Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review article integrates empirical findings from various scientific disciplines into a proposed psychoneuroimmunological (PNI) model of the acute coronary syndrome (ACS). Our starting point is an existing, mild, atherosclerotic plaque and a dysfunctional endothelium. The ACS is triggered by three stages. (1) Plaque instability: Pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha) and chemoattractants (MCP-1, IL-8) induce leukocyte chemoattraction to the endothelium, and together with other triggers such as the CD40L-CD40 co-stimulation system activate plaque monocytes (macrophages). The macrophages then produce matrix metalloproteinases that disintegrate extra-cellular plaque matrix, causing coronary plaque instability. Acute stress, hostility, depression and vital exhaustion (VE) have been associated with elevated pro-inflammatory cytokines and leukocyte levels and their recruitment. (2) Extra-plaque factors promoting rupture: Neuro-endocrinological factors (norepinephrine) and cytokines induce vasoconstriction and elevated blood pressure (BP), both provoking a vulnerable plaque to rupture. Hostility/anger and acute stress can lead to vasoconstriction and elevated BP via catecholamines. (3) Superimposed thrombosis at a ruptured site: Increases in coagulation factors and reductions in anticoagulation factors (e.g. protein C) induced by inflammatory factors enhance platelet aggregation, a key stage in thrombosis. Hostility, depression and VE have been positively correlated with platelet aggregation. Thrombosis can lead to severe coronary occlusion, clinically manifested as an ACS. Thus, PNI processes might, at least in part, contribute to the pathogenesis of the ACS. This chain of events may endure due to lack of neuroendocrine-to-immune negative feedback stemming from cortisol resistance. This model has implications for the use of psychological interventions in ACS patients.
Cardiovasc Res 2002 Oct
PMID:Molecular and cellular interface between behavior and acute coronary syndromes. 1223 62

The plasma protein, antithrombin, and its polysaccharide activator, heparin, are essential anticoagulant regulators of blood clotting proteinases that are critical for maintaining hemostasis. Heparin activates antithrombin both by inducing conformational changes in the protein that specifically enhances factor Xa binding and by providing a surface to promote thrombin or factor Xa binding alongside antithrombin in a ternary bridging complex. Although x-ray structures of antithrombin, free and complexed with heparin, have suggested that exposure of a reactive proteinase binding loop is a key feature of conformational activation, mutagenesis of reactive loop residues indicates that the function of this structural change is not to present an optimal loop sequence to target clotting proteinases. Rather, the reactive loop sequence provides only the minimal requirements for recognition by either thrombin or factor Xa, and heparin activation enhances antithrombin recognition by these proteinases through the presentation of exosites outside of the reactive loop. These and other findings suggest that the reactive loop sequence of antithrombin was designed not for optimal recognition by procoagulant proteinases but rather to prevent recognition by the anticoagulant proteinase, activated protein C, thus ensuring that antithrombin functions as an effective anticoagulant.
Trends Cardiovasc Med 2002 Nov
PMID:Heparin activates antithrombin anticoagulant function by generating new interaction sites (exosites) for blood clotting proteinases. 1253 19

Activated protein C (APC) is a vitamin K-dependent anticoagulant serine protease in plasma that downregulates the coagulation cascade by degrading cofactors Va and VIIIa by limited proteolysis. In addition to its anticoagulant function, APC also exhibits potent profibrinolytic and anti-inflammatory properties. The proteolytic activity of APC in plasma is slowly inhibited by three serpins: protein C inhibitor, plasminogen activator inhibitor-1, and alpha(1)-antitrypsin. Recent structural and mutagenesis data have indicated that basic residues of three exposed surface loops known as the 39-loop (Lys(37)-Lys(39)), 60-loop (Lys(62), Lys(63)), and 70-80-loop (Arg(74), Arg(75), and Lys(78)) (chymotrypsin numbering) constitute an anion-binding exosite in APC that interacts with these macromolecular substrates and inhibitors. Moreover, this exosite plays a critical role in the thrombomodulin-dependent activation of the zymogen protein C by thrombin. This article briefly reviews how the binding of physiological protein and polysaccharide cofactors on this exosite modulates the protein C anticoagulant pathway in plasma.
Trends Cardiovasc Med 2003 Jan
PMID:Exosite-dependent regulation of the protein C anticoagulant pathway. 1255 95

Systemic infection by various pathogens interacts with the endothelium and may result in altered coagulation, vasculitis and atherosclerosis. Endothelium plays a role in the initiation and regulation of both coagulation and fibrinolysis. Exposure of endothelial cells may lead to rapid activation of coagulation via tissue factor (TF) expression and the loss of anticoagulant properties by impairment of antithrombin III, TF pathway inhibitor (TFPI) and the protein C system. Endothelial-derived plasminogen activator inhibitor (PAI) is essential for the regulation of fibrinolysis and impaired endothelial function leads to imbalance in fibrinolysis, resulting in a procoagulant state. The interaction between inflammation and coagulation, soluble adhesion molecules and circulation endothelial cells is important in the pathogenesis of an unbalanced haemostatic system. Rather than being a unidirectional relationship, the interaction between inflammation and coagulation appears to be significant. In the crosstalk, the endothelium is playing a pivotal role.
Cardiovasc Res 2003 Oct 15
PMID:Infections and endothelial cells. 1452 5

Arterial and venous thrombosis are a major cause of morbidity and mortality. Anticoagulants are a cornerstone of treatment in patients with these disorders. The two most frequently used anticoagulants, heparin and warfarin, have pharmacological and/or biophysical limitations that make them difficult to use in day-to-day clinical practice. Development of new anticoagulants, which were designed to overcome these limitations, has been facilitated by an increased understanding of the coagulation cascade, the advent of molecular modeling and structure-based drug design, and the realization that the treatment of thrombosis and its complications consumes billions of dollars in annual healthcare expenditures. New anticoagulants target various steps in the coagulation pathway. Coagulation is triggered by the factor VIIa/tissue factor complex and propagated by factors Xa and IXa, together with their activated cofactors, factor Va and VIIIa, respectively. Thrombin, the final effector in coagulation, then converts soluble fibrinogen into insoluble fibrin, the major matrix protein of the clot. New anticoagulation drugs that target each of these clotting enzymes have been developed. This review will focus on those drugs in more advanced stages of clinical evaluation. These include inhibitors of initiation of coagulation (tissue factor pathway inhibitor, nematode anticoagulant peptide and active-site blocked factor VIIa), inhibitors of propagation of coagulation (active-site blocked factor IXa, antibodies against factor IX/IXa, fondaparinux sodium, direct factor Xa inhibitors, protein C derivatives and soluble thrombomodulin), and thrombin inhibitors (hirudin, bivalirudin, argatroban and ximelagatran).
Am J Cardiovasc Drugs 2003
PMID:New anticoagulants: current status and future potential. 1472 32

Venous thromboembolism is a common and potentially fatal disease. If properly used, anticoagulation therapy is effective in preventing recurrence of venous thromboembolism and in improving survival. Symptomatic patients with an objective diagnosis of acute deep vein thrombosis (DVT) or pulmonary embolism (PE) should receive immediate systemic heparin anticoagulation at dosages sufficient to rapidly prolong the activated partial thromboplastin time into the laboratory-specific therapeutic range; this range corresponds to a plasma heparin concentration of 0.2 to 0.4 IU/ml (as measured by protamine sulfate titration), or 0.3 to 0.7 anti-Xa IU/ml. An oral vitamin K antagonist (e.g. warfarin) should be started within 24 hours after starting heparin; the starting dose should be the estimated patient-specific daily dose with no loading dose. Heparin and warfarin anticoagulation should be overlapped for at least 4 to 5 days and until the international normalized ratio (INR) is within the therapeutic range (2.0 to 3.0) on 2 measurements made at least 24 hours apart. The duration of warfarin anticoagulation should be individualized based on the respective risks of venous thromboembolism recurrence and anticoagulant-related bleeding. In general, warfarin should be continued for at least 3 months, and longer for patients with recurrent or idiopathic venous thromboembolism, malignant neoplasm, neurologic disease with extremity paresis, obesity, or laboratory evidence of a lupus anticoagulant/anticardiolipin antibody, homozygous carrier or combined heterozygous carrier for the factor V R506Q (Leiden) and prothrombin G20210A mutations, and possibly deficiency of either antithrombin, protein C, or protein S. Low molecular weight heparin (LMWH) is effective and well tolerated as acute therapy for patients with DVT or stable PE, and does not require laboratory monitoring or dose adjustment. Outpatient LMWH therapy is also well tolerated and cost effective for most patients with DVT, and possibly for selected patients with PE.
Am J Cardiovasc Drugs 2001
PMID:Current management of acute symptomatic deep vein thrombosis. 1472 51

Intravascular fibrin deposition is believed to play an important role in the development of intimal hyperplasia, which is a hallmark of several human vascular disorders, including atherosclerosis and restenosis after balloon angioplasty. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor or tissue- and urinary-type plasminogen activator, plays a key role in fibrin homeostasis by controlling plasmin formation. PAI-1 may also modulate vascular pathology via alternative pathways, such as inhibiting activated protein C and altering interactions between vascular smooth muscle cells and the extracellular matrix. The diverse functional profile of PAI-1 likely accounts for the variation observed in its impact on intimal hyperplasia in different disease models. This review examines recent studies addressing the vascular function of PAI-1, and those assessing the role of fibrin as a downstream mediator of PAI-1's effects.
Trends Cardiovasc Med 2004 Jul
PMID:Plasminogen activator inhibitor 1, fibrin, and the vascular response to injury. 1526 92

Gram-negative sepsis is associated with disseminated intravascular coagulation (DIC) due to endothelial damage, which is induced by inflammatory mediators released from phagocytes activated by lipopolysaccharide (LPS). DIC is a systemic hemorrhagic syndrome, which results from the consumption of coagulation factors for the formation of multiple thrombi in the systemic microvessels; it is associated with multiple organ failure. Therefore, not only the systemic activation of coagulation but also the inflammatory response has been perceived as the therapeutic target for DIC in sepsis. We gave attention that protein C inhibitor (PCI) acts as an inhibitor of both plasma kallikrein and thrombin, which are known to act not only as procoagulant proteases but also as chemotactic factors toward phagocytes. Then, we hypothesized that PCI possibly acts as an anti-DIC agent rather than an inhibitor of the protein C anticoagulant pathway under the pathophysiology of DIC, accompanied by the decrease in the thrombomodulin expression on endothelial cells. Our studies have suggested that PCI purified from human urine (uPCI) improves the pathophysiology of DIC through the inhibition of activities of plasma kallikrein and thrombin, and the activities of PCI are regulated by N-glycans. This review introduces the anti-DIC action of PCI and about the modification of N-glycosylation site(s) of PCI to heighten the value of PCI as an anti-DIC agent.
Curr Med Chem Cardiovasc Hematol Agents 2004 Jan
PMID:Protein C inhibitor as an anti-disseminated intravascular coagulation agent--mechanism and modification. 1532 Aug 3

The acronym DIC is commonly interpreted as "death is coming." This pessimistic view emphasizes the deficiency of available treatment options following diagnosis of disseminated intravascular coagulation. Clinically, DIC manifests as a systemic hemorrhagic disorder associated with widespread activation and eventual exhaustion of the coagulation system, although events underlying DIC also involve effectors of inflammation. DIC can be associated with diverse conditions including sepsis and major trauma and, when identified, signifies a significant worsening in prognosis and expected mortality. Although recent clinical studies have shown that activated protein C reduces mortality in patients with severe sepsis, there is a need for further investigation and a better understanding of the underlying mechanisms.
Timely Top Med Cardiovasc Dis 2004 Aug 01
PMID:Alternative treatments for disseminated intravascular coagulation. 1554 51

The protein C pathway is a major regulator of blood coagulation, since it controls the conversion of prothrombin to thrombin through a feedback inhibition mechanism. Protein C circulates in plasma as an inactive zymogen and is activated on the surface of endothelial cells by the thrombin-thrombomodulin complex, a process that can be further enhanced when protein C binds to its membrane receptor, the endothelial-cell protein C receptor. Activated protein C (APC) is then released from the complex, binds protein S and inhibits thrombin formation by inactivating coagulation factors Va and VIIIa. The importance of the protein C anticoagulant pathway is emphasized by the increased risk of venous thromboembolism (VTE) associated with protein C and protein S deficiencies, the factor V Leiden mutation, and reduced circulating APC levels. The protein C pathway also plays a significant role in inflammatory processes, since it prevents the lethal effects of E. coli-associated sepsis in animal models and improves the outcome of patients with severe sepsis. APC seems to display anti-apoptotic and neuroprotective activities. Thus, it reduces organ damage in animal models of sepsis, ischemic injury, endothelial cell injury, or stroke. Further research will hopefully widen the current therapeutic perspectives in all these illnesses, where these effects might play a crucial role in their treatment. This review will summarize the mechanisms that contribute to these biological activities of the protein C pathway.
Curr Med Chem Cardiovasc Hematol Agents 2005 Apr
PMID:The multifunctional protein C system. 1585 99


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