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Pleiotropic Effects of the Protease-Activated Receptor 1 (PAR1) Inhibitor, Vorapaxar, on Atherosclerosis and Vascular Inflammation.

ABSTRACT: 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. 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. PAR1 inhibition with vorapaxar may be effective in reducing residual thrombo-inflammatory event risk in patients with atherosclerosis independent of its effect on platelets.

SUBMITTER: Friebel J

PROVIDER: S-EPMC8700178 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Pleiotropic Effects of the Protease-Activated Receptor 1 (PAR1) Inhibitor, Vorapaxar, on Atherosclerosis and Vascular Inflammation.

Friebel Julian J Moritz Eileen E Witkowski Marco M Jakobs Kai K Strässler Elisabeth E Dörner Andrea A Steffens Daniel D Puccini Marianna M Lammel Stella S Glauben Rainer R Nowak Franziska F Kränkel Nicolle N Haghikia Arash A Moos Verena V Schutheiss Heinz-Peter HP Felix Stephan B SB Landmesser Ulf U Rauch Bernhard H BH Rauch Ursula U

Cells 20211213 12

<h4>Background</h4>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.<h4>Methods and results</h4>Cellular targets of PAR1 signaling in the vasculature were identified in three ...[more]

PMID: 34944024

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Project description:Background: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Many types of senescing cells upregulate the THBD-PAR-1 signaling axis to remain viable. Vorapaxar, an FDA-approved PAR-1 inhibitor, blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH. Methods: We evaluated the THBD-PAR1 pathway in liver biopsies from NAFLD patient cohorts with a spectrum of liver fibrosis. Chow fed mice were treated with viral vectors to over-express p16 specifically in hepatocytes and induce replicative senescence. Effects on the THBD-PAR-1 axis and regenerative capacity were assessed; the transcriptome of p16 over-expressing hepatocytes was characterized and we examined how conditioned medium from senescent but viable (dubbed ‘undead’) hepatocytes reprograms hepatic stellate cells. A genetically obese mouse model of NASH with little liver fibrosis, and a diet-induced mouse model of NASH with advanced fibrosis were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Results: Inducing senescence up-regulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR-1 signaling with vorapaxar interrupts this process, reduces the burden of ‘undead’ senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress Conclusion: The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair.

Dataset Information

Pleiotropic Effects of the Protease-Activated Receptor 1 (PAR1) Inhibitor, Vorapaxar, on Atherosclerosis and Vascular Inflammation.

Publications

Pleiotropic Effects of the Protease-Activated Receptor 1 (PAR1) Inhibitor, Vorapaxar, on Atherosclerosis and Vascular Inflammation.

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