagonists / pharmacology*
Substances
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Receptor, Serotonin, 5-HT2A
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Serotonin 5-HT2 Receptor Antagonists
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Serotonin
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Ketanserin
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Protein Serine-Threonine Kinases