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Review
. 2008 Oct;155(4):455-62.
doi: 10.1038/bjp.2008.241. Epub 2008 Jun 9.

Pulmonary hypertension: therapeutic targets within the serotonin system

Y Dempsie  1 , M R MacLean
Affiliations
Review

Pulmonary hypertension: therapeutic targets within the serotonin system

Y Dempsie et al. Br J Pharmacol. 2008 Oct.

Abstract

Pulmonary arterial hypertension (PAH) is characterized by a sustained and progressive elevation in pulmonary arterial pressure and pulmonary vascular remodelling leading to right heart failure and death. Prognosis is poor and novel therapeutic approaches are needed. The serotonin hypothesis of PAH originated in the 1960s after an outbreak of the disease was reported among patients taking the anorexigenic drugs aminorex and fenfluramine. These are indirect serotonergic agonists and serotonin transporter substrates. Since then many advances have been made in our understanding of the role of serotonin in the pathobiology of PAH. The rate-limiting enzyme in the synthesis of serotonin is tryptophan hydroxylase (Tph). Serotonin is synthesized, through Tph1, in the endothelial cells of the pulmonary artery and can then act on underlying pulmonary arterial smooth muscle cells and pulmonary arterial fibroblasts in a paracrine fashion causing constriction and remodelling. These effects of serotonin can be mediated through both the serotonin transporter and serotonin receptors. This review will discuss our current understanding of 'the serotonin hypothesis' of PAH and highlight possible therapeutic targets within the serotonin system.

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Figures

Figure 1
Figure 1
Serotonin is synthesized in the pulmonary arterial endothelial cells by tryptophan hydroxylase1 (Tph1). Serotonin can then influence pulmonary vascular smooth muscle proliferation and/or contraction via activity at the serotonin transporter (SERT) and serotonin receptors (particularly the 5-HT1B receptor in humans). Intracellular accumulation of serotonin and activation of the 5-HT1B receptor may induce reactive oxygen species (ROS), activation of Rho-kinase (ROCK), leading to phosphorylation and nuclear translocation of extracellular-regulated kinase (ERK)1/2. Once inside the nucleus phosphorylated ERK1/2 can increase transcription of nuclear growth factors and mediate cellular proliferation. Activation of the bone morphogenetic receptor type II (BMPR-II) leads to signalling through the Smad 1/5/8 pathway. Smads1, 5 and 8 must dimerize with Smad 4 to enter the nucleus where they can activate anti-proliferative transcription factors. Serotonin may antagonize BMPR-II signalling as phosphorylated ERK1/2 can phosphorylate the linker region of Smad 1and inhibit nuclear translocation.
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