Rivaroxaban improves vascular response in LPS-induced acute inflammation in experimental models.

Armond Daci,Rrahman Ferizi,Rame Alaj,Shpejtim Shurdhiqi,Shaip Krasniqi,Giuseppe Danilo Norata,Lorenzo Da Dalt,Burim Neziri,Xianwu Cheng

doi:10.1371/journal.pone.0240669

Abstract

Rivaroxaban (RVX) was suggested to possess anti-inflammatory and vascular tone modulatory effects. The goal of this study was to investigate whether RVX impacts lipopolysaccharide (LPS)-induced acute vascular inflammatory response. Male rats were treated with 5 mg/kg RVX (oral gavage) followed by 10 mg/kg LPS i.p injection. Circulating levels of IL-6, MCP-1, VCAM-1, and ICAM-1 were measured in plasma 6 and 24 hours after LPS injection, while isolated aorta was used for gene expression analysis, immunohistochemistry, and vascular tone evaluation. RVX pre-treatment significantly reduced LPS mediated increase after 6h and 24h for IL-6 (4.4±2.2 and 2.8±1.7 fold), MCP-1 (1.4±1.5 and 1.3±1.4 fold) VCAM-1 (1.8±2.0 and 1.7±2.1 fold). A similar trend was observed in the aorta for iNOS (5.5±3.3 and 3.3±1.9 folds reduction, P<0.01 and P<0.001, respectively), VCAM-1 (1.3±1.2 and 1.4±1.3 fold reduction, P<0.05), and MCP-1 (3.9±2.2 and 1.9±1.6 fold reduction, P<0.01). Moreover, RVX pre-treatment, improved LPS-induced PE contractile dysfunction in aortic rings (Control vs LPS, Emax reduction = 35.4 and 31.19%, P<0.001; Control vs LPS+RVX, Emax reduction = 10.83 and 11.48%, P>0.05, respectively), resulting in 24.5% and 19.7% change in maximal constriction in LPS and LPS+RVX respectively. These data indicate that RVX pre-treatment attenuates LPS-induced acute vascular inflammation and contractile dysfunction.

Highlights

Coagulation plays a key role in cardiovascular disorders [1] and interfering with coagulation factors represents one of the main pharmacological approaches in CVD [2]
Increased iNOS, Monocyte Chemottractant Protein (MCP-1), and VCAM-1 immunoreactivity were observed in the aortic vascular tissues of LPS treated rats mainly in vascular endothelium, and the subendothelial layer was characterized by smooth muscle cells and perivascular adipose tissues compared to controls (P
We demonstrated that a specific inhibitor of FXa, namely rivaroxaban, improves acute inflammation and vascular dysfunction following LPS-induced endotoxin shock

Summary

Introduction

Coagulation plays a key role in cardiovascular disorders [1] and interfering with coagulation factors represents one of the main pharmacological approaches in CVD [2]. Coagulation factors, participate to the activation of the coagulation cascade and impact vascular function; this is the case for factor X (FXa), one of the main components in the coagulation. Effects of rivaroxaban on LPS induced vascular inflammation and PRIN 2017K55HLC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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