Abstract Number: OC 01.3
Meeting: ISTH 2020 Congress
Background: Atherosclerosis is a progressive inflammatory vascular disorder, complicated by plaque rupture causing atherothrombosis. Animal studies indicate that thrombin and factor Xa (FXa) promote atherosclerosis through activation of protease activated receptors. We showed that inhibition of FXa by rivaroxaban not only reduced atherogenesis, but also promoted regression of plaques in ApoE-/- mice.
Aims: By analyzing aortic bulk RNAseq data from ApoE-/- mice, we aim to find genes that could explain the beneficial effects of FXa inhibition on atherosclerosis.
Methods: Female ApoE-/- mice (age 8-9 weeks) on western type diet (WTD) or WTD+1.2mg/g rivaroxaban for 14 weeks. In a second arm, mice on WTD for 14 weeks, followed by WTD±1.2mg/g rivaroxaban for 6 weeks (total 20 weeks). For the purpose of this abstract we will focus only on the 14weeks group. RNA was isolated from aortic arches, sequenced with Illumina (30 mil. reads per sample n=6 per group), aligned to the transcriptome and analyzed with DEseq2. Differentially expressed genes with p-adjusted< 0.1 were considered to be significant. For gene enrichment analysis differentially expressed genes with ≥ 1.0-fold (log2 scale) and padj < 0.25 were used.
Results: 190 of 19704 genes were significantly differentially expressed: 90 were down- and 100 upregulated in the rivaroxaban-treated group. Top downregulated genes included Adamts1, Ighg2b and Hspa1a, whereas top upregulated genes included ADTRP, Ptgds, and Angptl8. Top enriched pathways included KEGG pathways of complement and coagulation (table 1 and Fig 1). Most enriched reactome pathways included those that are involved in IGF transport and uptake, regulation of TLR by endogenous ligand and platelet degranulation (table 1).
Conclusions: Direct inhibition of FXa by rivaroxaban attenuated atherosclerosis. RNA-seq and enrichment analysis showed that inhibition of FXa has a significant effect on gene expression. Modulation of multiple biological pathways related to atherosclerosis highlight the multi-faceted role of coagulation Factor Xa.
|KEGG Pathways Term Description||Observed Gene Count||Background Gene Count||P Value||Matching Proteins in Network|
|Complement and coagulation cascade||3||88||0.0204||Fga, Kng1, SerpinF2|
|Reactome Pathways Term Description||Observed Gene Count||Background Gene Count||P Value||Matching Proteins in Network|
|Regulation of insulin-like growth factor (IGF) transport and uptake by IGF binding protein||4||129||0.0045||Apob, Chgb, Fga, Kng1|
|Post-translational protein phosphorylation||4||114||0.0045||Apob, Chgb, Fga, Kng1|
|Regulation of TLR by endogenous ligand||2||13||0.0094||Apob, Fga|
|Platelet degranulation||3||121||0.0292||Fga, Kng1, Serpinf2|
|Formation of Fibrin Clot (clotting cascade)||2||34||0.0292||Fga, Kng1|
|G alpha (i) signaling events||4||338||0.0356||Apob, Ccr4, Kng1, Rgs9bp|
[Table 1. Enrichment Analysis ]
To cite this abstract in AMA style:Posma JJ, Van Oerle R, Cleuren AC, Van der Ent MA, Isaacs A, Stoll M, Ten Cate H, Spronk HM. Unraveling the Protective Effects of Factor Xa Inhibition by Rivaroxaban on Atherosclerosis by RNA Sequencing [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/unraveling-the-protective-effects-of-factor-xa-inhibition-by-rivaroxaban-on-atherosclerosis-by-rna-sequencing/. Accessed September 25, 2021.
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