Serotonin inhibits apoptosis of pulmonary artery smooth muscle cells through 5-HT_2A receptors involved in the pulmonary artery remodeling of pulmonary artery hypertension

ABSTRACT

Decreased pulmonary artery smooth muscle cell (PASMC) apoptosis play a key role in pulmonary artery remodeling during pulmonary artery hypertension (PAH), but the mechanisms involved are unclear. Serotonin (5-HT) inhibits apoptosis in many pathologic processes by activating the 5-HT_2A receptor. Therefore, we hypothesized that 5-HT may be the promoter of decreased apoptosis in PAH through the 5-HT_2A receptor. We found that inhibition of the 5-HT_2A receptor prevented the increase in pulmonary artery pressure and pulmonary artery remodeling in rats stimulated by monocrotaline. This effect was accompanied by increased apoptosis in the pulmonary artery. Cultured PASMCs stimulated with 5-HT showed a decrease in apoptosis with increased phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), pyruvate dehydrogenase kinase (PDK), and mitochondrial transmembrane potential. These effects were markedly prevented by a 5-HT_2A receptor inhibitor, an ERK1/2 activation inhibitor peptide I, or a PDK inhibitor. In conclusion, 5-HT inhibited PASMC apoptosis by activating the 5-HT_2A receptor through the pERK1/2 and PDK pathways.5-HT decreasing apoptosis through 5-HT_2A receptor is involved, at least in part, in pulmonary artery remolding.

KEYWORDS :

• apoptosis
• pulmonary artery hypertension
• serotonin
• smooth muscle cell