Activated protein C induces the release of microparticle-associated endothelial protein C receptor

Pérez-Casal, Margarita; Downey, Colin; Fukudome, Kenji; Marx, Gernot; Toh, Cheng Hock

doi:10.1182/blood-2004-05-1896

Cited by 132 publications

(116 citation statements)

References 32 publications

(43 reference statements)

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“…Our finding that gene induction in response to APC injection in pulmonary tissues is significantly diminished in PAR1-deficient mice supports the notion that PAR1 is the major receptor for APC signaling in both humans and mice. This conclusion is consistent with several studies demonstrating that PAR1 but not PAR2 mediates anti-apoptotic signaling (4), calcium flux (28), and microparticle release (29) by APC-EPCR in vitro and the protective effects of APC in mouse models (5,6). A recent study implicates both PAR1 and PAR3 in EPCR-dependent APC signaling in mouse neuronal cells (6).…”

Section: Discussionsupporting

confidence: 78%

Protease-activated Receptor-1 Signaling by Activated Protein C in Cytokine-perturbed Endothelial Cells Is Distinct from Thrombin Signaling

Riewald

Ruf

2005

Journal of Biological Chemistry

185

173

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Activated protein C (APC) has anti-inflammatory and vascular protective effects independent of anticoagulation. We previously identified the prototypical thrombin receptor, protease-activated receptor-1 (PAR1), as part of a novel APC-endothelial cell protein C receptor (EPCR) signaling pathway in endothelial cells. Experiments in wild-type and PAR1؊/؊ mice demonstrated that intravenous injection of APC leads to PAR1-dependent gene induction in the lung. The vascular endothelium undergoes profound changes in severe sepsis, the approved therapeutic indication for APC. Similar to PAR1, APC activated PAR2 through canonical cleavage. Although PAR2 was up-regulated in cytokine-stimulated endothelial cells, APC signaling remained PAR1-dependent. Large scale gene expression profiling documented marked differences in both up-and down-regulated genes between APC and thrombin signaling in cytokine-stimulated cells. APC down-regulated transcripts for proapoptotic proteins including p53 and thrombospondin-1, but p53 was unchanged, and thrombospondin was even upregulated by thrombin. Concordant PAR1-dependent effects on protein levels were found. Thus, by signaling through the same receptor PAR1, APC, and thrombin can exert distinct biological effects in perturbed endothelium. These data may explain how APC can be therapeutically protective through the EPCR-PAR1 signaling despite ongoing thrombin generation due to disseminated intravascular coagulopathy.

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Section: Discussionsupporting

confidence: 78%

Protease-activated Receptor-1 Signaling by Activated Protein C in Cytokine-perturbed Endothelial Cells Is Distinct from Thrombin Signaling

Riewald

Ruf

2005

Journal of Biological Chemistry

185

173

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“…Both the active site of APC and protease activated receptor-1 (PAR-1) were found to be necessary to induce microparticle formation. 16 The reported evidence support the concept that shed EMP do not display a univocal prothrombotic potential, anticoagulant properties counteracting the thrombotic propensity when EMP release is induced by APC stimulation (see below).…”

Section: Anticoagulant Potential Of Microparticlessupporting

confidence: 61%

“…30 Interestingly, APC was also demonstrated to be able to generate anticoagulant endothelial or monocyte-derived microparticles that harbor EPCR (see above). 16 In this issue of the journal, Pérez-Casal et al provide evidence that part of the cytoprotective effects of APC are mediated by microparticles harboring EPCR, therefore able to bind APC, termed APC + -microparticles. 3 A variety of cytoprotective properties of APC, namely: (i) alteration of genes profiles, (ii) modulation of cytokine or cytoadhesin transcription levels, (iii) anti-apoptotic activity, and (iv) endothelial barrier stabilization, could be mimicked in vitro by APC + -microparticles.…”

mentioning

confidence: 99%

Microparticles in endothelial cell and vascular homeostasis: are they really noxious?

Morel¹,

Toti²,

Morel³

et al. 2009

Haematologica

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“…Actually, some groups revealed anticoagulant and protective effects of some MP subsets [50][51][52], in contrast with the procoagulant and deleterious results reported by others [10,27,45,48,53]. Interestingly, these diverse effects could be attributed to the exposure of different mediators, such as activated protein C, tissue factor or von Willebrand factor among MP subsets.…”

Section: Discussionmentioning

confidence: 73%

Altered profile of circulating microparticles in rheumatoid arthritis patients

et al. 2014

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Microparticles (MPs) could be considered biomarkers of cell damage and activation as well as novel signalling structures. Since rheumatoid arthritis (RA) is characterized by immune and endothelial activation, the main aim of the present study was to analyse MP counts in RA patients. Citrated-blood samples were obtained from 114 RA patients, 33 healthy controls (HC) and 72 individuals with marked cardiovascular (CV) risk without autoimmune manifestations (CVR). MPs were analysed in platelet-poor plasma (PPP) and different subsets were identified by their surface markers: platelet-(CD41 + ), endothelial-(CD146 + ), granulocyte-(CD66 + ), monocyte-(CD14 + ) and Tang-derived (CD3 + CD31 + ). Disease activity (DAS28), clinical and immunological parameters as well as traditional CV risk factors (diabetes, hypertension, dyslipidemia and obesity) were registered from clinical records and all data were integrated using Principal Component Analysis (PCA). Absolute MP number was increased in RA patients compared with HC and positively correlated with traditional CV risk factors, similar to that of CVR subjects. In addition, frequency of the different MP subsets was different in RA patients and significantly associated to disease features. Moreover, in vitro assays revealed that MPs isolated from RA patients were able to promote endothelial activation and exhibited detrimental effects on HMEC-I endothelial cell functionality. Circulating MPs from RA Q1 patients displayed quantitative and qualitative alterations that are the result of both disease-specific and traditional CV risk factors. Accordingly, this MP pool exhibited in vitro detrimental effects on endothelial cells, thus supporting their role as biomarkers of vascular damage.

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Activated protein C induces the release of microparticle-associated endothelial protein C receptor

Cited by 132 publications

References 32 publications

Protease-activated Receptor-1 Signaling by Activated Protein C in Cytokine-perturbed Endothelial Cells Is Distinct from Thrombin Signaling

Protease-activated Receptor-1 Signaling by Activated Protein C in Cytokine-perturbed Endothelial Cells Is Distinct from Thrombin Signaling

Microparticles in endothelial cell and vascular homeostasis: are they really noxious?

Altered profile of circulating microparticles in rheumatoid arthritis patients

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