Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension.
Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of primary pulmonary hypertension (PPH). Here we found that PA-SMCs from patients with PPH grow faster than PA-SMCs from controls when stimulated by serotonin or serum and that these effects are due to increased expression of the serotonin transporter (5-HTT), which mediates internalization of indoleamine. In the presence of 5-HTT inhibitors, the growth stimulatory effects of serum and serotonin were markedly reduced and the difference between growth of PA-SMCs from patients and controls was no longer observed. As compared with controls, the expression of 5-HTT was increased in cultured PA-SMCs as well as in platelets and lungs from patients with PPH where it predominated in the media of thickened pulmonary arteries and in onion-bulb lesions. The L-allelic variant of the 5HTT gene promoter, which is associated with 5-HTT overexpression and increased PA-SMC growth, was present in homozygous form in 65% of patients but in only 27% of controls. We conclude that 5-HTT activity plays a key role in the pathogenesis of PA-SMC proliferation in PPH and that a 5HTT polymorphism confers susceptibility to PPH.
Eddahibi
S
S
Institut National de la Santé et de la Recherche Médicale (INSERM) U492, Hôpital Henri Mondor, AP-HP, 94010 Créteil, France.
Humbert
M
M
Fadel
E
E
Raffestin
B
B
Darmon
M
M
Capron
F
F
Simonneau
G
G
Dartevelle
P
P
Hamon
M
M
Adnot
S
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002352:Carrier Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D006801:Humans; D006965:Hyperplasia; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008168:Lung / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D009419:Nerve Tissue Proteins; D011651:Pulmonary Artery / Q000473:pathology*; D050486:Serotonin Plasma Membrane Transport Proteins; D013936:Thymidine / Q000378:metabolism
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D013936:Thymidine