Abstract
Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of pulmonary hypertension (PH). Serotonin (5-HT) is involved in the hyperplasia through its interactions with specific receptors and internalization by a specific plasma membrane transporter. We investigated the expression and role of the 5-HT transporter (5-HTT) and 5-HT1B, 5-HT2A, and 5-HT2B receptors in lungs and isolated PA-SMCs from patients with primary PH (n=14), pulmonary veno-occlusive disease (n=4), or secondary PH (SPH, n=8) and nonpulmonary hypertensive control subjects. Whereas strong immunostaining for the three receptor types and 5-HTT was seen in remodeled pulmonary vessels from patients in all PH categories, only 5-HTT expression was increased in lungs and cultured PA-SMCs from patients versus controls. The increased growth response of PA-SMCs from patients with primary PH, pulmonary veno-occlusive disease, or SPH to 5-HT or serum was entirely attributable to 5-HTT overexpression, because 5-HTT inhibitors but not 5-HT receptor antagonists abolished 5-HT mitogenic activity and reduced the serum-induced growth response to similar levels in patients as in controls. The L-allelic variant of the 5-HTT gene promoter, which is associated with 5-HTT overexpression, was present homozygously in 14 of 25 (56%) lung transplantation patients with SPH but in only 27% of controls. Polymorphism of the 5-HTT gene promoter was only partly responsible for the increased 5-HTT expression in PH, because PA-SMCs from patients exhibited higher 5-HTT levels than same-genotype cells from controls and no additional promoter sequence alterations were found. We conclude that 5-HTT overexpression is a common pathogenic mechanism in various forms of PH.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Alleles
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Division
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Cells, Cultured / pathology
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Culture Media, Serum-Free / pharmacology
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Female
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Gene Expression
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Genetic Predisposition to Disease
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Genotype
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Humans
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Hyperplasia
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Hypertension, Pulmonary / etiology
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Hypertension, Pulmonary / genetics*
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Hypertension, Pulmonary / pathology
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Hypertension, Pulmonary / surgery
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Introns / genetics
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Lung Diseases / complications
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Lung Diseases / pathology
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Lung Transplantation
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Male
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Membrane Transport Proteins*
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Middle Aged
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Muscle, Smooth, Vascular / pathology*
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Myocytes, Smooth Muscle / pathology
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Platelet-Derived Growth Factor / pharmacology
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Polymorphism, Genetic
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Promoter Regions, Genetic / genetics
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Pulmonary Artery / pathology*
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Pulmonary Veno-Occlusive Disease / genetics
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Pulmonary Veno-Occlusive Disease / pathology
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Pulmonary Veno-Occlusive Disease / surgery
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RNA, Messenger / biosynthesis
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Receptors, Serotonin / genetics
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Receptors, Serotonin / physiology
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Serotonin / physiology*
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Serotonin Antagonists / pharmacology
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Serotonin Plasma Membrane Transport Proteins
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Tunica Media / chemistry
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Tunica Media / pathology
Substances
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Carrier Proteins
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Culture Media, Serum-Free
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Platelet-Derived Growth Factor
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RNA, Messenger
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Receptors, Serotonin
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SLC6A4 protein, human
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Serotonin Antagonists
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Serotonin Plasma Membrane Transport Proteins
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Serotonin