Oncotarget

Research Papers:

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

Rui Ke, Xinming Xie, Shaojun Li, Yilin Pan, Jian Wang, Xin Yan, Weijin Zang, Li Gao and Manxiang Li _

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Oncotarget. 2017; 8:72910-72920. https://doi.org/10.18632/oncotarget.20582

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Abstract

Rui Ke1, Xinming Xie1, Shaojun Li1, Yilin Pan1, Jian Wang1, Xin Yan1, Weijin Zang2, Li Gao3 and Manxiang Li1

1Department of Respiratory Medicine, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China

2Department of Pharmacology, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, China

3Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA

Correspondence to:

Manxiang Li, email: [email protected]

Keywords: PPAR γ, β-catenin, GSK-3β, PASMCs, proliferation

Received: January 25, 2017    Accepted: August 02, 2017    Published: August 24, 2017

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.


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