Transcriptome Analysis of the Anti-TGFβ Effect of Schisandra chinensis Fruit Extract and Schisandrin B in A7r5 Vascular Smooth Muscle Cells.

Sanghoon Lee,Hyun Ho Park,Jung Nyeo Chun,Insuk So,Eun-Jung Park,Hae-Jeung Lee,Ju-Hong Jeon

doi:10.3390/life11020163

Abstract

Schisandra chinensis fruit extract (SCE) has been used as a traditional medicine for treating vascular diseases. However, little is known about how SCE and schisandrin B (SchB) affect transcriptional output-a crucial factor for shaping the fibrotic responses of the transforming growth factor β (TGFβ) signaling pathways in in vascular smooth muscle cells (VSMC). In this study, to assess the pharmacological effect of SCE and SchB on TGFβ-induced transcriptional output, we performed DNA microarray experiments in A7r5 VSMCs. We found that TGFβ induced distinctive changes in the gene expression profile and that these changes were considerably reversed by SCE and SchB. Gene Set Enrichment Analysis (GSEA) with Hallmark signature suggested that SCE or SchB inhibits a range of fibrosis-associated biological processes, including inflammation, cell proliferation and migration. With our VSMC-specific transcriptional interactome network, master regulator analysis identified crucial transcription factors that regulate the expression of SCE- and SchB-effective genes (i.e., TGFβ-reactive genes whose expression are reversed by SCE and SchB). Our results provide novel perspective and insight into understanding the pharmacological action of SCE and SchB at the transcriptome level and will support further investigations to develop multitargeted strategies for the treatment of vascular fibrosis.

Highlights

Fibrosis is a characteristic pathological feature of vascular diseases, such as atherosclerosis and restenosis [1,2,3]
We have reported the effect of Schisandra chinensis fruit extract (SCE) and its ingredient schisandrin B (SchB) on the Smad-dependent and -independent Transforming growth factor β (TGFβ) signaling cascades in vascular smooth muscle cells (VSMC) [20,21,22]
Little is known about their effect on TGFβ-induced transcriptional output, which is crucial for shaping fibrotic responses

Summary

Introduction

Fibrosis is a characteristic pathological feature of vascular diseases, such as atherosclerosis and restenosis [1,2,3]. Transforming growth factor β (TGFβ) has a profound pro-fibrotic effect on vascular tissues [3,4] by affecting a wide range of biological pathways, including cell proliferation and migration, inflammation, and trans-differentiation as well as the accumulation of extracellular matrix (ECM) proteins [1,5,6,7]. TGFβ induces the synthetic, non-contractile phenotypes (e.g., cell proliferation and migration) of vascular smooth muscle cells (VSMCs) in response to vascular injury [8,9]. The TGFβ signaling pathway has gained attention as a plausible target for attenuating vascular fibrosis [10,11]. TGFβ signals through the type II receptor kinase (TβRII)-mediated activation of TβRI [12,13]. The activated TβRI propagates its downstream signaling through both the Smad-dependent canonical pathways and the Smad-independent non-canonical pathways. TβRI phosphorylates Smad and Smad to form a heteromeric

Methods

Results

Conclusion