Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice

Abstract Rivaroxaban is an oral direct factor Xa inhibitor approved for the treatment of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation. Despite its efficacy, rivaroxaban therapy results in adverse effects and complications, such as bleeding. Angiotensin II (An...

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Autores principales:	Dan Yang, Junjie Shao, Ruifeng Hu, Haimei Chen, Ping Xie, Chang Liu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1ed48557023c41f4b6b512cdc3b6a862
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spelling	oai:doaj.org-article:1ed48557023c41f4b6b512cdc3b6a8622021-12-02T16:08:21ZAngiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice10.1038/s41598-017-00473-52045-2322https://doaj.org/article/1ed48557023c41f4b6b512cdc3b6a8622017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00473-5https://doaj.org/toc/2045-2322Abstract Rivaroxaban is an oral direct factor Xa inhibitor approved for the treatment of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation. Despite its efficacy, rivaroxaban therapy results in adverse effects and complications, such as bleeding. Angiotensin II (AngII) is implicated in many cardiovascular conditions, such as hypertension and heart failure. In this study, we investigate whether AngII influences anticoagulant effects of rivaroxaban by using an experimental mouse model with type 2 diabetes mellitus and advanced glycation end product (AGE)-exposed human umbilical vein endothelial cells (HUVECs). We found that AngII promoted the anticoagulant effects of rivaroxaban in KKAy mice. The combination of rivaroxaban and AngII enhanced in vivo tissue factor pathway inhibitor (TFPI) activity and induced TFPI expression and activity in AGE-exposed HUVECs. Angiotensin type 2 receptor (AT2R) and Mas antagonists attenuated the AngII-enhanced anticoagulant action of rivaroxaban in vivo, and abolished the increased endothelial TFPI expression and activity. However, angiotensin type 1 receptor (AT1R) antagonist exerted no effects. Additionally, combination of rivaroxaban and AngII induced aortic AT2R and Mas expression. Our data suggest that the anticoagulant effects of rivaroxaban are promoted by AngII via AT2R and Mas signaling. These findings are significant for the clinical administration of rivaroxaban.Dan YangJunjie ShaoRuifeng HuHaimei ChenPing XieChang LiuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dan Yang Junjie Shao Ruifeng Hu Haimei Chen Ping Xie Chang Liu Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice
description	Abstract Rivaroxaban is an oral direct factor Xa inhibitor approved for the treatment of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation. Despite its efficacy, rivaroxaban therapy results in adverse effects and complications, such as bleeding. Angiotensin II (AngII) is implicated in many cardiovascular conditions, such as hypertension and heart failure. In this study, we investigate whether AngII influences anticoagulant effects of rivaroxaban by using an experimental mouse model with type 2 diabetes mellitus and advanced glycation end product (AGE)-exposed human umbilical vein endothelial cells (HUVECs). We found that AngII promoted the anticoagulant effects of rivaroxaban in KKAy mice. The combination of rivaroxaban and AngII enhanced in vivo tissue factor pathway inhibitor (TFPI) activity and induced TFPI expression and activity in AGE-exposed HUVECs. Angiotensin type 2 receptor (AT2R) and Mas antagonists attenuated the AngII-enhanced anticoagulant action of rivaroxaban in vivo, and abolished the increased endothelial TFPI expression and activity. However, angiotensin type 1 receptor (AT1R) antagonist exerted no effects. Additionally, combination of rivaroxaban and AngII induced aortic AT2R and Mas expression. Our data suggest that the anticoagulant effects of rivaroxaban are promoted by AngII via AT2R and Mas signaling. These findings are significant for the clinical administration of rivaroxaban.
format	article
author	Dan Yang Junjie Shao Ruifeng Hu Haimei Chen Ping Xie Chang Liu
author_facet	Dan Yang Junjie Shao Ruifeng Hu Haimei Chen Ping Xie Chang Liu
author_sort	Dan Yang
title	Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice
title_short	Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice
title_full	Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice
title_fullStr	Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice
title_full_unstemmed	Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice
title_sort	angiotensin ii promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/1ed48557023c41f4b6b512cdc3b6a862
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Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice

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