Abstract
Serotonin (5-hydroxytryptamine (5-HT)) is a mitogen of pulmonary artery smooth muscle cells (PASMC) and plays an important role in the development of pulmonary hypertension. Signal transduction initiated by 5-HT involves serotonin transporter-dependent generation of reactive oxygen species and activation of the MEK-ERK pathway. However, the downstream transcriptional regulatory components have not been identified. In systemic smooth muscle cells, GATA-6 has been shown to regulate mitogenesis by driving cells into a quiescent state, and the down-regulation of GATA-6 induces mitogenesis. Thus, the present study tested the hypothesis that 5-HT induces mitogenesis of PASMC by down-regulating GATA-6. Quiescent bovine PASMC were treated with 5-HT, and the binding activity of nuclear extracts toward GATA DNA sequence was monitored. Surprisingly, PASMC express GATA-4, and 5-HT up-regulates the GATA DNA binding activity. Pretreatment of cells with inhibitors of serotonin transporter, reactive oxygen species, and MEK blocks GATA-4 activation by 5-HT. GATA-4 is not activated when the ERK phosphorylation site is mutated, indicating that 5-HT phosphorylates GATA-4 via the MEK/ERK pathway. GATA up-regulation is also induced by other mitogens of PASMC such as endothelin-1 and platelet-derived growth factor. Dominant negative mutants of GATA-4 suppress cyclin D2 expression and cell growth, indicating that GATA-4 activation regulates PASMC proliferation. Thus, GATA-4 mediates 5-HT-induced growth of PASMC and may be an important therapeutic target for the prevention of pulmonary hypertension.
Highlights
Serotonin (5-hydroxytryptamine (5-HT)) is a mitogen of pulmonary artery smooth muscle cells (PASMC) and plays an important role in the development of pulmonary hypertension
A further study showed that a continuous intravenous infusion of 5-HT during a 2-week exposure of rats to hypoxia potentiated the development of pulmonary hypertension [2]
The role of 5-HT in pulmonary hypertension appears to be through the serotonin transporter (SERT), as mice deficient for SERT developed less hypoxic pulmonary hypertension and vascular remodeling than did control animals exposed to the same conditions [3]
Summary
5-HT, 5-hydroxytryptamine; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; ERK, extracellular signal-regulated kinase; SERT, serotonin transporter; PASMC, pulmonary artery smooth muscle cells; ROS, reactive oxygen species; ET-1, endothelin-1; PDGF, platelet-derived growth factor; EMSA, Electrophoretic mobility shift assay. As superoxide [16] and H2O2 [17], presumably via the activation of NAD(P)H oxidase. These signaling events appear to activate the MEK-ERK pathway as PD98059 blocked the 5-HTinduced PASMC growth [18]. Downstream signaling components, which are activated by ERK for the 5-HT-mediated induction of cell growth, have not yet been identified. The mechanism appears to involve p21Cip, because the adenovirus-mediated overexpression of GATA-6 was found to inhibit cellular entry into S-phase by inducing this cyclin-dependent kinase inhibitor [22]. Our results show that PASMC express GATA-4 that is activated by 5-HT and enhances PASMC growth
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