PAR2 (Protease-Activated Receptor 2) Deficiency Attenuates Atherosclerosis in Mice

Jones, Shannon; Mann, Adrien; Conrad, Kelsey; Saum, Keith; Hall, David; McKinney, Lisa M.; Robbins, Nathan; Thompson, Joel C.; Peairs, Abigail; Camerer, Eric; Rayner, Katey J.; Tranter, Michael; Mackman, Nigel; Owens, A. Phillip

doi:10.1161/atvbaha.117.310082

Cited by 49 publications

(50 citation statements)

References 64 publications

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“…Novel preclinical data were reported by Owens and colleagues showing that PAR‐2 is a relevant mediator of proatherogenic effects; PAR‐2 deficient mice had smaller aortic plaques, possibly due to combined effects on cholesterol efflux from macrophages and attenuation of VSMC activity . While coagulation proteases like factors VIIa and Xa may be important ligands in PAR‐2 mediated effects, in the context of atherosclerosis this link needs further exploration.…”

Section: Isth Berlin Reportmentioning

confidence: 99%

“…PAR-2 deficient mice had smaller aortic plaques, possibly due to combined effects on cholesterol efflux from macrophages and attenuation of VSMC activity. 90 91 Posthuma and colleagues showed that rivaroxaban not only inhibited atherogenesis but even diminished existing lesions, the mechanisms of which need further study. 92 Data on hemostasis biomarkers of cardiovascular disease were reported by Komarov et al, showing that addition of D-dimer to wellknown scoring systems in patients after elective PCI could improve the diagnostic capacity to predict MACE in these patients.…”

Section: Isth Berlin Reportmentioning

confidence: 99%

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The coagulation system in atherothrombosis: Implications for new therapeutic strategies

Olie

Meijden

Cate

2018

Research and Practice in Thrombosis and Haemostasis

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Essentials A State of the Art lecture “Clotting factors and atherothrombosis” was presented at the ISTH congress 2017.Coagulation proteins are not only involved in hemostasis, they also play a role in atherogenesis.Inhibition of coagulation proteins could potentially protect the vessel wall against progression of atherosclerosis.Combining antiplatelet and anticoagulant therapy has been demonstrated to improve cardiovascular outcomes in patients with stable atherosclerotic disease. Clinical manifestations of atherosclerotic disease include coronary artery disease (CAD), peripheral artery disease (PAD), and stroke. Although the role of platelets is well established, evidence is now accumulating on the contribution of coagulation proteins to the processes of atherosclerosis and atherothrombosis. Coagulation proteins not only play a role in fibrin formation and platelet activation, but also mediate various biological and pathophysiologic processes through activation of protease‐activated‐receptors (PARs). Thus far, secondary prevention in patients with CAD/PAD has been the domain of antiplatelet therapy, however, residual atherothrombotic risks remain substantial. Therefore, combining antiplatelet and anticoagulant therapy has gained more attention. Recently, net clinical benefit of combining aspirin with low‐dose rivaroxaban in patients with stable atherosclerotic disease has been demonstrated. In this review, based on the State of the Art lecture “Clotting factors and atherothrombosis” presented at the ISTH Congress 2017, we highlight the role of coagulation proteins in the pathophysiology of atherothrombosis, and specifically focus on therapeutic strategies to decrease atherothrombotic events by optimization of vascular protection.

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Section: Isth Berlin Reportmentioning

confidence: 99%

Section: Isth Berlin Reportmentioning

confidence: 99%

The coagulation system in atherothrombosis: Implications for new therapeutic strategies

Olie

Meijden

Cate

2018

Research and Practice in Thrombosis and Haemostasis

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“…The data from Stine B Thomsen et al suggested that, in patients with ischemic heart disease, increased plasma MGP levels are indicative of a progressing calcification process [27]. Moreover, protease-activated receptor 2 (PAR2) in microvascular endothelial cells is indispensable for vascular stability, and its deficiency attenuates atherosclerosis [28,29] On the other hand, a Venn diagram allowed identifying 106 genes negatively co-expressed with NPPB.…”

Section: Discussionmentioning

confidence: 99%

Potential molecular mechanism of the NPPB gene in post-ischemic heart failure with and without T2DM

Guan

Yin

Deng

et al. 2020

Preprint

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Background This study aimed to investigate natriuretic peptide B ( NPPB ) co-expression genes and the pathways involved in post-ischemic heart failure (HF) among patients both with and without type 2 diabetes mellitus (T2DM). Methods The microarray dataset of GSE26887 was examined to detect the genes that co-expressed with NPPB from 19 post-ischemic HF patients’ peripheral blood samples (7 with T2DM and 12 without T2DM). NPPB co-expression genes were then screened using the R packet. Further, using online analytical tools, we determined the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, Gene Ontology (GO) annotation, and protein-protein interaction (PPI) network of the co-expression genes. The modules and hub genes of the PPI network were then identified using the Cytoscape software. Results In patients with T2DM, a total of 41 biological processes (BP), 20 cellular components (CC), 13 molecular functions (MF), and 41 pathways were identified. Further, a total of 61 BPs, 16 CCs, 13 MFs, and 22 pathways in patients without T2DM were identified. In both groups of patients, 17 BPs, 10 CCs, 6 MFs, and 13 pathways were enriched. We also identified 173 intersectional co-expression genes (63 positive, 106 negative, and 4 differently co-expressed in patients with and without T2DM, respectively) in both types of patients, which enriched in 16 BPs, 8 CCs, 3 MFs, and 8 KEGG pathways. Moreover, the PPI network (contained 237 edges and 170 nodes) with the top module significantly enriched in 4 BPs (the tricarboxylic acid metabolic process, citrate metabolic process, tricarboxylic acid cycle, and aerobic respiration) and 3 pathways (the citrate cycle, malaria parasite metabolic pathway, and AGE-RAGE signaling pathway in diabetic complications) was constructed. Conclusions This study used genome-wide co-expression genes to identify the potential functions and mechanisms of the NPPB gene in post-ischemic HF with and without T2DM. Our findings may elucidate the functions and roles of NPPB in patients with post-ischemic HF and facilitate HF management.

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“…Previously, PAR2 has been linked to inflammation-driven diseases of the brain, cardiovascular system, lungs, joints, and gastrointestinal tract [8][9][10][11][12][13][14][15][16], as well as cancer growth [17,18], migration, and metastasis [9,19]. Despite its importance in pathophysiological processes, no treatments based on interference with PAR2 have been established [20].…”

Section: Introductionmentioning

confidence: 99%

Thrombin cleaves and activates the protease-activated receptor 2 dependent on thrombomodulin co-receptor availability

Heuberger

Franchini

Madon

et al. 2019

Thrombosis Research

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Introduction: Protease-activated receptors (PARs) evolved to react to extracellular proteolytic activity. In mammals, three of the four PARs (PAR1, PAR3, and PAR4) that are expressed respond to the prototypical procoagulant enzyme thrombin, whereas PAR2 was assumed to resist activation by thrombin. To date, involvement of cell surface thrombin-recruiting co-receptors such as thrombomodulin (TM), which potentially facilitates PAR2 cleavage, has not been addressed. Thus, we examined whether TM-bound thrombin cleaved PAR2 and tested biological responses such as nuclear factor kappa B (NF-κB) DNA binding activity and cytokine release. Materials and methods: We examined 293T cells overexpressing PAR2 and TM for thrombin recruitment by TM promoting PAR2 cleavage. To test for the TM-thrombin interactions required for PAR2 cleavage and to map cleavage sites on PAR2, mutant constructs of TM or PAR2 were engineered. Biological effects because of PAR2 activation were investigated using an NF-κB reporter system and cytokine release. Results and conclusions: We identified that, at low to moderate concentrations, thrombin cleaved PAR2 in a TM co-receptor-dependent manner with cleavage efficiency comparable to that of trypsin. In TM's presence, thrombin efficiently cleaved both, PAR1 and PAR2, albeit kinetics differed. Whereas the majority of surface expressed PAR1 was immediately cleaved off, prolonged exposure to thrombin resulted in few additional cleavage. In contrast, PAR2 cleavage was sustained upon prolonged exposure to thrombin. However, TM EGFlike domain 5 was required and TM chondroitin sulfate (CS) proteoglycan sites serine 490 and serine 492 assisted in PAR2 cleavage, while thrombin preferentially cleaved at arginine 36 on PAR2's N-terminus. Note that thrombin-induced activation of NF-κB via PAR2 resulted in release of interleukin-8. Thus, we provide a novel concept of how thrombin efficiently cleaves PAR2 in a TM-dependent manner, resulting in pro-inflammatory interleukin-8 release. This unexpected pro-inflammatory role of TM, promoting cleavage and activation of PAR2 by thrombin, may lead to novel therapeutic options for treating inflammatory and malignant diseases.

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PAR2 (Protease-Activated Receptor 2) Deficiency Attenuates Atherosclerosis in Mice

Abstract: Our results indicate that PAR2 deficiency is associated with attenuation of atherosclerosis and may reduce lesion progression by blunting - and-induced monocyte infiltration.

Cited by 49 publications

References 64 publications

The coagulation system in atherothrombosis: Implications for new therapeutic strategies

The coagulation system in atherothrombosis: Implications for new therapeutic strategies

Potential molecular mechanism of the NPPB gene in post-ischemic heart failure with and without T2DM

Thrombin cleaves and activates the protease-activated receptor 2 dependent on thrombomodulin co-receptor availability

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