Unraveling the Protective Effects of Factor Xa Inhibition by Rivaroxaban on Atherosclerosis by RNA Sequencing

Atherosclerosis is a leading cause of vascular disease worldwide. Its major clinical manifestations include ischemic heart disease, ischemic stroke, and peripheral arterial disease. In high-income countries, there have been dramatic declines in the incidence and mortality from ischemic heart disease and ischemic stroke since the middle of the 20th century. Many modifiable risk factors for atherosclerosis have been identified, and the causal relevance of several risk factors is now well established (including but not limited to smoking, adiposity, blood pressure, blood cholesterol, and diabetes mellitus). One potential complication of atherosclerosis is atherothrombosis, which is an atherosclerotic plaque disruption with superimposed thrombosis. Animal studies suggest that thrombin and factor Xa (FXa) promote atherosclerosis through activation of protease-activated receptors. Jens Posma of the Maastricht University of the Netherlands and others sought to find genes that could explain the beneficial effects of FXa inhibition on atherosclerosis via analyzing aortic bulk RNA sequence data from ApoE^−/− mice. The ApoE^−/− mouse model is established for the study of human atherosclerosis due to poor lipoprotein clearance promoting the development of atherosclerotic plaques.

During Sunday’s ISTH 2020 Virtual Congress, Posma and team presented research on mice who were administered rivaroxaban and had their RNA isolated from aortic arches.  Animals were sequenced with Illumina (30 million reads per sample, n = 6 per group), aligned to the transcriptome, and analyzed with DEseq2. What was discovered was that, of the 19,704 genes examined, 200 were differentially expressed; 90 were top downregulated (such as Adamts1, Ighg2b, and Hspa1a) and 100 top upregulated (such as ADTRP, Ptgds, and Angptl8). Gene ontology enrichment analysis revealed that lipid-related metabolic processes were highly enriched in our dataset. Posma concluded that 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 highlights the multifaceted role of coagulation FXa.

Read the full abstract here.