Abstract
Atherosclerosis is a progressive inflammatory vascular disorder, complicated by plaque rupture and subsequently atherothrombosis. In vitro studies indicate that key clotting proteases, such as factor Xa (FXa), can promote atherosclerosis, presumably mediated through protease activated receptors (PARs). Although experimental studies showed reduced onset of atherosclerosis upon FXa inhibition, the effect on pre-existing plaques has never been studied. Therefore, we investigated effects of FXa inhibition by rivaroxaban on both newly-formed and pre-existing atherosclerotic plaques in apolipoprotein-e deficient (ApoE−/−) mice. Female ApoE−/− mice (age: 8–9 weeks, n = 10/group) received western type diet (WTD) or WTD supplemented with rivaroxaban (1.2 mg/g) for 14 weeks. In a second arm, mice received a WTD for 14 weeks, followed by continuation with either WTD or WTD supplemented with rivaroxaban (1.2 mg/g) for 6 weeks (total 20 weeks). Atherosclerotic burden in aortic arch was assessed by haematoxilin & eosin immunohistochemistry (IHC); plaque vulnerability was examined by IHC against macrophages, collagen, vascular smooth muscle cells (VSMC) and matrix metalloproteinases (MMPs). In addition, PAR1 and -2 expressions and their main activators thrombin and FXa in the plaque were determined in the plaque. Administration of rivaroxaban at human therapeutic concentrations reduced the onset of atherosclerosis (−46%, p < 0.05), and promoted a regression of pre-existing plaques in the carotids (−24%, p < 0.001). In addition, the vulnerability of pre-existing plaques was reduced by FXa inhibition as reflected by reduced macrophages (−39.03%, p < 0.05), enhanced collagen deposition (+38.47%, p < 0.05) and diminished necrotic core (−31.39%, p < 0.05). These findings were accompanied with elevated vascular smooth muscle cells and reduced MMPs. Furthermore, expression of PARs and their activators, thrombin and FXa was diminished after rivaroxaban treatment. Pharmacological inhibition of FXa promotes regression of advanced atherosclerotic plaques and enhances plaque stability. These data suggest that inhibition of FXa may be beneficial in prevention and regression of atherosclerosis, possibly mediated through reduced activation of PARs.
Highlights
Thrombosis, responsible for most acute coronary syndromes[2]
Treatment with rivaroxaban reduced ex vivo thrombin generation as reflected by increased lag time compared to controls (14 weeks: +56%, p < 0.0001, and 20 weeks: +60%, p < 0.001) and reduced endogenous thrombin potential (ETP) (14 weeks: −11%, p < 0.05, and 20 weeks: −9%, p < 0.05), whereas no statistically significant differences were observed in peak height (Table 1)
In this study we show that treatment with the factor Xa (FXa) inhibitor rivaroxaban decreases the onset and progression of atherosclerosis and induces regression of already developed atherosclerotic lesions in ApoE−/− mice
Summary
Thrombosis (atherothrombosis), responsible for most acute coronary syndromes[2]. Several studies showed that the plaque phenotype, a thin fibrous cap, large necrotic core, and presence of macrophages, determine atherosclerotic plaque vulnerability for rupturing and the risk of atherothrombosis[2,3,4,5]. Accumulating evidence shows that key coagulation enzymes, such as factor Xa (FXa) and thrombin, can influence a wide range of cellular actions related to cardiovascular function, such as vascular permeability, inflammation, and apoptosis. These non-haemostatic actions are predominantly mediated through activation of protease-activated receptors (PARs)[6,7,8,9]. Hara et al (2015) reduced the plaque formation, stabilized the plaque and decreased inflammation with a low dose of rivaroxaban in ApoE−/− mice They showed decreased MMP-9 expression[17]. We hypothesize that pharmacologic inhibition of FXa at human therapeutic levels of rivaroxaban reduces progression of pre-existing atherosclerotic plaques in a mouse model for atherosclerosis
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