FXa inhibition by Rivaroxaban modifies mechanisms associated with the pathogenesis of human abdominal aortic aneurysms.

Abstract

Aim

To evaluate if Rivaroxaban, an oral factor Xa (FXa) inhibitor, could in vitro modify the expression of inflammatory and oxidative stress biomarkers in abdominal aortic aneurysmal (AAA) sites showing intraluminal thrombus.

Methods

AAA sites with intraluminal mural thrombus were obtained from six patients undergoing elective AAA repair. In addition, control abdominal aortic samples were obtained from six organ donors. AAA sites were incubated in the presence and absence of 50 nmol/L Rivaroxaban.

Results

AAA sites showing thrombus demonstrated higher content of FXa than control. Interleukin-6 (IL-6) levels released from AAA (IL-6: Control: medians: 23.45 (25^th:16.17-75^th:37.15) vs AAA: median: 153.07 (25^th:100.80-75^th:210.69) pg/ml/mg tissue. P<0.05) and the expression levels of nitric oxide synthase 2 (NOS2) were significantly higher in AAA than in control. The protein expression level of NADPH oxidase subunits gp67-and gp91-phox, but did not gp47-phox, were also significantly higher in the AAA sites than in control. Addition of Rivaroxaban to AAA sites explants significantly reduced the release of IL-6 (medians: 51.61 (25^th:30.87-75^th:74.03) pg/ml/mg tissue P<0.05 with respect to AAA alone) and the content of NOS2, gp67 and gp91-phox NADPH subunits. The content of matrix metallopeptidase 9 (MMP9) was significantly higher in the AAA sites as compare to control. Rivaroxaban also reduced MMP9 content in AAA sites to similar levels to control.

Conclusions

FXa inhibition by Rivaroxaban exerted anti-inflammatory and anti-oxidative stress properties in human AAA sites, suggesting a role of FXa in these mechanisms associated with the pathogenesis of AAA.

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