Rivaroxaban protects from the oxysterol-induced damage and inflammatory activation of the vascular endothelium

Gorzelak-Pabiś, Paulina; Broncel, Marlena; Wojdan, Katarzyna; Gajewski, Adrian; Chałubiński, Maciej; Gawrysiak, Mateusz; Woźniak, Ewelina

doi:10.1080/21688370.2021.1956284

Cited by 9 publications

(12 citation statements)

References 30 publications

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“…Studies indicate that 25‐OHC is involved in a number of processes, such as inflammation and vascular proliferation, which promote the development of atherosclerosis 5 . It has been demonstrated that, in the endothelium, the 25‐OHC treatment induced DNA single‐strand (SSBs) oxidative damage to purines and pyrimidines damage, as shown in the decreased nitric oxide (NO) production by inhibiting endothelial NO synthase (eNOS) activity and increased superoxide anion generation; this may play an important role in endothelial integrity and immune responses 15,22,23 . Dabigatran and rivaroxaban decreased ROS level 15 .…”

Section: Discussionmentioning

confidence: 99%

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Expression of anti and pro‐inflammatory genes in human endothelial cells activated by 25‐hydroxycholesterol: A comparison of rivaroxaban and dabigatran

Gorzelak-Pabiś

Pawlos

Broncel

et al. 2022

Clin Exp Pharma Physio

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Atherosclerosis is associated with a haemostatic imbalance characterized by excessive activation of pro‐inflammatory and pro‐coagulant pathways. Non‐vitamin K antagonists oral anticoagulant (NOACs) may reduce the incidence of cardiovascular events, cerebral ischemia, thromboembolic events and atherosclerosis. Chronic inflammation, vascular proliferation and the development of atherosclerosis is also influenced by 25‐hydroxycholesterol (25‐OHC). The aim of the study was to assess the effect of rivaroxaban and dabigatran on the messenger RNA (mRNA) expression of anti‐inflammatory cytokines transforming growth factor β (TGF‐β), interleukin (IL)‐37, IL‐35 as well as of pro‐inflammatory cytokines IL‐18 and IL‐23, in endothelial cells damaged by 25‐OHC. Human umbilical vascular endothelial cells (HUVECs) were treated with 25‐OHC (10 μg/mL), rivaroxaban (100, 500 ng/mL), dabigatran (100, 500 ng/mL), 25‐OHC + rivaroxaban, and 25‐OHC + dabigatran. The mRNA expression of TGF‐β, IL‐37, IL‐35 subunits EBI3 and p35, IL‐18, and IL‐23 was analysed using real‐time polymerase chain reaction (PCR). The results showed that 25‐OHC decreased TGF‐β and IL‐37 mRNA expression and increased EBI3, p35, IL‐18, IL‐23 mRNA expression in endothelial cell as compared to an untreated control (P < .05). Messenger RNA expression of TGF‐β and IL‐37 significantly increased following stimulation with rivaroxaban and dabigatran as compared to an untreated control (P < .01). In HUVECs pre‐treated with oxysterol, rivaroxaban and dabigatran increased mRNA expression of TGF‐β, IL‐37 and decreased mRNA expression of EBI3, p35, IL‐23 and IL‐18 as compared to 25‐OHC (P < .01). Our finding suggests that both rivaroxaban and dabigatran inhibit the inflammatory activation caused by oxysterol in vitro.

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Section: Discussionmentioning

confidence: 99%

“…Thrombin is an activator of PAR1, whereas FXa activates PAR1, -2 and -3 alone or in complex with TF-FVIIa. 12 Protease activated 15,22,23 Dabigatran and rivaroxaban decreased ROS level. 15 Moreover, dabigatran was able to completely repair the DNA SSBs induced by 25-OHC.…”

Section: Discussionmentioning

confidence: 99%

Expression of anti and pro‐inflammatory genes in human endothelial cells activated by 25‐hydroxycholesterol: A comparison of rivaroxaban and dabigatran

Gorzelak-Pabiś

Pawlos

Broncel

et al. 2022

Clin Exp Pharma Physio

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“…DOAC-related enhancement of cell growth is debatable. Studies are showing that DOACs promote cell growth and proliferation (Wu et al, 2015;Sanada et al, 2016;Shi et al, 2018;Álvarez et al, 2018;Almengló et al, 2020), while in other studies no such effect was found (Woźniak et al, 2020;Gorzelak-Pabis et al, 2021;Gorzelak-Pabiś et al, 2022a). These contradictory effects may uncover real differences or be the result of different experimental settings.…”

Section: Figurementioning

confidence: 97%

Distinct pleiotropic effects of direct oral anticoagulants on cultured endothelial cells: a comprehensive review

Atzemian,

Kareli,

Ragia

et al. 2023

Front. Pharmacol.

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Direct Oral Anticoagulants (DOACs) have simplified the treatment of thromboembolic disease. In addition to their established anticoagulant effects, there are indications from clinical and preclinical studies that DOACs exhibit also non-anticoagulant actions, such as anti-inflammatory and anti-oxidant actions, advocating overall cardiovascular protection. In the present study, we provide a comprehensive overview of the existing knowledge on the pleiotropic effects of DOACs on endothelial cells (ECs) in vitro and their underlying mechanisms, while also identifying potential differences among DOACs. DOACs exhibit pleiotropic actions on ECs, such as anti-inflammatory, anti-atherosclerotic, and anti-fibrotic effects, as well as preservation of endothelial integrity. These effects appear to be mediated through inhibition of the proteinase-activated receptor signaling pathway. Furthermore, we discuss the potential differences among the four drugs in this class. Further research is needed to fully understand the pleiotropic effects of DOACs on ECs, their underlying mechanisms, as well as the heterogeneity between various DOACs. Such studies can pave the way for identifying biomarkers that can help personalize pharmacotherapy with this valuable class of drugs.

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“…Forearm blood flow was also improved in diabetic patients administered rivaroxaban for 20 weeks, although treatment was associated with higher bleeding events ( 150 ). In vitro , rivaroxaban reduced ROS (reactive oxygen species), improved DNA repair ( 151 ) and reduced inflammatory gene expression in ECs exposed to hydroxycholesterol ( 152 , 153 ). Rivaroxaban also stimulated blood flow and increased capillary density in a mouse model of diabetic PAD ( 154 ).…”

Section: Current Treatments and Clinical Trials Which Target And Impr...mentioning

confidence: 99%

Endothelial cell dysfunction: Implications for the pathogenesis of peripheral artery disease

Kavurma

Bursill

Stanley

et al. 2022

Front. Cardiovasc. Med.

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Peripheral artery disease (PAD) is caused by occluded or narrowed arteries that reduce blood flow to the lower limbs. The treatment focuses on lifestyle changes, management of modifiable risk factors and vascular surgery. In this review we focus on how Endothelial Cell (EC) dysfunction contributes to PAD pathophysiology and describe the largely untapped potential of correcting endothelial dysfunction. Moreover, we describe current treatments and clinical trials which improve EC dysfunction and offer insights into where future research efforts could be made. Endothelial dysfunction could represent a target for PAD therapy.

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Rivaroxaban protects from the oxysterol-induced damage and inflammatory activation of the vascular endothelium

Cited by 9 publications

References 30 publications

Expression of anti and pro‐inflammatory genes in human endothelial cells activated by 25‐hydroxycholesterol: A comparison of rivaroxaban and dabigatran

Expression of anti and pro‐inflammatory genes in human endothelial cells activated by 25‐hydroxycholesterol: A comparison of rivaroxaban and dabigatran

Distinct pleiotropic effects of direct oral anticoagulants on cultured endothelial cells: a comprehensive review

Endothelial cell dysfunction: Implications for the pathogenesis of peripheral artery disease

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