The protective effect of dabigatran and rivaroxaban on DNA oxidative changes in a model of vascular endothelial damage with oxidized cholesterol

E Woźniak,M Broncel,B Bukowska,P Gorzelak-Pabiś

doi:10.1016/j.atherosclerosis.2020.10.348

E Woźniak, M Broncel + Show 2 more

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https://doi.org/10.1016/j.atherosclerosis.2020.10.348

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Abstract

Background: Atherosclerotic plaques are unstable, and their release may result in thrombosis; therefore, currently, antiplatelet therapy with anticoagulants is recommended for the treatment of acute coronary syndrome. The aim of this study was to assess the effect of oxidized cholesterol on human umbilical vascular endothelial cells (HUVECs). The study also examines the protective and repairing effect of dabigatran and rivaroxaban in a model of vascular endothelial damage with 25-hydroxycholesterol (25-OHC). Methods: HUVECs were treated with compounds induce DNA single-strand breaks (SSBs) using the comet assay. Oxidative DNA damage was detected using endonuclease III (Nth) or human 8 oxoguanine DNA glycosylase (hOOG1). Reactive oxygen species (ROS) formation was determined using flow cytometry. Results: 25-hydroxycholesterol caused DNA SSBs, induced oxidative damage and increased ROS in the HUVECs; ROS level was lowered by dabigatran and rivaroxaban. Only dabigatran was able to completely repair the DNA SSBs induced by oxysterol. Dabigatran was able to reduce the level of oxidative damage of pyrimidines induced by oxysterol to the level of control cells. Conclusions: Observed changes strongly suggest that the tested anticoagulants induced indirect repair of DNA by inhibiting ROS production. Furthermore, dabigatran appears to have a higher antioxidant activity than rivaroxaban.

Highlights

Cardiovascular diseases, such as hypertension and atherosclerosis, are characterized by changes in the structure and activity of endothelial cells and the vasculature [1]. 25-hydroxycholesterol (25-OHC) is a type of oxidized cholesterol belonging to a subgroup of oxidized low-density lipoproteins which play major roles in atherosclerosis [2,3]
The present study examines the ability of anticoagulants such as dabigatran and rivaroxaban to protect against the production of reactive oxygen species (ROS) and DNA oxidative damage in a model of vascular endothelial damage with oxidized cholesterol: an area of research that is currently unknown
The present study is the first to investigate the effect of oxidized cholesterol 25-hydroxycholesterol, on endothelial cells, and two selected anticoagulants: dabigatran and rivaroxaban

Summary

Introduction

Cardiovascular diseases, such as hypertension and atherosclerosis, are characterized by changes in the structure and activity of endothelial cells and the vasculature [1]. 25-hydroxycholesterol (25-OHC) is a type of oxidized cholesterol belonging to a subgroup of oxidized low-density lipoproteins (oxLDLs) which play major roles in atherosclerosis [2,3]. Certain common cardiovascular diseases (CVDs), such as venous thromboembolism, stroke or systemic embolism in non-valvular atrial fibrillation, can be controlled or treated using non-vitamin-K oral anticoagulants (NOAC). One such NOAC is dabigatran: a reversible competitive inhibitor of thrombin that inhibits both free and clot-bound thrombin and thrombin-induced platelet activation [8]. The study examines the protective and repairing effect of dabigatran and rivaroxaban in a model of vascular endothelial damage with 25-hydroxycholesterol (25-OHC). Results: 25-hydroxycholesterol caused DNA SSBs, induced oxidative damage and increased ROS in the HUVECs; ROS level was lowered by dabigatran and rivaroxaban. Dabigatran appears to have a higher antioxidant activity than rivaroxaban

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