5-HT induces PPAR γ reduction and proliferation of pulmonary artery smooth muscle cells via modulating GSK-3β/β-catenin pathway

Studies have shown that peroxisome proliferator-activated receptor γ (PPAR γ) is down-regulated in pulmonary vascular lesions of patients with pulmonary hypertension (PH) and animal models of PH. Yet, the detailed molecular mechanisms underlying this alteration are not fully defined; the aim of this study is to address this issue. 5-HT dose- and time-dependently reduced PPAR γ expression and promoted pulmonary artery smooth muscle cells (PASMCs) proliferation; this was accompanied with the phosphorylation of Akt, inactivation of GSK-3β and up-regulation of β-catenin. Importantly, pre-treatment of cells with PI3K inhibitor (Ly294002) or prior silencing of β-catenin with siRNA blocked 5-HT-induced PPAR γ reduction and PASMCs proliferation. In addition, inactivation or lack of GSK-3β or inhibition of proteasome function up-regulated β-catenin protein without affecting its mRNA level and reduced PPAR γ protein expression. Taken together, our study indicates that 5-HT suppresses PPAR γ expression and stimulates PASMCs proliferation by modulating GSK-3β/β-catenin axis, and suggests that targeting this pathway might have potential value in the management of PH.