Abstract
Background: Protease-activated receptor 1 (PAR1) and toll-like receptors (TLRs) are inflammatory mediators contributing to atherogenesis and atherothrombosis. Vorapaxar, which selectively antagonizes PAR1-signaling, is an approved, add-on antiplatelet therapy for secondary prevention. The non-hemostatic, platelet-independent, pleiotropic effects of vorapaxar have not yet been studied. Methods and Results: Cellular targets of PAR1 signaling in the vasculature were identified in three patient cohorts with atherosclerotic disease. Evaluation of plasma biomarkers (n = 190) and gene expression in endomyocardial biopsies (EMBs) (n = 12) revealed that PAR1 expression correlated with endothelial activation and vascular inflammation. PAR1 colocalized with TLR2/4 in human carotid plaques and was associated with TLR2/4 gene transcription in EMBs. In addition, vorapaxar reduced atherosclerotic lesion size in apolipoprotein E–knock out (ApoEko) mice. This reduction was associated with reduced expression of vascular adhesion molecules and TLR2/4 presence, both in isolated murine endothelial cells and the aorta. Thrombin-induced uptake of oxLDL was augmented by additional TLR2/4 stimulation and abrogated by vorapaxar. Plaque-infiltrating pro-inflammatory cells were reduced in vorapaxar-treated ApoEko mice. A shift toward M2 macrophages paralleled a decreased transcription of pro-inflammatory cytokines and chemokines. Conclusions: PAR1 inhibition with vorapaxar may be effective in reducing residual thrombo-inflammatory event risk in patients with atherosclerosis independent of its effect on platelets.
Highlights
Thrombo-inflammation in atherosclerosis has been described as a complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases (CVDs)
The direct cellular downstream targets of the tissue factor (TF)/FXa/FIIa/Protease-activated receptor 1 (PAR1) axis, which go beyond hemostatic effects, have been identified only in preclinical studies
peripheral blood mononuclear cells (PBMCs) were used as an indicator for augmented signaling through the TF/FXa/FIIa-PAR1 axis [22]
Summary
Thrombo-inflammation in atherosclerosis has been described as a complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases (CVDs). Thrombo-inflammation is associated with residual cardiovascular risk [1,2,3,4,5]. Protease-activated receptors are considered nonclassical “pattern-recognition receptors” [12]. PAR signaling is linked to innate immunity via cooperation with toll-like receptors (TLRs) [12]. Protease-activated receptor 1 is the thrombin receptor expressed on platelets, but it is expressed in endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and immune cells [13,14,15,16]. PAR1 signaling is central in mediating thrombo-inflammation. Protease-activated receptor 1 (PAR1) and toll-like receptors (TLRs) are inflammatory mediators contributing to atherogenesis and atherothrombosis. Vorapaxar, which selectively antagonizes PAR1-signaling, is an approved, add-on antiplatelet therapy for secondary prevention.
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