Serotonin inhibits apoptosis of pulmonary artery smooth muscle cell by pERK1/2 and PDK through 5-HT_1B receptors and 5-HT transporters

Background: Decreased apoptosis of pulmonary artery smooth muscle cells (PASMCs) plays a key role in pulmonary vascular remodeling in pulmonary hypertension (PH). However, the cause and mechanism of this decrease in apoptosis are still unclear. Serotonin (5-HT) has been shown to be involved in PH by inducing PASMC proliferation through the activation of 5-HT_1B receptors (5-HT_1BR) and 5-HT transporter (5-HTT). 5-HT_1BR and 5-HTT are also involved in abnormal apoptosis in many other pathological processes. Therefore, we hypothesized that 5-HT induces decreases in PASMC apoptosis through 5-HT_1BR and 5-HTT. Methods: PASMCs were treated with 5-HT, and their proliferation and apoptosis were assayed. 5-HT _1BR agonists, 5-HT_1BR antagonist, 5-HTT antagonist, combined 5-HT_1BR/5-HTT antagonists, extracellular signalregulated kinase (ERK1/2) activation inhibitor peptide I (EPI) and pyruvate dehydrogenase kinase (PDK) inhibitor sodium dichloroacetate (DCA) were used to explore the mechanism by which 5-HT induce decrease in PASMC apoptosis. Results: PASMCs stimulated by 5-HT showed an increase in proliferation and a decrease in apoptosis, accompanied by increase in pERK1/2, PDK, and mitochondrial transmembrane potential. The effects of 5-HT on the proliferation and apoptosis of PASMCs were similar to those of 5-HT_1BR agonists and were markedly prevented by 5-HT_1BR antagonist, 5-HTT antagonist, combined 5-HT1BR/5-HTT antagonists, EPI, or DCA. Conclusions: 5-HT inhibits PASMC apoptosis through 5-HT_1BR or 5-HTT. pERK1/2 and PDK are involved in the process of 5-HT inhibition PASMC apoptosis through 5-HT_1BR or 5-HTT.