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STAT6 Upregulation Promotes M2 Macrophage Polarization to Suppress Atherosclerosis

Min Gong, Xiaozhen Zhuo, Aiqun Ma

Department of Cardiovascular Internal Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China (mainland)

Med Sci Monit Basic Res 2017; 23:240-249

DOI: 10.12659/MSMBR.904014

Available online: 2017-06-15

Published: 2017-06-15


BACKGROUND: Macrophages are highly heterogeneous and plastic cells that are involved in all stages of atherogenesis. They can undergo polarization by shifting between M1 and M2 functional phenotypes. However, the role of macrophage polarization and the molecular mechanism in modulating atherosclerotic plaque stability remain incompletely understood. Our study investigated the role of STAT6 in regulating macrophage phenotypes to affect atherosclerotic plaque stability.
MATERIAL AND METHODS: A murine atherosclerosis model with vulnerable plaques was induced with high-cholesterol diet and PCCP surgeries in ApoE–/– mice. Murine macrophages RAW264.7 treated with ox-LDL or IL-4 were used to simulate the in vitro process. pcDNA3.1(–)/STAT6-expressing vectors were transfected into RAW264.7 to evaluate its effect on cell polarization and the involved molecules.
RESULTS: Unstable plaques presented significantly increased M1 markers (CD86 and iNOS) and less M2 markers (Arg-1 and TGF-β) than the stable plaques. Moreover, we found that STAT6 and p-STAT6 were greatly decreased in the vulnerable plaques and ox-LDL-induced macrophages, while their expression was elevated after IL-4 stimulation. The overexpression of STAT6 substantially reversed the ox-LDL-stimulated macrophage apoptosis and lipid accumulation. STAT6 upregulation promoted the differentiation of macrophage to M2 subtype as reflected by the increased expression of Arg-1 and TGF-β. Furthermore, we found that STAT6 overexpression activated the Wnt-β-catenin signaling by enhancing the translocation of β-catenin, while β-catenin suppression inhibited STAT6 overexpression-induced M2 polarization.
CONCLUSIONS: STAT6 facilitated atherosclerotic plaque stabilization by promoting the polarization of macrophages to M2 subtype and antagonizing ox-LDL-induced cell apoptosis and lipid deposition in a Wnt-β-catenin-dependent manner.

Keywords: atherosclerosis, Macrophage Activation, Plaque, Atherosclerotic, STAT6 Transcription Factor, Wnt Signaling Pathway