Factor Xa inhibition by rivaroxaban attenuates cardiac remodeling due to intermittent hypoxia

Imano, Hideki; Kato, Ryuichi; Tanikawa, Shota; Yoshimura, Fumi; Nomura, Atsuo; Ijiri, Yoshio; Yamaguchi, Takehiro; Izumi, Yasukatsu; Yoshiyama, Minoru; Hayashi, Toshio

doi:10.1016/j.jphs.2018.07.002

Cited by 27 publications

(25 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…While rivaroxaban at the highest concentration (5.6 mM) did not affect the mitochondrial ROS generation. These results are in agreement with previous studies that showed rivaroxaban has been able to reduce ROS generation [19,20].…”

Section: Discussionsupporting

confidence: 94%

See 1 more Smart Citation

Contrasting Role of Concentration in Rivaroxaban Induced Toxicity and Oxidative Stress in Isolated Kidney Mitochondria

et al. 2019

View full text Add to dashboard Cite

Rivaroxaban as a small molecule is able to directly and reversibly inhibit the factor Xa. This study was designed to figure out the evaluation effect of rivaroxaban on mitochondria obtained from rat kidneys. We isolated mitochondria from rat kidneys using gradient centrifugation. Then, the toxicity parameters including succinate dehydrogenase (SDH) activity, reactive oxygen species (ROS) formation, mitochondrial swelling, mitochondrial membrane potential (MMP) collapse and cytochrome c release were measured in kidneys mitochondria following the exposure to rivaroxaban. The results showed that rivaroxaban (1.4 and 2.8 mM) raised the reactive oxygen species (ROS) generation, swelling in the mitochondria, collapse in the mitochondrial membrane potential (MMP) and cytochrome c release in the mitochondria isolated from kidneys. While, rivaroxaban at a higher concentration of 5.6 mM showed the opposite effect compared to other lower concentrations. The results indicate that rivaroxaban may have antioxidant effects at high concentrations. The results suggest that rivaroxaban (5.6 mM) has protective effects against oxidative stress and mitochondrial toxicity.

show abstract

Section: Discussionsupporting

confidence: 94%

“…Therefore, rivaroxaban may cause complications due to accumulation and elimination through the kidney [16][17][18]. Previous studies have shown that rivaroxaban has been able to reduce the level of ROS [19,20]. Furthermore, the rivaroxaban has reduced the inflammatory signal caused by FXa [21].…”

Section: Introductionmentioning

confidence: 99%

Contrasting Role of Concentration in Rivaroxaban Induced Toxicity and Oxidative Stress in Isolated Kidney Mitochondria

et al. 2019

View full text Add to dashboard Cite

show abstract

“…How coagulation promotes AAA and the role of inflammation is not clear. A recent study found that the FXa inhibitor rivaroxaban prevents NFkB activation in a murine model of inflammation-driven cardiac remodeling (40). Here we found that genetic deletion of Alox15 significantly abrogated the ability of Ang II to elevate both IL6 and CCL2 gene expression (Fig.…”

Section: Discussionmentioning

confidence: 99%

Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity

Allen-Redpath

Aldrovandi

Lauder

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE−/− mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE−/− deletion, and many were absent in Alox−/− mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.

show abstract

“…In carotid bodies, IH-induced ROS generation is associated with HIF-1 activity and results in a sensory long-term facilitation of carotid bodies [39,40,41]. Several in vivo and in vitro studies have also observed that IH induces the activation of NF-κB in cardiovascular tissues and endothelial cells [42,43,44,45]. Our previous research, using reporter gene assays, also confirmed that IH induces the activation of NF-κB in cultured rat aortic smooth muscle cells (RASMCs) [34].…”

Section: Reactive Oxygen Species (Ros) and Transcriptional Factorsmentioning

confidence: 99%

Proliferative Pathways of Vascular Smooth Muscle Cells in Response to Intermittent Hypoxia

Kyotani

Takasawa

Yoshizumi

2019

IJMS

View full text Add to dashboard Cite

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia (IH) and is a risk factor for cardiovascular diseases (e.g., atherosclerosis) and chronic inflammatory diseases (CID). The excessive proliferation of vascular smooth muscle cells (VSMCs) plays a pivotal role in the progression of atherosclerosis. Hypoxia-inducible factor-1 and nuclear factor-κB are thought to be the main factors involved in responses to IH and in regulating adaptations or inflammation pathways, however, further evidence is needed to demonstrate the underlying mechanisms of this process in VSMCs. Furthermore, few studies of IH have examined smooth muscle cell responses. Our previous studies demonstrated that increased interleukin (IL)-6, epidermal growth factor family ligands, and erbB2 receptor, some of which amplify inflammation and, consequently, induce CID, were induced by IH and were involved in the proliferation of VSMCs. Since IH increased IL-6 and epiregulin expression in VSMCs, the same phenomenon may also occur in other smooth muscle cells, and, consequently, may be related to the incidence or progression of several diseases. In the present review, we describe how IH can induce the excessive proliferation of VSMCs and we develop the suggestion that other CID may be related to the effects of IH on other smooth muscle cells.

show abstract

Factor Xa inhibition by rivaroxaban attenuates cardiac remodeling due to intermittent hypoxia

Cited by 27 publications

References 30 publications

Contrasting Role of Concentration in Rivaroxaban Induced Toxicity and Oxidative Stress in Isolated Kidney Mitochondria

Contrasting Role of Concentration in Rivaroxaban Induced Toxicity and Oxidative Stress in Isolated Kidney Mitochondria

Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity

Proliferative Pathways of Vascular Smooth Muscle Cells in Response to Intermittent Hypoxia

Contact Info

Product

Resources

About