Peroxynitrite causes endoplasmic reticulum stress and apoptosis in human vascular endothelium: implications in atherogenesis.

Objective: Peroxynitrite, a potent oxidant generated by the reaction of NO with superoxide, has been implicated in the promotion of atherosclerosis. We designed this study to determine whether peroxynitrite induces its proatherogenic effects through induction of endoplasmic reticulum (ER) stress.

Methods And Results: Human vascular endothelial cells treated with Sin-1, a peroxynitrite generator, induced the expression of the ER chaperones GRP78 and GRP94 and increased eIF2alpha phosphorylation.

Oncogenes and Angiogenesis: down-regulation of thrombospondin-1 in normal fibroblasts exposed to factors from cancer cells harboring mutant ras.

The onset of angiogenesis in cancer often involves down-regulation of endogenous angiogenesis inhibitors, of which thrombospondin-1 (TSP-1) is a paradigm. As this effect is thought to occur under the influence of transforming genetic lesions (e.g.

In vivo rabbit acute model tests of polyurethane catheters coated with a novel antithrombin-heparin covalent complex.

Catheter use has been associated with an increased risk of thrombotic complications. The objective was to make catheters less thrombogenic with the use of antithrombin-heparin covalent complex (ATH). The antithrombotic activity of ATH-coated catheters was compared to uncoated (control) and heparincoated catheters in an acute rabbit model of accelerated occluding clot formation.

Downregulation of the angiogenesis inhibitor thrombospondin 1 in fibroblasts exposed to platelets and their related phospholipids.

Platelets play many important roles in maintenance and formation of blood vessels. The latter is usually attributed to release of direct acting proangiogenic influences, e.g.

The effects of high-dose heparin on inflammatory and coagulation parameters following cardiopulmonary bypass.

Systemic inflammation and the activation of the coagulation system following cardiopulmonary bypass (CPB) may contribute to postoperative complications. In vitro studies have demonstrated that heparin possesses anti-inflammatory properties. To ascertain the relative benefits of high versus low heparin doses, we studied the impact of varying heparin doses on the inflammatory response and coagulation system during and following CPB.

A randomized trial of diagnostic strategies after normal proximal vein ultrasonography for suspected deep venous thrombosis: D-dimer testing compared with repeated ultrasonography.

Background: With suspected deep venous thrombosis and normal results on proximal vein ultrasonography, a negative d-dimer result may exclude thrombosis and a positive D-dimer result may be an indication for venography.

Objective: To evaluate and compare the safety of 2 diagnostic strategies for deep venous thrombosis.

Design: Randomized, multicenter trial.

Activation of the unfolded protein response occurs at all stages of atherosclerotic lesion development in apolipoprotein E-deficient mice.

Background: Apoptotic cell death contributes to atherosclerotic lesion instability, rupture, and thrombogenicity. Recent findings suggest that free cholesterol (FC) accumulation in macrophages induces endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and apoptotic cell death; however, it is not known at what stage of lesion development the UPR is induced in macrophages or whether a correlation exists between UPR activation, FC accumulation, and apoptotic cell death.

Methods And Results: Aortic root sections from apolipoprotein E-deficient (apoE-/-) mice at 9 weeks of age (early-lesion group) or 23 weeks of age (advanced-lesion group) fed a standard chow diet were examined for markers of UPR activation (GRP78, phospho-PERK, CHOP, and TDAG51), apoptotic cell death (TUNEL and cleaved caspase-3), and lipid accumulation (filipin and oil red O).

Heparin compromises streptokinase-induced arterial patency in rabbits.

Introduction: Little is known with regard to efficacy of heparin as an adjunct to fibrinolytics under conditions of severe vascular damage. In this study, we compared the effects of unfractionated heparin (UH), low-molecular weight heparin (LMWH), and recombinant desulfohirudin (HIR) in combination with streptokinase (SK) in such settings.

Materials And Methods: We used an established rabbit model, in which thrombosis, critical stenosis, and vascular wall damage were introduced to a segment of the abdominal aorta and the effects of the respective therapies were assessed by time to patency (TTP in minutes), cumulative patency (CP (%)), lysis of original clot (CL (%)), and net clot accretion (NCA (%)).

New anticoagulants: beyond heparin, low-molecular-weight heparin and warfarin.

The limitations of traditional anticoagulants, heparin and warfarin, have prompted the development of new anticoagulant drugs for prevention and treatment of both venous and arterial thromboembolism. After a brief review of thrombogenesis and its regulation, this paper focuses on new anticoagulant agents in more advanced stages of clinical testing.

Modes and consequences of thrombin's interaction with fibrin.

Thrombin mediates the balance between coagulant and fibrinolytic forces and has numerous cellular effects. This intricate balance is maintained by biochemical mechanisms that regulate thrombin activity. Disruption of this balance could lead to bleeding or thrombosis.

Comparative benefits of clopidogrel and aspirin in high-risk patient populations: lessons from the CAPRIE and CURE studies.

Clopidogrel has been evaluated in clinical trials that included cardiovascular patients with different risk levels for a cardiovascular event. We reviewed the results of the Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) and Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trials, with special emphasis on comparing the outcomes in high-risk patients with those of the total populations in the trials. The results in the high-risk subgroups and total populations were compared by recording total event rates, absolute risk reduction, relative risk reduction, and number needed to treat.

Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis.

Tissue factor (TF) is the primary cellular initiator of blood coagulation and a modulator of angiogenesis and metastasis in cancer. Indeed, systemic hypercoagulability in patients with cancer and TF overexpression by cancer cells are both closely associated with tumor progression, but their causes have been elusive. We now report that in human colorectal cancer cells, TF expression is under control of 2 major transforming events driving disease progression (activation of K-ras oncogene and inactivation of the p53 tumor suppressor), in a manner dependent on MEK/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3'-kinase (PI3K).

Examining the correlations between GSK-3 inhibitory properties and anti-convulsant efficacy of valproate and valproate-related compounds.

A family of compounds based upon the chemical structure of valproate were synthesized and assayed for their ability to inhibit glycogen synthase kinase (GSK)-3 alpha and beta activity in vitro. This data is correlated to the known anti-convulsant properties of these compounds in order to determine the potential role of GSK-3 inhibition in the therapeutic efficacy of these drugs.

Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

This chapter about hemorrhagic complications of anticoagulant treatment is part of the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Bleeding is the major complication of anticoagulant therapy. The criteria for defining the severity of bleeding varies considerably between studies, accounting in part for the variation in the rates of bleeding reported.

New anticoagulant drugs: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

This article about new anticoagulant drugs is part of the seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. The limitations of existing oral and parenteral anticoagulant agents have prompted a search for novel agents. Focusing on new anticoagulant drugs for the prevention and treatment of arterial and venous thrombosis, this article (1) reviews arterial and venous thrombogenesis, (2) discusses the regulation of coagulation, (3) describes the pathways for testing new anticoagulant agents, (4) describes new anticoagulant strategies focusing primarily on agents in phase II or III clinical testing, and (5) provides clinical perspective as to which of these new strategies is most likely to succeed.

Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

This article about unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) is part of the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a pentasaccharide, catalyzing the inactivation of thrombin and other clotting factors. UFH also binds endothelial cells, platelet factor 4, and platelets, leading to rather unpredictable pharmacokinetic and pharmacodynamic properties.

New anticoagulants for treatment of venous thromboembolism.

Treatment of venous thromboembolism (VTE) usually starts with concomitant administration of heparin or low-molecular-weight heparin (LMWH) and a vitamin K antagonist. The parenteral anticoagulant, which is given for at least 5 days, is stopped once the vitamin K antagonist produces a therapeutic level of anticoagulation. Although the introduction of LMWH has simplified the initial treatment of VTE, problems remain.

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease.

Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease. Mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine beta-synthase (CBS) or 5,10-methylenetetrahydrofolate reductase (MTHFR), result in severe forms of HHcy. Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or B12 (methylcobalamin), can induce HHcy.

Association of multiple cellular stress pathways with accelerated atherosclerosis in hyperhomocysteinemic apolipoprotein E-deficient mice.

Background: A causal relation between hyperhomocysteinemia (HHcy) and accelerated atherosclerosis has been established in apolipoprotein E-deficient (apoE-/-) mice. Although several cellular stress mechanisms have been proposed to explain the atherogenic effects of HHcy, including oxidative stress, endoplasmic reticulum (ER) stress, and inflammation, their association with atherogenesis has not been completely elucidated.

Methods And Results: ApoE-/- mice were fed a control or a high-methionine (HM) diet for 4 (early lesion group) or 18 (advanced lesion group) weeks to induce HHcy.

Orally active direct thrombin inhibitors.

Anticoagulants are widely used for the prevention and treatment of venous and arterial thrombosis. Current treatment strategies often employ a combination of parenteral and oral agents because the only available orally active anticoagulants, vitamin K antagonists, have a delayed onset of action. Furthermore, vitamin K antagonists have a narrow therapeutic window that necessitates careful anticoagulation monitoring, and dosing is problematic because of multiple food and drug interactions.

Management of anticoagulation in patients who require invasive procedures.

When orally anticoagulated patients need to have surgery, the goals of management are to minimize the risks of thromboembolism and of bleeding from the invasive procedure. Some invasive procedures can be performed while patients are fully or partially anticoagulated because bleeding is rare and/or easily controlled. When it is necessary to reverse oral anticoagulant therapy it should be interrupted for as short a time as possible, usually 4 or 5 days.

Novel antithrombotic therapies for the prevention of stroke in patients with atrial fibrillation.

Atrial fibrillation (AF), the most common type of arrhythmia in adults, is a major risk factor for stroke. The prevalence of AF increases with age, occurring in 1% of persons <60 years of age and in almost 10% of those >80 years of age. Recent studies show that treatment strategies that combine control of ventricular rate with antithrombotic therapy are as effective as strategies aimed at restoring sinus rhythm.

The intrinsic threshold of the fibrinolytic system is modulated by basic carboxypeptidases, but the magnitude of the antifibrinolytic effect of activated thrombin-activable fibrinolysis inhibitor is masked by its instability.

Activated thrombin-activable fibrinolysis inhibitor (TAFIa) is intrinsically unstable, a property that complicates the study of its role in regulating fibrinolysis. To investigate the effect of basic carboxypeptidases on fibrinolysis under conditions of constant carboxypeptidase activity, we employed pancreatic carboxypeptidase B (CPB), a homologous, stable basic carboxypeptidase, as a surrogate for TAFIa. Clots formed from TAFI-depleted plasma or from purified components were supplemented with tissue-type plasminogen activator and either CPB or TAFIa.