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Abstract
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.
Highlights
Pulmonary hypertension (PH) is a common clinical syndrome characterized by sustained elevation of pulmonary vascular resistance and increased pulmonary arterial pressure, leading to right heart failure and death [1]
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 peroxisome proliferator-activated receptor γ (PPAR γ) expression and promoted pulmonary artery smooth muscle cells (PASMCs) proliferation; this was accompanied with the phosphorylation of Akt, inactivation of glycogen synthase kinase-3β (GSK-3β) and up-regulation of β-catenin
We have shown that 5-HT causes the reduction of PPAR γ expression in primary cultured PASMCs, this effect is coupled to the phosphorylation of Akt and inactivation of GSK-3β and subsequent posttranscriptional up-regulation of β-catenin, which further suppresses the expression of PPAR γ and leads to PASMCs proliferation
Summary
Pulmonary hypertension (PH) is a common clinical syndrome characterized by sustained elevation of pulmonary vascular resistance and increased pulmonary arterial pressure, leading to right heart failure and death [1]. Pulmonary vascular remodeling characterized by thickening of all layers of vascular wall is a hallmark of PH [3], and pulmonary arterial smooth muscle cells (PASMCs) proliferation is critical in this process [4]. Besides its metabolic actions [5], emerging evidences have demonstrated that PPAR γ regulates diverse cellular processes including cell proliferation, apoptosis, differentiation and migration [6, 7]. Further studies have demonstrated that genetic deletion of PPAR γ in mice pulmonary vascular SMCs is sufficient to causes spontaneous PH [9], while activation of PPAR γ www.impactjournals.com/oncotarget strongly attenuates PASMCs proliferation and inhibits the development of PH [10,11,12]. The exact mechanisms underlying down-regulation of PPAR γ in PASMCs of PH are still largely unknown
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