Review Article
Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension?

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Abstract

Investigations on the effects of serotonin (5-HT) and the serotonin transporter (5-HTT) on the pulmonary circulation are of special interest because of the reported increased risk of primary pulmonary hypertension (PPH) in patients who used some appetite suppressants that interfere with 5-HT. In addition to its vasoactive effects, 5-HT exerts mitogenic and comitogenic effects on pulmonary artery smooth muscle cells (PASMCs). These mitogenic and comitogenic effects require 5-HT internalization by the high-affinity 5-HTT, which can be competitively inhibited by specific drugs such as fluoxetine and paroxetine. In a recent study, we showed that hypoxia increases the rate of 5-HTT gene transcription in PASMCs and potentiates the growth-promoting effect of 5-HT on these cells. An increase in the levels of 5-HTT messenger ribonucleic acid was observed in smooth-muscle cells from remodeled pulmonary arteries in rats subjected to long-term hypoxia. Two series of especially relevant data further support the idea that 5-HT plays a key role in PASMC proliferation in vivo: (1) treatments that increase plasma 5-HT levels aggravate pulmonary hypertension in rats subjected to long-term hypoxia, and this effect can be prevented by combined simultaneous treatment with 5-HTT inhibitors; and (2) knockout mice with disruption of the 5-HTT gene exhibit lesser degree of hypoxic pulmonary hypertension and pulmonary vascular remodeling than control mice despite increased hypoxic pulmonary vasoconstriction. These observations indicate that 5-HTT expression, activity, or both in PASMCs contribute to pulmonary vascular remodeling and that the inducing effects of some appetite suppressants on pulmonary hypertension may be related to possible effects of these drugs on 5-HTT expression, activity, or both. (J Lab Clin Med 2002;139:194-201)

Section snippets

Serotonin

Serotonin is an endogenous vasoactive indolamine substance found mainly in enterochromaffin tissue, brain, and blood platelets. The neutral amino acid l-tryptophan is the primary precursor of serotonin, the synthesis of which first involves hydroxylation of the benzene ring of tryptophan by the rate-limiting monooxygenase tryptophan hydroxylase to form 5-hydroxytryptophan and, second, decarboxylation of its aminocarboxy terminal group by an aromatic l-amino-acid decarboxylase to form 5-HT.

The

The serotonin transporter

5-HTT belongs to a large family of integral membrane proteins that are responsible for terminating the action of neurotransmitters released from neurons. This family also includes α-aminobutyric acid transporters and the norepinephrine and dopamine transporters.16 In addition to 5-HT reuptake into neurons, 5-HTT is responsible for uptake of indolamine by platelets and endothelial and vascular SMCs. The 5-HT uptake process is driven mainly by the electrochemical potential associated with Na+ and

5-HTT and PASMC proliferation

Serotonin in the micromolar range is a known mitogen for SMCs isolated from bovine, porcine, and rat aorta, as well as rat and bovine pulmonary arteries.11, 12, 21 The mechanisms by which 5-HT causes SMC proliferation may vary among cell types and species. Most cellular transduction systems for 5-HT seem to depend on initiation of the signal by a cell-surface receptor. Several subtypes of 5-HT receptors have been characterized pharmacologically and cloned. These receptors may interact with

Transduction of 5-HT signals beyond the serotonin transporter

Mitogenesis of PASMCs induced by 5-HT appears to occur by way of signaling through a MAP kinase-dependent pathway.29 Exposure of bovine PASMCs to 5-HT increases phosphorylation of ERK1 and ERK2 MAP kinase five- to sevenfold within 5 minutes. Omission of Na+ from the incubating medium or cell pretreatment with 5-HT-uptake inhibitors prevents the stimulation of MAP kinase by 5-HT. Moreover, inhibition of MAP kinase kinase by 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD-98059) inhibits

Effect of hypoxia on 5-HTT expression and PASMC proliferation

Hypoxia is a recognized stimulus that affects both the tone and structure of pulmonary blood vessels. Acute hypoxia causes vasoconstriction of distal pulmonary arteries, with a subsequent increase in pulmonary arterial pressure. Moreover, chronic hypoxia is associated with hypertrophy and hyperplasia of PASMCs. This process results in increased thickness of the walls of muscular arteries and extension of muscularization to precapillary arteries, which are normally nonmuscularized. One possible

5-HTT and pulmonary vascular remodeling

A role for 5-HT in the development of hypoxic PH is further suggested by our data showing that continuous intravenous infusion of indolamine during a two-week exposure to severe hypoxia aggravated PH in rats.41 Indeed, along with higher pulmonary arterial pressure and more severe right ventricular hypertrophy, we noted that the percentage of muscularized arteries at the alveolar duct and alveolar wall level was greater in rats exposed for long periods to 10% O2 and continuously infused with

5-HTT as the target for drugs that increase the risk of PH

The effects of 5-HT on the pulmonary vessels became a matter of renewed interest when consumption of anorectic drugs interfering with 5-HT uptake and metabolism was noticed in a number of patients with PPH. An association between the anorectic drug aminorex and PPH was first reported in the 1960s, which led to its withdrawal from the market. In the 1980s, PPH was associated with the use of fenfluramine or its derivatives, and it was subsequently estimated that the disease occurs approximately

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    Reprint requests: S. Eddahibi, INSERM U492 et Département de Physiologie, CHU Henri Mondor, 94010 Créteil, France; e-mail: [email protected].

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