Bidirectional Pathologic Effects of Thrombin
Received Date: Jan 30, 2018 / Accepted Date: Feb 07, 2018 / Published Date: Feb 20, 2018
Hemostasis is an essential reaction in organisms with circulatory systems. To stop bleeding as soon as possible, reactions of the coagulation system proceed rapidly and are regulated by positive feedback loops. However, coagulation can be harmful when induced at inappropriate sites, potentially resulting in local thromboembolisms in vital organs such as the heart and brain and systemic microthrombi in conditions such as disseminated intravascular coagulopathy. Increasingly, reports indicate that coagulation-related factors can cause serious diseases without obvious thromboembolism-associated ischemia, for example, atherosclerosis and Alzheimer disease. Thrombin is an essential coagulation factor that can also cause tissue injury, particular to endothelial cells. However, thrombin can also function as a tissue-protective factor depending on conditions. Endothelial protein C receptor (EPCR) and protease-activated receptors (PARs) regulate thrombin activity, but many details regarding the mechanisms remain unknown. This short review summarizes the bidirectional effects of thrombin signaling via EPCR and PAR1 and discusses points relevant to translating the tissue-protective effects of thrombin into clinical benefits.
Blood coagulation must be strictly regulated, as genetic or pharmacologic inhibition of the coagulation system can induce lifethreatening bleeding. Coagulation occurring at the wrong time or wrong location can cause perfusion disturbances that result in organ failure. For example, infarctions occurring in the heart or brain are major causes of death in developed countries. Additionally, excessive and expanded coagulation beyond physiologic control can lead to disseminated intravascular coagulopathy (DIC) with sepsis. An increasing number of reports indicate that the coagulation system dysfunction could be involved in many other diseases, including atherosclerosis, cancer, neurodegenerative diseases, and bronchial asthma [1-3]. In each of these diseases, deleterious activity of a major coagulation factor, thrombin, is thought to worsen the medical condition, independent of thromboembolism.
The coagulation process involves positive feedback reactions that are essential for rapid and sufficient hemostasis; however, these reactions can occasionally proceed in an uncontrolled manner, which has stimulated significant research and therapeutic interest . Despite continual additions to the list of approved anti-coagulation drugs, abnormal coagulation and associated diseases are still clinically important. Over the past few decades, an increasing number of studies have begun to target cellular responses to coagulation instead of the coagulation system per se. The most well-studied coagulation factor is thrombin (activated coagulation factor II), which is vitamin K dependent. After receptors for thrombin were identified on platelets and endothelial cells, researchers began to intensively examine the effects of thrombin on cells . Thrombin increases the permeability of the endothelial cell layer and induces apoptosis of endothelial cells [6-8]. These functions play an important role in wound healing in conjunction with hemostasis. Specific proteins in plasma exudate facilitate cell migration and apoptosis to promote tissue reconstruction. However, when activated inappropriately, these functions of thrombin can negatively impact the blood vessels.
Protease-activated receptors (PARs), which are members of the Gprotein- coupled receptor (GPCR) family, mediate thrombin signaling (Figure 1). PAR1 plays a particularly pivotal role in thrombin signaling. Similar to other GPCRs, PAR1 forms complexes with many different plasma membrane proteins to transmit differential signals. Endothelial cells express endothelial protein C receptor (EPCR) in the plasma membrane. EPCR serves as a receptor for activated protein C, which has anti-coagulation activity. Binding of PAR1 to EPCR in the membrane reportedly induces thrombin activities that are beneficial and protective for endothelial cells. This ‘switching’ mechanism is thus an attractive therapeutic target and has been the focus of numerous studies .
Figure 1: Membrane localization and signaling of PAR1. PAR1 is a member of seven-transmembrane GPCRs. Upon cleavage of the partial ligand block by a protease such as thrombin and aPC, the ligand becomes free to bind to its receptor and remains tethered to the receptor. PAR1 with EPCR and PAR1 activated by low concentration of thrombin mediate the cell protective signals. PAR1 activated by high concentration of thrombin is involved in cytotoxic signaling. Ligand-free PAR1 is internalized and recycled via clathrin-coated pits (CCP). Ligand-stimulated PAR1 is endocytosed via clathrin-mediated process and degraded in lysosomes. Lipid raft is essential for the cytoprotective and cytotoxic signaling via PAR1.
This short review will discuss the current state of knowledge regarding thrombin signaling via PAR1 and its regulatory mechanism. The effect of thrombin on endothelial cells is of particular focus due to the associations between thrombin and a number of serious diseases involving injury to endothelial cells, such as atherosclerosis and sepsis. Furthermore, from the perspective of therapeutic development, potential future targets in the thrombin signaling pathway are discussed. Although other PARs are involved in thrombin signaling and other ligands activate PAR1, these are not discussed here; excellent reviews of these subjects are available elsewhere, however [2,9,10]. Among cells affected by thrombin, platelets are the most well-studied to date. Nieman and Jamasbi have written excellent reviews concerning PARs in platelets [11,12].
Coagulation and its Regulation
Coagulation is a sequential reaction involving various proteases and co-factors known as coagulation factors . Coagulation begins with the binding of coagulation factor VII (VII) in the blood with tissue factor derived from injured tissue and ends with the formation of fibrin clots catalyzed by thrombin. Several vitamin K–dependent enzymes produced in the liver play key roles in coagulation: factors II (prothrombin), VII, IX, and X. These enzymes have a Gla domain that requires vitamin K for normal function. The Gla domain binds to phosphatidylserine residues on the cell surface to initiate the coagulation process. Except for prothrombin, VII, IX, and X share an EGF motif that is essential for enzymatic activity. VII, IX, and X require cofactors for maximal activity. Tissue factor, activated factor VIII (VIIIa) and activated factor V (Va) are cofactors for activated VII (VIIa), activated factor X (Xa), and activated factor IX (IXa), respectively. These cofactors amplify the activity of the coagulation factors 30,000- to 9,000,000-fold.
Amplification of responses is essential for coagulation to produce rapid and effective hemostasis. Thrombin is localized downstream in the coagulation cascade and serves as a key molecule in the positive feedback loop. When a small amount of thrombin is generated by coagulation, it forms a positive feedback loop via three reactions, the activation of XI, V, and VIII. In addition to this feedback loop, concentration of coagulation factors on the cell membrane via the Gla domain accelerates these reactions.
Coagulation is strictly regulated via an inhibitory system comprised of four primary components: 1) protein C-thrombomodulin, 2) antithrombin (AT)-heparin, 3) tissue factor pathway inhibitor (TFPI)- protein S, and 4) Protein Z-protein Z–dependent protease inhibitor (ZPI). Although thrombin is a potent coagulation factor, it plays an inhibitory role in conjunction with thrombomodulin on the endothelial cell membrane, leading to activation of the anticoagulation factor, protein C. Activated protein C (aPC) inactivates Va and VIIIa, whereas AT inactivates thrombin and Xa in conjunction with heparin. TFPI inactivates VIIa and Xa in cooperation with protein S. Finally, ZPI inactivates Va, IXa, and XIa in conjunction with protein Z.
Thrombin Signaling via PARs
Thrombin signaling is mediated by PARs, which are members of the GPCR family. The GPCRs constitute a large family of proteins that share various characteristics in terms of signal transduction. Desensitization is one of the most important functions of GPCRs, protecting cells from excessive and toxic reactions . Desensitization has been intensively studied with a prototypical GPCR, beta-2 adrenergic receptor. Desensitization involves receptor-transducer uncoupling in the short-term and down-regulation of GPCR in the long-term. Receptor-transducer uncoupling is caused by phosphorylation of the GPCR, binding of GPCR to beta-arrestin, and subsequent clathrin-dependent endocytosis. Down-regulation is caused by GPCR endocytosis and degradation and a decrease in mRNA levels.
Another important characteristic of GPCR is “biased ligand,” a term that refers to different agonists initiating differential signaling via the same GPCR via distinct mechanisms [3,15]. G-proteins consist of three subunits, each of which can be one of several types. Different Gproteins recognize their own specific effectors, resulting in a variety of possible signaling pathways via one GPCR. Additionally, signaling via phosphorylated GPCRs is mediated via beta-arrestin instead of Gproteins, although details of the signaling mechanism remain unclear . Some receptor cofactors appear to play significant roles in signal transduction, however.
To date, four PARs have been identified: PAR1-4. Each of these PARs can mediate thrombin signaling. PAR2 and PAR4 respond to high concentrations of thrombin [4,17]. The extracellular domain of the PARs has its ligand at the C-terminus and a partial ligand block at the N-terminus (Figure 1). Upon cleavage of the partial ligand block by a protease such as thrombin, the ligand becomes free to bind to its receptor and remains tethered to the receptor after binding. This mechanism enables a single thrombin molecule to activate more than one receptor.
PAR1 functions as a major thrombin receptor. Ligand binding induced by thrombin causes binding of G-protein to the receptor. Ga12/13, Gaq, and Gai bind PAR1. Signaling via Ga12/13 activates the RhoA-ROCK (rho-associated coiled coil–containing protein kinase) axis and induces stress fiber formation. In endothelial cells, activation of the RhoA-ROCK axis increases endothelial permeability and induces apoptosis. Signaling via Gaq activates phospholipase C, which increases intracellular calcium levels and stimulates PKC activity, resulting in increased secretion of cell adhesion molecules and inflammatory cytokines. Signaling via Gi suppresses adenylyl cyclase, leading to decreased levels of cAMP. In addition to signaling via Gprotein, PAR1 signaling also involves a pathway mediated by betaarrestin. Thrombin signaling via Ga12/13 and Gaq can damage tissues, as it induces hyper-permeability, apoptosis, and inflammation, whereas thrombin signaling via Gai and beta-arrestin is protective. Therapeutic targeting of PAR1 thus necessitates that its beneficial protective activity be preferentially stimulated.
Bidirectional Activities of Thrombin
The bidirectional activities of thrombin are regulated via two mechanisms. One mechanism involves interaction between EPCR and aPC on the cell membrane, whereas the other mechanism is dependent upon the concentration of thrombin (Figure 1). Interaction between EPCR and aPC in conjunction with low thrombin concentrations has a protective effect on cells. The bidirectional activities of thrombin are thought to involve biased ligands.
As mentioned above, thrombin activates protein C in the presence of thrombomodulin. aPC affects endothelial cells independent of coagulation. Like thrombin, aPC is a vitamin K–dependent serine protease that cleaves the extracellular domain of PAR1 to extricate its ligand. However, aPC cleaves a different site in PAR1 than doe’s thrombin, and this difference was thought to be the reason for the cytoprotective effects of aPC. However, more recent research has revealed that the cytoprotective effects are associated with binding between PAR1, EPCR, and aPC, even if thrombin has cleaved PAR1 . EPCR acts as a switch for the bidirectional activities of PAR1 . EPCR-dependent cytoprotective signaling is mediated by PAR1 phosphorylation by GRK5 through beta-arrestin, resulting in reduced endothelial permeability due to Rac1 activation [16,19]. The contribution of Gai to these reactions is not well understood, however.
Thrombin reportedly exhibits opposing effects depending on its concentration in a variety of cell types, including endothelial cells, neurons, and glia cells [20-22]. At concentrations less than 50 pM, thrombin exhibits cytoprotective effects. At concentrations greater than 1 nM, by contrast, thrombin acts as a cytotoxic protein. The bidirectional activities of thrombin have been demonstrated not only through in vitro and in vivo experiments but also in human clinical studies [23,24]. A 1-year observational study of patients with acute coronary syndrome demonstrated that patients with a thrombin concentration between 1.5 and 1.9 nM have the lowest incidence of coronary events. Thrombin concentrations above or below this range were associated with a higher rate of coronary events.
Thrombin signaling is regulated by its membrane localization. PAR1 and its cofactors, including G-proteins and EPCR, are localized in lipid rafts, which are specialized cell surface microdomains with or without caveolin [18,19,25]. Endothelial cells are rich in lipid raft. Lipid rafts are thought to be platforms for signal transduction involving many different ligands [26,27]. Caveolin 1 plays pivotal roles in signal transduction regulation . In the absence of ligand, Ga12/13 binds caveolin1. Signaling via Ga12/13 is suppressed by inhibition of raft formation, but not by targeting caveolin1. Raft formation is essential for signaling involving the Ga12/13-Rho axis, which appears to be regulated by caveolin1. The cytoprotective effects of the EPCR and PAR1 complex are abolished by targeting caveolin1 [8,29]. However, in signaling mediated by aPC, binding between EPCR and caveolin1 is reversed.
Ligand-stimulated PAR1 is endocytosed via a clathrin-mediated process and degraded in lysosomes [30,31]. PAR1 internalization plays a role in desensitization of PAR1. By contrast, although ligand-free PAR1 is also internalized, it is recycled to the plasma membrane . These two distinct internalization mechanisms are regulated by rab11A and B . In many GPCRs, beta-arrestin is involved in internalization; however, it is not involved in internalization PAR1 . Instead, beta-arrestin plays a role in cytoprotective signaling involving non-internalized EPCR .
Signal transduction via PAR1 is regulated by its localization and trafficking. Studies to elucidate the mechanism through which PAR1 signaling is regulated are in early stages. The role of caveolin1 in switching between cytotoxic and cytoprotective signaling is poorly understood, as is the mechanism of PAR1 translocation from rafts to clathrin pits. Post-translational ubiquitination and palmitoylation could be important steps in these processes [35-37]. As describe below, deleterious effects of thrombin have been linked to numerous serious diseases. PARs could be therapeutic targets in treating these diseases, but further investigations of PAR localization and trafficking are necessary.
Clinical Aspects of Thrombin and PAR1
Under normal circumstances, the blood coagulation process is slightly activated and thrombin does not cause injury. However, infection-associated inflammation or metabolic disorders can lead to dysregulation of thrombin activity, resulting in adverse effects in numerous organs and tissues. Continuous activation of thrombin can cause serious diseases even in the absence of obvious thrombotic events. The bidirectional effects of thrombin appear to play pivotal roles in the pathogenesis of these diseases.
Thrombin induces the expression of various adhesion molecules (Pselection, E-selection, ICAM-1, VCAM-1) and chemokines (IL-1, IL-6, IL-8, TNF-alpha) in endothelial cells, inducing platelets and leukocytes to adhere to the surface of endothelial cells, resulting in local inflammation [1,4]. Inflammation increases the expression of VEGF receptors and matrix metalloproteinases (MMPs) . VEGF and MMPs accelerate the proliferation and migration of endothelial cells, resulting in angiogenesis. Thrombin stimulates endothelial cells to reconstruct the cytoskeleton, thus altering the cell form and degrading intercellular adhesion mediated by VE-cadherin . Thrombin also induces the apoptosis of endothelial cells [6-8]. These responses decrease endothelial permeability, leading to thrombin localization under endothelial cells. As in endothelial cells, thrombin induces apoptosis and expression of MMPs in smooth muscle cells. These processes reportedly affect the structure of blood vessels in a manner that promotes atherosclerosis [39-43]. In atherosclerotic lesions, PAR1 expression is increased . While thrombin promotes atherosclerotic lesion formation, it can simultaneously suppress apoptosis and decrease endothelial permeability. These cytoprotective effects involve complex interactions between EPCR and PAR1 .
Central nervous system
Recent research has focused on the role of thrombin in the pathogenesis of neurodegenerative disorders such as Alzheimer disease and Parkinson disease in addition to brain infarction and bleeding . Most thrombin is generated in the liver. However, the brain is now thought to be a source of prothrombin and PAR1 [46,47]. The thrombin-PAR system in the brain may play significant roles in various brain-related diseases. In animal models of brain ischemia, traumatic brain and spinal cord injury, aPC significantly suppressed brain edema by protecting the integrity of the blood brain barrier, thus improving the prognosis . This signaling is mediated via complex interaction between EPCR and PAR1. aPC also protects neural cells via PAR1 and PAR3. Clinical trials of therapies targeting aPC in brain infarction are ongoing .
The cornified epithelium expresses thrombin, protein C, EPCR, thrombomodulin, and PARs [50,51]. The barrier function of keratinocytes is promoted by the EPCR-PAR1 complex. Tie2 and epidermal growth factor receptor (EGFR), which are cross-activated with PAR1, are also involved in the protective effects of thrombin. Signaling via EPCR-PAR1 and EGFR also stimulates the proliferation of keratinocytes [52,53].
Bidirectional effects of thrombin have also been observed in podocytes under high glucose stress . Low concentrations of thrombin are protective, whereas high concentrations lead to cell death in high-glucose culture. In many disease models, such as diabetic nephropathy, ischemia-reperfusion, and acute tubular injury, aPC signaling via EPCR and PAR1 reportedly restores renal function, protecting glomerular endothelial cells and renal tubular cells [55-57].
The opposing effects of thrombin and aPC via PAR1 and EPCR reportedly control hematopoietic stem cell differentiation [58,59]. Thrombomodulin, which is essential for the activation of protein C, maintains hematopoietic stem cells in a quiescent state and causes retention of them in the bone marrow. Administration of aPC or soluble thrombomodulin improves hematopoietic progenitor activity after total body irradiation .
Among therapies for diseases involving pathologic coagulation, tissue plasminogen activator has shown tremendous promise for use in the treatment of brain and heart infarctions due to formation of massive thrombi. However, limited effects of anticoagulation therapy have been reported for sepsis and DIC involving systemic microthrombi [61,62]. One reason for this limited efficacy could be endothelial cell dysfunction in these diseases. Therapies to restore endothelial function should be provided in addition to anti-thrombotic therapy. From this perspective, the protective effects of thrombin are attractive in the development of therapeutic approaches. EPCR is thought to be a key molecule in mediating the protective effects of thrombin, and therapeutic methods employing recombinant EPCRs are being developed [44,63,64]. However, the mechanisms leading to switching between the protective and deleterious signaling via thrombin remain poorly understood. Considering that the signaling via EPCR is intrinsically overcome by deleterious signaling, elucidation of the switching mechanism could lead to improved efficiency of therapies employing recombinant EPCRs. Intracellular trafficking of EPCR and PAR1 likely play pivotal roles in the activation, inactivation, and down-regulation of those receptors, because they function in lipid rafts and are degraded via clathrin-dependent endocytosis. Additionally, lipid rafts are rich in cholesterol and phosphatidylserine, an essential lipid for activation of coagulation factors, including thrombin, FVII, FIX, and FX. Development of therapies targeting the regulation of lipid raft formation in endothelial cells during the coagulation process is a worthy goal .
- Martorell L, Martinez-Gonzalez J, Rodriguez C, Gentile M, Calvayrac O, et al. (2008) Thrombin and protease-activated receptors (PARs) in atherothrombosis. ThrombHaemost 99: 305-315.
- Wojtukiewicz MZ, Hempel D, Sierko E, Tucker SC, Honn KV (2015) Protease-activated receptors (PARs)--biology and role in cancer invasion and metastasis. Cancer Metastasis Rev 34: 775-796.
- Isermann B (2017) Homeostatic effects of coagulation protease-dependent signaling and protease activated receptors. J ThrombHaemost 15: 1273-1284.
- Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407: 258-264.
- Vu TK, Hung DT, Wheaton VI, Coughlin SR (1991) Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64: 1057-1068.
- Flynn AN, Buret AG (2004) Proteinase-activated receptor 1 (PAR-1) and cell apoptosis. Apoptosis 9: 729-737.
- Feistritzer C, Riewald M (2005) Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 105: 3178-3184.
- Bae JS, Yang L, Manithody C, Rezaie AR (2007) The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood 110: 3909-3916.
- Rezaie AR (2014) Protease-activated receptor signalling by coagulation proteases in endothelial cells. ThrombHaemost 112: 876-882.
- Austin KM, Covic L, Kuliopulos A (2013) Matrix metalloproteases and PAR1 activation. Blood 121: 431-439.
- Nieman MT (2016) Protease-activated receptors in hemostasis. Blood 128: 169-177.
- Jamasbi J, Ayabe K, Goto S, Nieswandt B, Peter K (2017) Platelet receptors as therapeutic targets: Past, present and future. ThrombHaemost 117: 1249-1257.
- Bos M, vant Veer C, Reitsma PH (2016) Williams Hematology, 9th Edition, (New York: McGraw-Hill).
- Rajagopal S, Shenoy SK (2017) GPCR desensitization: Acute and prolonged phases. Cell Signal.
- Stott LA, Hall DA, Holliday ND (2016) Unravelling intrinsic efficacy and ligand bias at G protein coupled receptors: A practical guide to assessing functional data. BiochemPharmacol 101: 1-12.
- Jean-Charles PY, Kaur S, Shenoy SK (2017) G Protein-Coupled Receptor Signaling Through beta-Arrestin-Dependent Mechanisms. J CardiovascPharmacol 70: 142-158.
- Mihara K, Ramachandran R, Saifeddine M, Hansen KK, Renaux B, et al. (2016) Thrombin-Mediated Direct Activation of Proteinase-Activated Receptor-2: Another Target for Thrombin Signaling. MolPharmacol 89: 606-614.
- Roy RV, Ardeshirylajimi A, Dinarvand P, Yang L, Rezaie AR (2016) Occupancy of human EPCR by protein C induces beta-arrestin-2 biased PAR1 signaling by both APC and thrombin. Blood 128: 1884-1893.
- Soh UJ, Trejo J (2011) Activated protein C promotes protease-activated receptor-1 cytoprotective signaling through beta-arrestin and dishevelled-2 scaffolds. ProcNatlAcadSci 108: E1372-1380.
- Bae JS, Kim YU, Park MK, Rezaie AR (2009) Concentration dependent dual effect of thrombin in endothelial cells via Par-1 and Pi3 Kinase. J Cell Physiol 219: 744-751.
- Miyake Y, Alessandro-Gabazza CN, Takagi T, Naito M, Hataji O, et al. (2013) Dose-dependent differential effects of thrombin in allergic bronchial asthma. J ThrombHaemost 11: 1903-1915.
- Vaugha PJ, Pike CJ, Cotman CW, Cunningham DD (1995) Thrombin receptor activation protects neurons and astrocytes from cell death produced by environmental insults. J Neurosci 15: 5389-5401.
- Ardissino D, Merlini PA, Bauer KA, Galvani M, Ottani F, et al. (2003) Coagulation activation and long-term outcome in acute coronary syndromes. Blood 102: 2731-2735.
- Schneider JG, Isermann B, Kleber ME, Wang H, Boehm BO, et al. (2014) Inverse association of the endogenous thrombin potential (ETP) with cardiovascular death: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Int J Cardiol 176, 139-144.
- Klusacek M, Rizzo V (2007) Endothelial cytoskeletal reorganization in response to PAR1 stimulation is mediated by membrane rafts but not caveolae. Am J Physiol Heart CircPhysiol 293: H366-375.
- Katoh, S.Y, Kamimoto, T, Yamakawa, D, and Takakura, N (2009) Lipid rafts serve as signaling platforms for Tie2 receptor tyrosine kinase in vascular endothelial cells. Exp Cell Res 315: 2818-2823.
- Head BP, Patel HH, Insel PA (2014) Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. BiochimBiophysActa 1838: 532-545.
- Labrecque L, Royal I, Surprenant DS, Patterson C, Gingras D, Beliveau R (2003) Regulation of vascular endothelial growth factor receptor-2 activity by caveolin-1 and plasma membrane cholesterol. MolBiol Cell 14: 334-347.
- Russo A, Soh UJ, Paing MM, Arora P, Trejo J (2009) Caveolae are required for protease-selective signaling by protease-activated receptor-1. ProcNatlAcadSci 106: 6393-6397.
- Hein L, Ishii K, Coughlin SR, Kobilka BK (1994) Intracellular targeting and trafficking of thrombin receptors. A novel mechanism for resensitization of a G protein-coupled receptor. J BiolChem 269: 27719-27726.
- Chen B, Dores MR, Grimsey N, Canto I, Barker BL (2011) Adaptor protein complex-2 (AP-2) and epsin-1 mediate protease-activated receptor-1 internalization via phosphorylation- and ubiquitination-dependent sorting signals. J BiolChem 286: 40760-40770.
- Paing MM, Johnston CA, Siderovski DP, Trejo J (2006) Clathrin adaptor AP2 regulates thrombin receptor constitutive internalization and endothelial cell resensitization. Mol Cell Biol 26: 3231-3242.
- Grimsey NJ, Coronel LJ, Cordova IC, Trejo J (2016) Recycling and Endosomal Sorting of Protease-activated Receptor-1 Is Distinctly Regulated by Rab11A and Rab11B Proteins. J BiolChem 291: 2223-2236.
- Paing MM, Stutts AB, Kohout TA, Lefkowitz RJ, TrejoJ (2002) beta -Arrestins regulate protease-activated receptor-1 desensitization but not internalization or Down-regulation. J BiolChem 277: 1292-1300.
- Wolfe BL, Marchese A, Trejo J (2007) Ubiquitination differentially regulates clathrin-dependent internalization of protease-activated receptor-1. J Cell Biol 177: 905-916.
- Russo A, Soh UJ, Trejo J (2009) Proteases display biased agonism at protease-activated receptors: location matters! MolInterv 9: 87-96.
- Morris G, Walder K, Puri BK, Berk M, Maes, M (2016) The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders. MolNeurobiol 53: 4638-4658.
- Rodrigues SF, Granger DN (2015) Blood cells and endothelial barrier function. Tissue Barriers 3: e978720.
- McNamara CA, Sarembock IJ, Gimple LW, Fenton JW (1993) Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor. J Clin Invest 91: 94-98.
- Rossignol P, Bouton MC, Jandrot-Perrus M, Bryckaert M, Jacob MP, et al. (2004) A paradoxical pro-apoptotic effect of thrombin on smooth muscle cells. Exp Cell Res 299: 279-285.
- Koo BH, Park MY, Jeon OH, Kim DS (2009) Regulatory mechanism of matrix metalloprotease-2 enzymatic activity by factor Xa and thrombin. J BiolChem 284: 23375-23385.
- Mahajan SG, Fender AC, Meyer-Kirchrath J, Kurt M, Barth M, et al. (2012) A novel function of FoxO transcription factors in thrombin-stimulated vascular smooth muscle cell proliferation. ThrombHaemost 108: 148-158.
- Austin KM, Nguyen N, Javid G, Covic L, Kuliopulos A (2013) Noncanonical matrix metalloprotease-1-protease-activated receptor-1 signaling triggers vascular smooth muscle cell dedifferentiation and arterial stenosis. J BiolChem 288: 23105-23115.
- Griffin JH, Zlokovic BV, Mosnier LO (2015) Activated protein C: biased for translation. Blood 125: 2898-2907.
- Krenzlin H, Lorenz V, Danckwardt S, Kempski O, Alessandri B (2016) The Importance of Thrombin in Cerebral Injury and Disease. Int J MolSci 17.
- Dihanich M, Kaser M, Reinhard E, Cunningham D, Monard D (1991) Prothrombin mRNA is expressed by cells of the nervous system. Neuron 6: 575-581.
- Striggow F, Riek-Burchardt M, Kiesel A, Schmidt W, Henrich-Noack P, et al. (2001) Four different types of protease-activated receptors are widely expressed in the brain and are up-regulated in hippocampus by severe ischemia. Eur J Neurosci 14: 595-608.
- Zlokovic BV, Griffin JH (2011) Cytoprotective protein C pathways and implications for stroke and neurological disorders. Trends Neurosci 34: 198-209.
- Griffin JH, Fernandez JA, Lyden PD, Zlokovic BV (2016) Activated protein C promotes neuroprotection: mechanisms and translation to the clinic. Thromb Res 141: S62-S64.
- Artuc M, Hermes B, Algermissen B, Henz BM (2006) Expression of prothrombin, thrombin and its receptors in human scars. ExpDermatol 15: 523-529.
- Xue M, Campbell D, Jackson CJ (2007) Protein C is an autocrine growth factor for human skin keratinocytes. J BiolChem 282: 13610-13616.
- Xue M, Chow SO, Dervish S, Chan YK, Julovi SM (2011) Activated protein C enhances human keratinocyte barrier integrity via sequential activation of epidermal growth factor receptor and Tie2. J BiolChem 286: 6742-6750.
- McKelvey K, Jackson CJ, Xue M (2014) Activated protein C: A regulator of human skin epidermal keratinocyte function. World J BiolChem 5: 169-179.
- Wang H, Madhusudhan T, He T, Hummel B, Schmidt S, et al. (2011) Low but sustained coagulation activation ameliorates glucose-induced podocyte apoptosis: protective effect of factor V Leiden in diabetic nephropathy. Blood 117: 5231-5242.
- Bock F, Shahzad K, Wang H, Stoyanov S, Wolter J, et al. (2013) Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc. ProcNatlAcadSci 110: 648-653.
- Isermann B, Vinnikov IA, Madhusudhan T, Herzog S, Kashif M, et al. (2007) Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med 13: 1349-1358.
- Madhusudhan T, Wang H, Straub BK, Grone E, Zhou Q, et al. (2012) Cytoprotective signaling by activated protein C requires protease-activated receptor-3 in podocytes. Blood 119: 874-883.
- Pepler L, Yu P, Dwivedi DJ, Trigatti BL, Liaw PC (2015) Characterization of mice harboring a variant of EPCR with impaired ability to bind protein C: novel role of EPCR in hematopoiesis. Blood 126: 673-682.
- Gur-Cohen S, Itkin T, Chakrabarty S, Graf C, Kollet O, et al. (2015) PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells. Nat Med 21: 1307-1317.
- Geiger H, Pawar SA, Kersche EJ, Nattamai KJ, Hernandez I (2012) Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat Med 18: 1123-1129.
- Dhainaut JF, Yan SB, Joyce DE, Pettila V, Basson B (2004) Treatment effects of drotrecoginalfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J ThrombHaemost 2: 1924-1933.
- Vincent L, Ramesh MK, Ernest D, LaRosa (2013) A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Care Med 41: 2069-2079.
- Lopez-Sagaseta J, Montes R, Hermida J (2009) Recombinant expression of biologically active murine soluble EPCR. Protein ExprPurif 64: 194-197.
- Bouwens EA, Stavenuiter F, Mosnier LO (2015) Cell painting with an engineered EPCR to augment the protein C system. ThrombHaemost 114: 1144-1155.
- Hidai C, Fujiwara Y, Kokubun S, Kitano H (2017) EGF domain of coagulation factor IX is conducive to exposure of phosphatidylserine. Cell BiolInt 41, 374-383.
Citation: Hidai C (2018) Bidirectional Pathologic Effects of Thrombin. Anat Physiol 8: 291. DOI: 10.4172/2161-0940.1000291
Copyright: © 2018 Hidai C. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
Select your language of interest to view the total content in your interested language
Share This Article
- Total views: 731
- [From(publication date): 0-2018 - Sep 22, 2018]
- Breakdown by view type
- HTML page views: 686
- PDF downloads: 45