Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury

Sevastos, Jacob; Kennedy, Seán; Davis, Darren R.; Sam, Melissa; Peake, Philip W.; Charlesworth, J. A.; Mackman, Nigel; Erlich, Jonathan

doi:10.1182/blood-2006-03-008870

Cited by 86 publications

(77 citation statements)

References 39 publications

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“…33 Considering the established role of TM in modulating thrombin and aPC activity and previous data, which established a detrimental role of thrombin and PAR1 in renal IRI, we conclude that TM provides a functional switch between thrombin-and aPC-dependent signaling in the context of renal IRI (and current data). 5,10 Of note, soluble recombinant TM, but not the direct thrombin inhibitor argatroban, likewise protect kidneys from IRI, 12 supporting the notion that a TMmediated switch from thrombin-to aPCdependent signaling is required, whereas inhibition of thrombin is not sufficient for nephroprotection in renal IRI. The efficacy of soluble TM in renal IRI suggests that the nephroprotective pathway identified within this study may be amendable to therapeutic interventions not only by aPC, but also by soluble TM.…”

Section: Discussionmentioning

confidence: 80%

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Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination

Wang¹,

Wang

Shahzad

et al. 2015

Journal of the American Society of Nephrology

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Ischemia-reperfusion injury (IRI) is the leading cause of ARF. A pathophysiologic role of the coagulation system in renal IRI has been established, but the functional relevance of thrombomodulin (TM)-dependent activated protein C (aPC) generation and the intracellular targets of aPC remain undefined. Here, we investigated the role of TM-dependent aPC generation and therapeutic aPC application in a murine renal IRI model and in an in vitro hypoxia and reoxygenation (HR) model using proximal tubular cells. In renal IRI, endogenous aPC levels were reduced. Genetic or therapeutic reconstitution of aPC efficiently ameliorated renal IRI independently of its anticoagulant properties. In tubular cells, cytoprotective aPC signaling was mediated through protease activated receptor-1-and endothelial protein C receptor-dependent regulation of the cold-shock protein Y-box binding protein-1 (YB-1). The mature 50 kD form of YB-1 was required for the nephro-and cytoprotective effects of aPC in vivo and in vitro, respectively. Reduction of mature YB-1 and K48-linked ubiquitination of YB-1 was prevented by aPC after renal IRI or tubular HR injury. aPC preserved the interaction of YB-1 with the deubiquitinating enzyme otubain-1 and maintained expression of otubain-1, which was required to reduce K48-linked YB-1 ubiquitination and to stabilize the 50 kD form of YB-1 after renal IRI and tubular HR injury. These data link the cyto-and nephroprotective effects of aPC with the ubiquitin-proteasome system and identify YB-1 as a novel intracellular target of aPC. These insights may provide new impetus for translational efforts aiming to restrict renal IRI.

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Section: Discussionmentioning

confidence: 80%

“…5 Unlike thrombin, the anticoagulant serine protease activated protein C (aPC) is nephroprotective, ameliorating chronic 6,7 and acute 8,9 renal injury. The opposing effects of thrombin and aPC are largely controlled by thrombomodulin (TM).…”

mentioning

confidence: 99%

Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination

Wang¹,

Wang

Shahzad

et al. 2015

Journal of the American Society of Nephrology

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“…I/R causes thrombosis and inflammation (32)(33)(34)(35)(36)(37)(38). We detected reduced expression of TM and a concomitant increase in the deposition of fibrin in lungs after I/R ( Figure 3A).…”

Section: Anticoagulant and Antiinflammatory Effects Of Scfv/tm In Lunmentioning

confidence: 85%

Anchoring Fusion Thrombomodulin to the Endothelial Lumen Protects against Injury-induced Lung Thrombosis and Inflammation

Ding¹,

Hong²,

Christofidou‐Solomidou³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Endothelial thrombomodulin (TM) regulates thrombosis and inflammation. Diverse forms of pulmonary and vascular injury are accompanied by down-regulation of TM, which aggravates tissue injury. We postulated that anchoring TM to the endothelial surface would restore its protective functions. Objectives: To design an effective and safe strategy to treat pulmonary thrombotic and inflammatory injury. Methods: We synthesized a fusion protein, designated scFv/TM, by linking the extracellular domain of mouse TM to a single-chain variable fragment of an antibody to platelet endothelial cell adhesion molecule-1 (PECAM-1). The targeting and protective functions of scFv/TM were tested in mouse models of lung ischemia-reperfusion and acute lung injury (ALI) caused by intratracheal endotoxin and hyperoxia, both of which caused approximately 50% reduction in the endogenous expression of TM. Measurements and Main Results: Biochemical assays showed that scFv/ TM accelerated protein C activation by thrombin and bound mouse PECAM-1 and cytokine high mobility group-B1. After intravenous injection, scFv/TM preferentially accumulated in the mouse pulmonary vasculature. In a lung model of ischemia-reperfusion injury, scFv/TM attenuated elevation of early growth response-1, inhibited pulmonary deposition of fibrin and leukocyte infiltration, and preserved blood oxygenation more effectively than soluble TM. In an ALI model, scFv/TM, but not soluble TM, suppressed activation of nuclear factor-kB, inflammation and edema in the lung and reduced mortality without causing hemorrhage. Conclusions: Targeting TM to the endothelium using an scFv anchor enhances its antithrombotic and antiinflammatory effectiveness in models of ALI.

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“…Although PAR1 mRNA has been detected in rat cardiomyocyte cell cultures [23], neither the mRNA nor the protein has been shown to be present in the rat heart. Since mRNA expression does not always correlate with protein production and because culturing cells in vitro may change gene expression patterns, we extended these findings and show that both PAR1 mRNA and protein are found in intact rat hearts.…”

Section: Discussionmentioning

confidence: 99%

“…PAR1 was originally detected in platelets where its activation causes platelet activation and aggregation [26]. In addition, PAR1 has been shown to be expressed in endothelial cells, vascular smooth muscle cells, and cardiomyocytes [10,17,23]. PARs modulate a variety of physiological processes depending on which PAR is expressed, which cell type it is acting on, and which serine protease activates it.…”

Section: Introductionmentioning

confidence: 99%

SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts

Strande

Hsu

et al. 2007

Basic Res Cardiol

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Myocardial ischemia/reperfusion (I/R) injury is partly mediated by thrombin. In support, the functional inhibition of thrombin has been shown to decrease infarct size after I/R. Several cellular responses to thrombin are mediated by a G-protein coupled protease-activated receptor 1 (PAR1). However, the role of PAR1 in myocardial I/R injury has not been well characterized. Therefore, we hypothesized that PAR1 inhibition will reduce the amount of myocardial I/R injury. After we detected the presence of PAR1 mRNA and protein in the rat heart by RT-PCR and immunoblot analysis, we assessed the potential protective role of SCH 79797, a selective PAR1 antagonist, in two rat models of myocardial I/R injury. SCH 79797 treatment immediately before or during ischemia reduced myocardial necrosis following I/R in the intact rat heart. This response was dose-dependent with the optimal dose being 25 μg/kg IV. Likewise, SCH 79797 treatment before ischemia in the isolated heart model reduced infarct size and increased ventricular recovery following I/R in the isolated heart model with an optimal concentration of 1 μM. This reduction was abolished by a PAR1 selective agonist. SCH 79797-induced resistance to myocardial ischemia was abolished by wortmannin, an inhibitor of PI3 kinase; L-NMA, a NOS inhibitor; and glibenclamide, a nonselective K ATP channel blocker. PAR1 activating peptide, wortmannin, L-NMA and glibenclamide alone had no effect on functional recovery or infarct size. A single treatment of SCH 79797 administered prior to or during ischemia confers immediate cardioprotection suggesting a potential therapeutic role of PAR1 antagonist in the treatment of injury resulting from myocardial ischemia and reperfusion.

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Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury

Cited by 86 publications

References 39 publications

Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination

Activated Protein C Ameliorates Renal Ischemia-Reperfusion Injury by Restricting Y-Box Binding Protein-1 Ubiquitination

Anchoring Fusion Thrombomodulin to the Endothelial Lumen Protects against Injury-induced Lung Thrombosis and Inflammation

SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts

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