Rivaroxaban Suppresses Atherosclerosis by Inhibiting FXa-Induced Macrophage M1 Polarization-Mediated Phenotypic Conversion of Vascular Smooth Muscle Cells

Background: Factor Xa (FXa) is a mediator initiating and accelerating atherosclerosis (AS). Both macrophage and vascular smooth muscle cells (VSMCs) participate in AS progression. This study was aimed to investigate the mechanisms underlying the effects of the FXa inhibitor rivaroxaban on AS.Methods...

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Autores principales:	Yanpeng Ma, Yong Zhang, Chuan Qiu, Chunhui He, Ting He, Shuang Shi, Zhongwei Liu
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	atherosclerosis macrophage vascular smooth muscle cell polarization phenotypic conversion factor Xa Diseases of the circulatory (Cardiovascular) system RC666-701
Acceso en línea:	https://doaj.org/article/a7add0d4b0d14c739543f1735eee950e
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spelling	oai:doaj.org-article:a7add0d4b0d14c739543f1735eee950e2021-11-15T05:58:13ZRivaroxaban Suppresses Atherosclerosis by Inhibiting FXa-Induced Macrophage M1 Polarization-Mediated Phenotypic Conversion of Vascular Smooth Muscle Cells2297-055X10.3389/fcvm.2021.739212https://doaj.org/article/a7add0d4b0d14c739543f1735eee950e2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcvm.2021.739212/fullhttps://doaj.org/toc/2297-055XBackground: Factor Xa (FXa) is a mediator initiating and accelerating atherosclerosis (AS). Both macrophage and vascular smooth muscle cells (VSMCs) participate in AS progression. This study was aimed to investigate the mechanisms underlying the effects of the FXa inhibitor rivaroxaban on AS.Methods: Rivaroxaban was administered to AS mice. Primary macrophages were exposed to FXa, treated with rivaroxaban, and transfected with siRNA silencing protease-activated receptor 2 (PAR2), hypoxia-inducible factor 1α (HIF1α), delta-like receptor 4 (Dll4), and Akt. Interaction between macrophages and VSMCs was assessed by co-culturing systems. Atherosclerotic lesions were evaluated by oil red O stain. Fluorescent staining was used to determine the cell phenotypes. Secretions of inflammatory cytokines and collagen were assessed by ELISA and Sircol assays. Western blotting was used to evaluate the protein expression and phosphorylation levels.Results: Rivaroxaban reduced lesion area, accumulation of M1 macrophages, and contractile-synthetic phenotypic conversion of VSMCs in atherosclerotic plaques. FXa exposure induced polarization of macrophages toward M1 and Dll4 high expression, which were inhibited by PAR2, Akt1, and HIF1α silencing. Rivaroxaban treatment inhibited PAR2/Akt/HIF1α signaling activation and Dll4 expression in FXa-exposed macrophages. By cell-to-cell contact, M1 macrophages induced Notch signaling activation in VSMCs which committed contractile-synthetic conversion. Rivaroxaban treatment and Dll4 silencing incapacitated macrophage in inducing phenotypic conversion of VSMCs upon cell-to-cell contact.Conclusion: Rivaroxaban suppresses AS by inhibiting FXa-induced PAR2/Akt/HIF1α signaling activation-mediated macrophage M1 polarization and high Dll4 expression. These macrophages facilitated VSMCs to perform contractile-synthetic phenotypic conversion upon macrophage-VSMCs cell-to-cell contact.Yanpeng MaYong ZhangChuan QiuChunhui HeTing HeShuang ShiZhongwei LiuFrontiers Media S.A.articleatherosclerosismacrophagevascular smooth muscle cellpolarizationphenotypic conversionfactor XaDiseases of the circulatory (Cardiovascular) systemRC666-701ENFrontiers in Cardiovascular Medicine, Vol 8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	atherosclerosis macrophage vascular smooth muscle cell polarization phenotypic conversion factor Xa Diseases of the circulatory (Cardiovascular) system RC666-701
spellingShingle	atherosclerosis macrophage vascular smooth muscle cell polarization phenotypic conversion factor Xa Diseases of the circulatory (Cardiovascular) system RC666-701 Yanpeng Ma Yong Zhang Chuan Qiu Chunhui He Ting He Shuang Shi Zhongwei Liu Rivaroxaban Suppresses Atherosclerosis by Inhibiting FXa-Induced Macrophage M1 Polarization-Mediated Phenotypic Conversion of Vascular Smooth Muscle Cells
description	Background: Factor Xa (FXa) is a mediator initiating and accelerating atherosclerosis (AS). Both macrophage and vascular smooth muscle cells (VSMCs) participate in AS progression. This study was aimed to investigate the mechanisms underlying the effects of the FXa inhibitor rivaroxaban on AS.Methods: Rivaroxaban was administered to AS mice. Primary macrophages were exposed to FXa, treated with rivaroxaban, and transfected with siRNA silencing protease-activated receptor 2 (PAR2), hypoxia-inducible factor 1α (HIF1α), delta-like receptor 4 (Dll4), and Akt. Interaction between macrophages and VSMCs was assessed by co-culturing systems. Atherosclerotic lesions were evaluated by oil red O stain. Fluorescent staining was used to determine the cell phenotypes. Secretions of inflammatory cytokines and collagen were assessed by ELISA and Sircol assays. Western blotting was used to evaluate the protein expression and phosphorylation levels.Results: Rivaroxaban reduced lesion area, accumulation of M1 macrophages, and contractile-synthetic phenotypic conversion of VSMCs in atherosclerotic plaques. FXa exposure induced polarization of macrophages toward M1 and Dll4 high expression, which were inhibited by PAR2, Akt1, and HIF1α silencing. Rivaroxaban treatment inhibited PAR2/Akt/HIF1α signaling activation and Dll4 expression in FXa-exposed macrophages. By cell-to-cell contact, M1 macrophages induced Notch signaling activation in VSMCs which committed contractile-synthetic conversion. Rivaroxaban treatment and Dll4 silencing incapacitated macrophage in inducing phenotypic conversion of VSMCs upon cell-to-cell contact.Conclusion: Rivaroxaban suppresses AS by inhibiting FXa-induced PAR2/Akt/HIF1α signaling activation-mediated macrophage M1 polarization and high Dll4 expression. These macrophages facilitated VSMCs to perform contractile-synthetic phenotypic conversion upon macrophage-VSMCs cell-to-cell contact.
format	article
author	Yanpeng Ma Yong Zhang Chuan Qiu Chunhui He Ting He Shuang Shi Zhongwei Liu
author_facet	Yanpeng Ma Yong Zhang Chuan Qiu Chunhui He Ting He Shuang Shi Zhongwei Liu
author_sort	Yanpeng Ma
title	Rivaroxaban Suppresses Atherosclerosis by Inhibiting FXa-Induced Macrophage M1 Polarization-Mediated Phenotypic Conversion of Vascular Smooth Muscle Cells
title_short	Rivaroxaban Suppresses Atherosclerosis by Inhibiting FXa-Induced Macrophage M1 Polarization-Mediated Phenotypic Conversion of Vascular Smooth Muscle Cells
title_full	Rivaroxaban Suppresses Atherosclerosis by Inhibiting FXa-Induced Macrophage M1 Polarization-Mediated Phenotypic Conversion of Vascular Smooth Muscle Cells
title_fullStr	Rivaroxaban Suppresses Atherosclerosis by Inhibiting FXa-Induced Macrophage M1 Polarization-Mediated Phenotypic Conversion of Vascular Smooth Muscle Cells
title_full_unstemmed	Rivaroxaban Suppresses Atherosclerosis by Inhibiting FXa-Induced Macrophage M1 Polarization-Mediated Phenotypic Conversion of Vascular Smooth Muscle Cells
title_sort	rivaroxaban suppresses atherosclerosis by inhibiting fxa-induced macrophage m1 polarization-mediated phenotypic conversion of vascular smooth muscle cells
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/a7add0d4b0d14c739543f1735eee950e
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Rivaroxaban Suppresses Atherosclerosis by Inhibiting FXa-Induced Macrophage M1 Polarization-Mediated Phenotypic Conversion of Vascular Smooth Muscle Cells

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