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1.
Cells ; 11(21)2022 10 25.
Article in English | MEDLINE | ID: mdl-36359765

ABSTRACT

BACKGROUND: Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are characterized by systemic inflammation and high mortality, but there is no effective clinical treatment. As a classic traditional Chinese medicine (TCM) formula, MaHuang-LianQiao-ChiXiaoDou decoction (MHLQD) has been used clinically for centuries to treat liver diseases. METHODS: The LPS/D-GalN-induced ALF mice model and the CCl4+LPS/D-GalN-induced ACLF mice model were used to observe the therapeutic effects of MHLQD on mice mortality, hepatocytes death, liver injury, and immune responses. RESULTS: MHLQD treatment significantly improved mice mortality. Liver injury and systemic and hepatic immune responses were also ameliorated after MHLQD treatment. Mechanistically, proteomic changes in MHLQD-treated liver tissues were analyzed and the result showed that the thrombogenic von Willebrand factor (VWF) was significantly inhibited in MHLQD-treated ALF and ACLF models. Histological staining and western blotting confirmed that VWF/RAP1B/ITGB3 signaling was suppressed in MHLQD-treated ALF and ACLF models. Furthermore, mice treated with the VWF inhibitor ADAMTS13 showed a reduced therapeutic effect from MHLQD treatment. CONCLUSIONS: Our study indicated that MHLQD is an effective herbal formula for the treatment of ALF and ACLF, which might be attributed to the protection of hepatocytes from death via VWF/RAP1B/ITGB3 signaling.


Subject(s)
Acute-On-Chronic Liver Failure , Drugs, Chinese Herbal , von Willebrand Factor , Animals , Mice , Acute-On-Chronic Liver Failure/drug therapy , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Lipopolysaccharides , Proteomics , Signal Transduction , von Willebrand Factor/drug effects , von Willebrand Factor/metabolism
2.
Bull Exp Biol Med ; 171(4): 480-482, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34542754

ABSTRACT

We studied the effect of nitinol, the most prevalent material for endovascular stents, on metabolic and coagulation activity of a primary culture of human umbilical vein endothelial cells (HUVEC). Metabolic activity was evaluated using MTS-test and by the level of stable NO metabolites in the conditioned medium, coagulation activity was assessed by activity of von Willebrand factor (vWF) and levels of plasminogen activator inhibitor-1 (PAI-1) and soluble endothelial protein C receptors (sEPCR). Exposure to nitinol reduced metabolic activity of the cell culture by 11.1% in comparison with the control (p<0.001). Although absolute activity of vWF and absolute level of sEPCR were elevated, incubation with nitinol did not lead to a statistically significant elevation of these parameters in comparison with the control, which can indicate the absence of substantial hypercoagulation effects of nitinol.


Subject(s)
Alloys/pharmacology , Endothelium, Vascular/drug effects , Human Umbilical Vein Endothelial Cells/drug effects , Blood Coagulation/drug effects , Blood Coagulation Factors/metabolism , Cells, Cultured , Endothelial Protein C Receptor/drug effects , Endothelial Protein C Receptor/metabolism , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiology , Human Umbilical Vein Endothelial Cells/metabolism , Human Umbilical Vein Endothelial Cells/physiology , Humans , Plasminogen Activator Inhibitor 1/drug effects , Plasminogen Activator Inhibitor 1/metabolism , Thrombosis/metabolism , Thrombosis/pathology , von Willebrand Factor/drug effects , von Willebrand Factor/metabolism
3.
J Clin Pharmacol ; 61(7): 889-900, 2021 07.
Article in English | MEDLINE | ID: mdl-33719084

ABSTRACT

Recombinant factor VIII Fc fusion protein (rFVIIIFc) has been indicated for adults and children with hemophilia A. The objective of this article was to build a population pharmacokinetic (PK) model using adult and pediatric data sets and explore relevant dosing scenarios across all ages. The activity-time profiles of rFVIIIFc from 3 clinical studies (all trials registered at https://www.clinicaltrials.gov: NCT01027377, NCT01181128, and NCT01458106) were characterized, and covariates that determine variability of rFVIIIFc PK in children and adults were identified and implemented. Data sets were pooled to estimate population PK parameters. Simulations were conducted to generate activity-time profiles at steady state (SS). The proportion of subjects maintaining SS trough >1 and >3 IU/dL and time >10 IU/dL were estimated. The rFVIIIFc model was a two-compartment model that identified weight and von Willebrand factor as significant covariates. Model-predicted SS peaks and troughs of rFVIIIFc activity-time profiles confirmed the necessity of modifying dosing in pediatric subjects. The model also predicted that the average subject in the adult and adolescent group dosed with 40 IU/kg every 2 days maintained factor VIII activity >10 IU/dL for the entire duration. Children aged <6 years and aged 6 to <12 years receiving this dose maintained factor VIII activity of >10 IU/dL for nearly two-thirds and three-quarters of their time, respectively. In conclusion, these population PK analyses characterize activity-time profiles for rFVIIIFc among pediatric and adult subjects. The model was used for simulation of clinically relevant dosing scenarios, which can provide better protection and better clinical outcomes.


Subject(s)
Factor VIII/pharmacokinetics , Hemophilia A/drug therapy , Recombinant Fusion Proteins/pharmacokinetics , Adolescent , Age Factors , Body Weight , Child , Computer Simulation , Drug Dosage Calculations , Factor VIII/administration & dosage , Half-Life , Humans , Immunoglobulin Fc Fragments/administration & dosage , Male , Metabolic Clearance Rate , Models, Biological , Patient Acuity , Recombinant Fusion Proteins/administration & dosage , von Willebrand Factor/drug effects
4.
Sci Rep ; 11(1): 3092, 2021 02 04.
Article in English | MEDLINE | ID: mdl-33542410

ABSTRACT

The effect of conventional anti-platelet agents is limited in secondary stroke prevention, and their effects are blunted under high shear stress in the presence of increased levels of circulating von Willebrand factor (VWF). VWF is critically involved in thrombus formation at sites of stenotic extracranial/intracranial arteries. A third generation anti-VWF aptamer (BT200) has been generated which could be useful for secondary stroke prevention. To characterize the effects of BT200 in blood of patients with large artery atherosclerosis stroke (LAA). Blood samples were obtained from 33 patients with acute stroke or transient ischemic attack to measure inhibition of VWF activity and VWF-dependent platelet function. Patients who received clopidogrel or dual antiplatelet therapy did not differ in VWF dependent platelet function tests from aspirin treated patients. Of 18 patients receiving clopidogrel with or without aspirin, only 3 had a prolonged collagen adenosine diphosphate closure time, and none of the patients had ristocetin induced aggregation in the target range. BT200 concentration-dependently reduced median VWF activity from 178 to < 3%, ristocetin induced platelet aggregation from 40U to < 10U and prolonged collagen adenosine diphosphate closure times from 93 s to > 300 s. Baseline VWF activity correlated (r = 0.86, p < 0.001) with concentrations needed to reduce VWF activity to < 20% of normal, indicating that BT200 acts in a target concentration-dependent manner. Together with a long half-life supporting once weekly administration, the safety and tolerability observed in an ongoing phase I trial, and the existence of a reversal agent, BT200 is an interesting drug candidate.


Subject(s)
Aptamers, Peptide/pharmacology , Ischemic Attack, Transient/blood , Stroke/drug therapy , von Willebrand Factor/drug effects , Aged , Aspirin/therapeutic use , Blood Platelets/drug effects , Collagen/metabolism , Female , Humans , Intracranial Arteriosclerosis/blood , Intracranial Arteriosclerosis/complications , Intracranial Arteriosclerosis/pathology , Ischemic Attack, Transient/pathology , Ischemic Attack, Transient/prevention & control , Male , Platelet Aggregation/drug effects , Stroke/blood , Stroke/etiology , Stroke/pathology , Thrombosis/blood , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/pathology
5.
Cardiovasc Drugs Ther ; 35(3): 521-532, 2021 06.
Article in English | MEDLINE | ID: mdl-32651897

ABSTRACT

PURPOSE: Chronic kidney disease (CKD) associates with inflammatory and prothrombotic phenotypes, resulting in higher cardiovascular risk. Factor Xa displays functions beyond coagulation, exhibiting proinflammatory effects. The aim of the present study was to investigate whether a direct FXa inhibitor protects from the endothelial dysfunction (ED) caused by uremia. METHODS: Macro (HUVEC) and microvascular (HMEC) endothelial cells (ECs) were exposed to serum from uremic patients or healthy donors, in absence and presence of apixaban (60 ng/ml). We evaluated changes in surface VCAM-1 and ICAM-1, intracellular eNOS, reactive oxygen species (ROS), and von Willebrand Factor (VWF) production by immunofluorescence, reactivity of the extracellular matrix (ECM) towards platelets, and intracellular signaling. RESULTS: ECs exposed to uremic serum triggered dysregulation of all the parameters. Presence of apixaban resulted in decreased expression of VCAM-1 (178 ± 14 to 89 ± 2% on HMEC and 324 ± 71 to 142 ± 25% on HUVEC) and ICAM-1 (388 ± 60 to 111 ± 10% on HMEC and 148 ± 9% to 90 ± 7% on HUVEC); increased eNOS (72 ± 8% to 95 ± 10% on HMEC); normalization of ROS levels (173 ± 21 to 114 ± 13% on HMEC and 165 ± 14 to 127 ± 7% on HUVEC); lower production of VWF (168 ± 14 to 92 ± 4% on HMEC and 151 ± 22 to 99 ± 11% on HUVEC); and decreased platelet adhesion onto ECM (134 ± 22 to 93 ± 23% on HMEC and 161 ± 14 to 117 ± 7% on HUVEC). Apixaban inhibited p38MAPK and p42/44 activation in HUVEC (139 ± 15 to 48 ± 15% and 411 ± 66 to 177 ± 57%, respectively) (p < 0.05 vs control for all parameters). CONCLUSION: Anti-FXa strategies, such as apixaban, prevented ED caused by the uremic milieu, exhibiting anti-inflammatory and antioxidant properties and modulating the reactivity of the ECM.


Subject(s)
Factor Xa Inhibitors/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Pyrazoles/pharmacology , Pyridones/pharmacology , Uremia/physiopathology , Endothelial Cells/drug effects , Extracellular Matrix/drug effects , Humans , Inflammation/physiopathology , Intercellular Adhesion Molecule-1/drug effects , Nitric Oxide Synthase Type III/drug effects , Phenotype , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Vascular Cell Adhesion Molecule-1/drug effects , von Willebrand Factor/drug effects
6.
Blood ; 133(14): 1597-1606, 2019 04 04.
Article in English | MEDLINE | ID: mdl-30692122

ABSTRACT

The third-generation tyrosine kinase inhibitor (TKI) ponatinib has been associated with high rates of acute ischemic events. The pathophysiology responsible for these events is unknown. We hypothesized that ponatinib produces an endothelial angiopathy involving excessive endothelial-associated von Willebrand factor (VWF) and secondary platelet adhesion. In wild-type mice and ApoE-/- mice on a Western diet, ultrasound molecular imaging of the thoracic aorta for VWF A1-domain and glycoprotein-Ibα was performed to quantify endothelial-associated VWF and platelet adhesion. After treatment of wild-type mice for 7 days, aortic molecular signal for endothelial-associated VWF and platelet adhesion were five- to sixfold higher in ponatinib vs sham therapy (P < .001), whereas dasatinib had no effect. In ApoE-/- mice, aortic VWF and platelet signals were two- to fourfold higher for ponatinib-treated compared with sham-treated mice (P < .05) and were significantly higher than in treated wild-type mice (P < .05). Platelet and VWF signals in ponatinib-treated mice were significantly reduced by N-acetylcysteine and completely eliminated by recombinant ADAMTS13. Ponatinib produced segmental left ventricular wall motion abnormalities in 33% of wild-type and 45% of ApoE-/- mice and corresponding patchy perfusion defects, yet coronary arteries were normal on angiography. Instead, a global microvascular angiopathy was detected by immunohistochemistry and by intravital microscopy observation of platelet aggregates and nets associated with endothelial cells and leukocytes. Our findings reveal a new form of vascular toxicity for the TKI ponatinib that involves VWF-mediated platelet adhesion and a secondary microvascular angiopathy that produces ischemic wall motion abnormalities. These processes can be mitigated by interventions known to reduce VWF multimer size.


Subject(s)
Cardiovascular Diseases/chemically induced , Fusion Proteins, bcr-abl/antagonists & inhibitors , Imidazoles/toxicity , Pyridazines/toxicity , Thrombotic Microangiopathies/complications , Animals , Aorta/metabolism , Endothelium/metabolism , Humans , Ischemia/chemically induced , Mice , Mice, Knockout , Platelet Adhesiveness/drug effects , Protein Kinase Inhibitors/toxicity , Ventricular Dysfunction/chemically induced , von Willebrand Factor/drug effects , von Willebrand Factor/metabolism
7.
Acta Cir Bras ; 33(8): 664-672, 2018 Aug.
Article in English | MEDLINE | ID: mdl-30208128

ABSTRACT

PURPOSE: To investigate the correlation of inhaled nitric oxide (NO) on plasma levels of cardiac troponin I (cTnI) and von Willebrand factor (vWF), glycoprotein (GP) IIb/IIIa, granule membrane protein 140 (GMP-140) in rabbits with acute massive pulmonary embolism (PE). METHODS: Thirty apanese white rabbits were divided into 3 groups, thrombus were injected in model group (n = 10), NO were inhalated for 24 h after massive PE in NO group (n = 10), saline were injected in control group (n = 10). The concentrations of vWF, GP IIb/IIIa, GMP-140 and cTnI were tested at 4, 8, 12, 16, 20, and 24 h, Correlation analyses were conducted between cTnI and vWF, GP IIb/IIIa, and GMP-140 by Pearson's correlation. RESULTS: The concentration of cTnI and vWF, GP IIb/IIIa, and GMP-140 was increased in the model group, compared to control group. In the inhaled group, the concentrations of cTnI, vWF, GP IIb/IIIa, and GMP-140 were reduced compared to model group. There was a positive correlation between cTnI and vWF, GP IIb/IIIa, and GMP-140. CONCLUSION: Inhaled nitric oxide can lead to a decrease in levels of cardiac troponin I, von Willebrand factor, glycoprotein, and granule membrane protein 140, after an established myocardial damage, provoked by acute massive pulmonary embolism.


Subject(s)
Nitric Oxide/administration & dosage , P-Selectin/blood , Platelet Glycoprotein GPIIb-IIIa Complex/analysis , Pulmonary Embolism/blood , Pulmonary Embolism/drug therapy , Troponin I/blood , von Willebrand Factor/analysis , Administration, Inhalation , Animals , Disease Models, Animal , Heart Ventricles/pathology , Myocardium/pathology , P-Selectin/drug effects , Platelet Glycoprotein GPIIb-IIIa Complex/drug effects , Pulmonary Embolism/pathology , Rabbits , Reference Values , Reproducibility of Results , Time Factors , Treatment Outcome , Troponin I/drug effects , X-Ray Microtomography , von Willebrand Factor/drug effects
8.
Acta cir. bras ; 33(8): 664-672, Aug. 2018. tab, graf
Article in English | LILACS | ID: biblio-949374

ABSTRACT

Abstract Purpose: To investigate the correlation of inhaled nitric oxide (NO) on plasma levels of cardiac troponin I (cTnI) and von Willebrand factor (vWF), glycoprotein (GP) IIb/IIIa, granule membrane protein 140 (GMP-140) in rabbits with acute massive pulmonary embolism (PE). Methods: Thirty apanese white rabbits were divided into 3 groups, thrombus were injected in model group (n = 10), NO were inhalated for 24 h after massive PE in NO group (n = 10), saline were injected in control group (n = 10). The concentrations of vWF, GP IIb/IIIa, GMP-140 and cTnI were tested at 4, 8, 12, 16, 20, and 24 h, Correlation analyses were conducted between cTnI and vWF, GP IIb/IIIa, and GMP-140 by Pearson's correlation. Results: The concentration of cTnI and vWF, GP IIb/IIIa, and GMP-140 was increased in the model group, compared to control group. In the inhaled group, the concentrations of cTnI, vWF, GP IIb/IIIa, and GMP-140 were reduced compared to model group. There was a positive correlation between cTnI and vWF, GP IIb/IIIa, and GMP-140. Conclusion: Inhaled nitric oxide can lead to a decrease in levels of cardiac troponin I, von Willebrand factor, glycoprotein, and granule membrane protein 140, after an established myocardial damage, provoked by acute massive pulmonary embolism.


Subject(s)
Animals , Rabbits , Pulmonary Embolism/blood , von Willebrand Factor/analysis , Platelet Glycoprotein GPIIb-IIIa Complex/analysis , Platelet Glycoprotein GPIIb-IIIa Complex/drug effects , P-Selectin/blood , Troponin I/blood , Nitric Oxide/administration & dosage , Pulmonary Embolism/pathology , Pulmonary Embolism/drug therapy , Reference Values , Time Factors , Administration, Inhalation , von Willebrand Factor/drug effects , Reproducibility of Results , Treatment Outcome , P-Selectin/drug effects , Troponin I/drug effects , Disease Models, Animal , X-Ray Microtomography , Heart Ventricles/pathology , Myocardium/pathology
9.
Przegl Lek ; 73(5): 280-6, 2016.
Article in English | MEDLINE | ID: mdl-29629740

ABSTRACT

Aim of the study: To compare effect of six month transdermal 17 ß-estradiol supplementation with oral medroxyprogresterone acetate to oral simvastatin treatment on nitric oxide (NO), endothelin-1, ß-thromboglobulin, vascular endothelial growth factor (VEGF) and von Willebrand factor (vWF) levels during standard exercise test in post menopausal women. Patients and Methods: 32 women were included to the study. Group 1 treated with 17ß-estradiol combined with medroxyprogesterone. Group 2 treated with simvastatin, group 3 was the controls. VEGF plasma levels as well as basal and standard exercise test induced levels of vWF, NO, endothelin- 1, ß-thromboglobulin were measured at the beginning of the study, at 3rd and 6th month of the study. During standard exercise test these parameters were measured three times: at the beginning, at peak exercise and at the 15th minute of recovery. Results: 17ß-estradiol supplementation and simvastatin treatment reduced basal and exercise test induced endothelin-1 plasma level. 17ß-estradiol supplementation gradually increased NO release, whereas simvastatin initially reduced and finally increased nitric oxide release. NO/ET-1 ratio was increased at peak exercise and recovery time in group 1 whereas only at peak exercise in group 2. Basal VEGF plasma level and ß-thromboglobulin level at recovery time were reduced after 6 month of simvastatin therapy. Conclusion: Six months long oral simvastatin exerted beneficial influence on endothelial function equal to that of continuous transdermal 17ß-estradiol supplementation combined with medroxyprogesterone acetate. Simvastatin only exerted benefical effect on platelet function. The protective effect of both therapies was more pronounced during exercise and recovery time.


Subject(s)
Endothelin-1/drug effects , Estradiol/pharmacology , Nitric Oxide/blood , Simvastatin/pharmacology , Vascular Endothelial Growth Factors/drug effects , von Willebrand Factor/drug effects , Administration, Cutaneous , Administration, Oral , Adult , Aged , Drug Therapy, Combination , Endothelin-1/blood , Estradiol/administration & dosage , Estradiol/therapeutic use , Exercise Test , Female , Hormone Replacement Therapy , Humans , Medroxyprogesterone/administration & dosage , Medroxyprogesterone/pharmacology , Medroxyprogesterone/therapeutic use , Middle Aged , Postmenopause , Simvastatin/administration & dosage , Simvastatin/therapeutic use , Vascular Endothelial Growth Factors/blood , von Willebrand Factor/analysis
10.
Inflammopharmacology ; 22(6): 367-72, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25055995

ABSTRACT

OBJECTIVE: The role of inflammatory and endothelial dysfunction markers in the atherogenic process has been well recognized. The data have made both C-reactive protein (CRP) and von Willebrand factor (vWF) promising targets for the cardiovascular disease research and drug development. Inhibition of CRP and vWF synthesis, therefore, might be a potential therapeutic strategy. METHODS: The effect of sodium salicylate on vWF production by human umbilical vein endothelial cells (HUVECs) using enzyme-linked immunosorbent Assays (ELISA) and real-time PCR was examined. In addition, small interfering RNA (siRNA) against NF-κB was used to investigate the existence of a role for this signaling pathway. RESULTS: Our findings demonstrated that sodium salicylate decreased vWF, but not CRP production at both mRNA and protein levels significantly and this might not occur via nuclear transcription factor (NF-κB) inhibition. CONCLUSION: Our results indicated a further rationalization of the effects of sodium salicylate on atherothrombotic events by attenuation of vWF production.


Subject(s)
C-Reactive Protein/drug effects , Human Umbilical Vein Endothelial Cells/drug effects , Sodium Salicylate/pharmacology , von Willebrand Factor/drug effects , C-Reactive Protein/metabolism , Enzyme-Linked Immunosorbent Assay , Human Umbilical Vein Endothelial Cells/metabolism , Humans , NF-kappa B/antagonists & inhibitors , RNA, Messenger/metabolism , RNA, Small Interfering/administration & dosage , Real-Time Polymerase Chain Reaction , Signal Transduction/drug effects , von Willebrand Factor/metabolism
11.
J Rheumatol ; 41(4): 714-22, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24532831

ABSTRACT

OBJECTIVE: To prospectively evaluate the effect of tumor necrosis factor (TNF)-α inhibitors on hemostatic and fibrinolytic variables in subjects with psoriatic arthritis (PsA). METHODS: Among subjects with PsA who were taking traditional disease-modifying antirheumatic drugs (DMARD), 98 patients with active disease who switched to treatment with TNF-α inhibitors were enrolled in this study (Group 1). In parallel, 98 matched subjects with minimal disease activity (MDA) and treated with DMARD were enrolled (Group 2). In all patients, hemostatic and fibrinolytic variables were evaluated at enrollment and after a 6-month followup. Results were stratified according to treatment and to MDA achievement. RESULTS: Seventy-six Group 1 and 80 Group 2 subjects completed the 6-month followup. During the followup, significant changes in hemostatic and fibrinolytic variables were found in Group 1, but not in Group 2 subjects. At the end of the followup, patients treated with TNF-α inhibitors showed significantly lower levels of hemostatic and fibrinolytic variables as compared to those treated with traditional DMARD. Among Group 1 subjects, changes in hemostatic and fibrinolytic variable levels were significantly higher in those who achieved MDA versus in those who did not. Multivariate analyses showed that a treatment with TNF-α blockers affected fibrinolytic variables [plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA)] and some acute-phase proteins (D-dimer, coagulation factor VIII, and von Willebrand factor). In contrast, the MDA achievement during treatment with TNF-α blockers maximally affected fibrinolytic variables (PAI-1 and t-PA). CONCLUSION: TNF-α inhibitors brought about a significant improvement of hemostatic and fibrinolytic balance in subjects with PsA. Maximal changes were found in patients achieving MDA.


Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Psoriatic/diagnosis , Arthritis, Psoriatic/drug therapy , Fibrinolysis/drug effects , Hemostasis/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Age Factors , Analysis of Variance , C-Reactive Protein/drug effects , C-Reactive Protein/metabolism , Chi-Square Distribution , Cohort Studies , Female , Fibrin Fibrinogen Degradation Products/drug effects , Fibrin Fibrinogen Degradation Products/metabolism , Follow-Up Studies , Humans , Male , Middle Aged , Multivariate Analysis , Prospective Studies , Reference Values , Risk Factors , Severity of Illness Index , Sex Factors , Statistics, Nonparametric , Tissue Plasminogen Activator/drug effects , Tissue Plasminogen Activator/metabolism , Treatment Outcome , Tumor Necrosis Factor-alpha/therapeutic use , von Willebrand Factor/drug effects , von Willebrand Factor/metabolism
12.
Expert Opin Ther Targets ; 18(1): 43-53, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24073984

ABSTRACT

INTRODUCTION: Animal studies show that von Willebrand factor (vWF) deficiency is associated with lower risks for atherosclerosis and atherothrombosis, including events such as acute myocardial infarction and ischemic stroke. vWF enables the binding of platelets along the damaged vessels leading to thrombogenesis. Interruption of this early stage of thrombus formation may prevent downstream amplification of the inflammatory and thrombotic processes that contribute to the plaque instability. AREAS COVERED: Increased levels of vWF have been related to the atherothrombotic complications and endothelial damage. Therefore, vWF has been suggested as a useful biomarker of endothelial damage/dysfunction. Preliminary data from Phase II trials in patients with acute myocardial infarction and thrombotic disorders have been promising, but many unanswered questions remain regarding the optimal therapeutic use of vWF blockade. This article describes the molecular structure of vWF, its functions and its interactions with the platelet membrane glycoprotein (GP) receptors GPIb and GPIIb-IIIa, as well as collagen. In addition, the article provides an overview of most promising investigational compounds tested as antithrombotic agents targeting vWF. METHODS: Preclinical and clinical data for vWF blockage are discussed. EXPERT OPINION: The therapeutic approaches aiming to block the collagen-vWF-platelet axis have potentially beneficial effects for prevention and treatment of cardiovascular disease. However, the evidence directly associating vWF blockage with beneficial clinical outcomes is limited and needs further research. Optimal treatment regimes need to be established in relation of specific clinical circumstances and conditions.


Subject(s)
Atherosclerosis/drug therapy , Cardiovascular Diseases/drug therapy , von Willebrand Factor/drug effects , Atherosclerosis/blood , Atherosclerosis/prevention & control , Cardiovascular Diseases/blood , Humans , Platelet Activation , Protein Conformation , Proteolysis , von Willebrand Factor/chemistry , von Willebrand Factor/physiology
13.
Drug Des Devel Ther ; 7: 233-42, 2013.
Article in English | MEDLINE | ID: mdl-23589679

ABSTRACT

PURPOSE: 7-Difluoromethyl-5, 4'-dimethoxygenistein (DFMG), prepared by the difluoromethylation and alkylation of Genistein, is an active new chemical entity. Its anti-atherosclerosis effect was found in a series of studies in vitro. In this article, we explored and evaluated the anti-atherosclerosis effect via its protection of endothelial function in ApoE(-/-) mice that were fed a high-fat diet. METHODS: Five C57BL/6J mice were selected as a control group and were fed a 1% high-fat diet (control group, n = 5). Five ApoE(-/-) mice that were fed a high-fat diet for 16 weeks were selected as the atherosclerosis model group (model group, n = 5). In the phase I study, 25 ApoE(-/-) mice were provided a prophylactic treatment with different drugs at the beginning of the 16 week high-fat diet: 5 mg/gk genistein (genistein 1 group, n = 5), 5 mg/kg lovastatin (lovastatin1 group, n = 5), 2.5 mg/kg DFMG (DFMG L1 group, n = 5), 5 mg/kg DFMG (DFMG M1 group, n = 5), and 10 mg/kg DFMG (DFMG H1 group, n = 5). In the phase II study, 25 atherosclerosis model, ApoE(-/-) mice were treated with different drugs and fed a high-fat diet for 16 weeks: 5 mg/gk genistein (genistein 2 group, n = 5), 5 mg/kg lovastatin (lovastatin 2 group, n = 5), 2.5 mg/kg DFMG (DFMG L2 group, n = 5), 5 mg/kg DFMG (DFMG M2 group, n = 5), and 10 mg/kg DFMG (DFMG H2 group, n = 5). The plasma levels of lipids, von Willebrand factor (vWF), and nitrite were compared between phases I and II. Endothelium-dependent relaxation (EDR), aortic lesion development, and quantification in thoracic aortas were measured during these two phase studies. RESULTS: Compared to the model group, the lipid and vWF plasma levels were significantly lower, the plasma nitrite levels were significantly higher, the fatty streaks of aortic lesions were significantly lower, and the endothelium dependent relaxation was significantly higher after both phase studies (P < 0.05). The DFMG supplementation led to significant plasma nitrite increment in all groups after both phase studies (P < 0.05). There were significantly decreased fatty streaks of aortic lesions in DFMG-prevented and DFMG-treated mice (P < 0.05). There was a significant increase in EDR in all prophylactic treatment groups and treatment groups (P < 0.05). We further demonstrated that the preventative effect was more obvious than the therapeutic effect. CONCLUSION: Our results suggest that DFMG could work in prophylactic and therapeutic treatments for atherosclerosis development.


Subject(s)
Apolipoproteins E/genetics , Atherosclerosis/drug therapy , Genistein/analogs & derivatives , Hyperlipidemias/drug therapy , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/pathology , Atherosclerosis/pathology , Diet, High-Fat , Disease Models, Animal , Dose-Response Relationship, Drug , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Genistein/administration & dosage , Genistein/pharmacology , Lipids/blood , Lovastatin/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nitrites/metabolism , Vasodilation/drug effects , von Willebrand Factor/drug effects , von Willebrand Factor/metabolism
14.
Arterioscler Thromb Vasc Biol ; 33(6): 1230-7, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23539221

ABSTRACT

OBJECTIVE: Cocaine use is associated with arterial thrombosis, including myocardial infarction and stroke. Cocaine use results in increased plasma von Willebrand factor (VWF), accelerated atherosclerosis, and platelet-rich arterial thrombi, suggesting that cocaine activates the endothelium, promoting platelet-VWF interactions. APPROACH AND RESULTS: Human umbilical vein endothelial cells, brain microvasculature endothelial cells, or coronary artery endothelial cells were treated with cocaine or metabolites benzoylecgonine, cocaethylene, norcocaine, or ecgonine methylester. Supernatant VWF concentration and multimer structure were measured, and platelet-VWF strings formed on the endothelial surface under flow were quantified. Cocaine, benzoylecgonine, and cocaethylene induced endothelial VWF release, with the 2 metabolites being more potent than the parent molecule. Brain microvasculature endothelial cells were more sensitive to cocaine and metabolites than were human umbilical vein endothelial cells or coronary artery endothelial cells. Coronary artery endothelial cells released VWF into the supernatant but did not form VWF-platelet strings. Intracellular cAMP concentration was not increased after treatment with cocaine or its metabolites. CONCLUSIONS: Both cocaine and metabolites benzoylecgonine and cocaethylene induced endothelial VWF secretion, possibly explaining thrombotic risk after cocaine ingestion. VWF secretion is likely to vary between vascular beds, with brain endothelial cells being particularly sensitive. These results suggest that clinical management of cocaine-induced ischemia may benefit from therapies aimed at disrupting the VWF-platelet interaction.


Subject(s)
Cocaine/analogs & derivatives , Cocaine/pharmacology , Endothelial Cells/drug effects , P-Selectin/drug effects , von Willebrand Factor/drug effects , Brain/cytology , Cells, Cultured , Coronary Vessels/cytology , Coronary Vessels/drug effects , Endothelial Cells/metabolism , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , In Vitro Techniques , P-Selectin/metabolism , Sensitivity and Specificity , Thrombosis/physiopathology , von Willebrand Factor/metabolism
15.
Eur Cell Mater ; 23: 161-9; discussion 169, 2012 Mar 13.
Article in English | MEDLINE | ID: mdl-22415802

ABSTRACT

The aim of the present study was to test the hypothesis that sandblasted and acid etched titanium surfaces can be functionalised with vascular endothelial growth factor (VEGF) using oligonucleotides for anchorage and slow release. rhVEGF165 molecules were conjugated to strands of 30-mer non-coding DNA oligonucleotides (ODN) and hybridised to complementary ODN anchor strands which had been immobilised to the surface of sandblasted/acid etched (SAE) Ti specimens. Specimens with non-conjugated VEGF adsorbed to ODN anchor strands and to blank SAE surfaces served as controls. Specific binding of conjugated VEGF exhibited the highest percentage of immobilised VEGF (71.0 %), whereas non-conjugated VEGF only achieved 53.2 and 30.7 %, respectively. Cumulative release reached 54.0 % of the immobilised growth factor in the group of specifically bound VEGF after 4 weeks, whereas non-conjugated VEGF adsorbed to ODN strands released 78.9% and VEGF adsorbed to SAE Ti surfaces released 97.4 %. Proliferation of human umbilical vein endothelial cells (HUVECs) was significantly increased on the surfaces with specifically bound VEGF compared to the control surfaces and SAE Ti surfaces without VEGF. Moreover, the released conjugated VEGF exhibited biological activity by induction of von Willebrand Factor (vWF) in mesenchymal stem cells. It is concluded that the angiogenic functionalisation of SAE titanium surfaces can be achieved by conjugation of VEGF to ODN strands and hybridisation to complementary ODN strands that are anchored to the titanium surface. The angiogenic effect is exerted both through the immobilised and the released portion of the growth factor.


Subject(s)
Neovascularization, Physiologic/drug effects , Titanium/metabolism , Vascular Endothelial Growth Factor A/administration & dosage , Vascular Endothelial Growth Factor A/metabolism , Cell Proliferation/drug effects , Cells, Cultured , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/metabolism , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Immobilized Proteins/metabolism , In Vitro Techniques , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Oligonucleotides/chemistry , Oligonucleotides/metabolism , Recombinant Proteins/metabolism , Surface Properties , Titanium/chemistry , von Willebrand Factor/drug effects , von Willebrand Factor/metabolism
16.
Stroke ; 43(2): 599-606, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22180250

ABSTRACT

Thrombus formation is of paramount importance in the pathophysiology of acute ischemic stroke. Current antithrombotics used to treat or prevent cerebral ischemia are only moderately effective or bear an increased risk of severe bleeding. von Willebrand factor (VWF) has long been known to be a key player in thrombus formation at sites of vascular damage. While the association between VWF and coronary heart disease has been well studied, knowledge about the role of VWF in stroke is much more limited. However, in recent years, an increasing amount of clinical and preclinical evidence has revealed the critical involvement of VWF in stroke development. This review summarizes the latest insights into the pathophysiologic role of VWF-related processes in ischemic brain injury under experimental conditions and in humans. Potential clinical merits of novel inhibitors of VWF-mediated platelet adhesion and activation as powerful and safe tools to combat thromboembolic disorders including ischemic stroke are discussed. Preclinical and clinical evidence illustrates an important role of VWF in ischemic stroke, suggesting that VWF could become a promising target in stroke therapy.


Subject(s)
Stroke/therapy , von Willebrand Factor/physiology , ADAM Proteins/physiology , ADAMTS13 Protein , Blood Platelets/drug effects , Blood Platelets/physiology , Fibrinolytic Agents/pharmacology , Fibrinolytic Agents/therapeutic use , Hemostasis/physiology , Humans , Inflammation/pathology , Inflammation/therapy , Intracranial Thrombosis/pathology , Intracranial Thrombosis/therapy , Stroke/drug therapy , von Willebrand Factor/antagonists & inhibitors , von Willebrand Factor/drug effects
17.
Eur J Clin Invest ; 42(3): 254-9, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21834801

ABSTRACT

BACKGROUND: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently described entity, linked to gain-of-function mutations (R137C and R137L) in arginine vasopressin (AVP) gene leading to chronic activation of tubular V2 AVP receptor (V2R) and thus free water reabsorption. In addition to collecting duct cells, the V2R is also expressed in endothelial cells, where it mediates the rise in circulating levels of von Willebrand factor (vWF) and coagulation factor VIII (fVIII). Recent in vitro data showed that these mutant receptors are resistant to vasopressin-stimulated cAMP production. We aimed to explore by clinical observations the sensitivity to vasopressin of the R137C-V2R mutant in vivo. MATERIAL AND METHODS: We performed a stimulation test with 1-desamino-D arginin vasopressin (dDAVP) 0·3 µg/kg of bodyweight in three patients (two hemizygous male and one heterozygous female) with NSIAD with R137C mutation and measured on the one hand the levels of vWF and fVIII and the other hand urine osmolality and albumin excretion (UAE). RESULTS: Whereas the female heterozygous patient displayed normal response to simulation by dDAVP (except for UAE), no increase in vWF, fVIII, urinary osmolality and UAE was observed among hemizygous male patients. CONCLUSIONS: Coherent with in vitro observation in transfected cells, our clinical observations demonstrate that the R137C-V2R mutant is resistant to vasopressin stimulation in its physiological sites of expression.


Subject(s)
Antidiuretic Agents/pharmacology , Deamino Arginine Vasopressin/pharmacology , Diabetes Insipidus, Nephrogenic/genetics , Inappropriate ADH Syndrome/genetics , Adult , Arginine Vasopressin/drug effects , Arginine Vasopressin/genetics , DNA Mutational Analysis , Diabetes Insipidus, Nephrogenic/drug therapy , Factor VIII/drug effects , Factor VIII/genetics , Female , Homeostasis/drug effects , Homeostasis/genetics , Humans , Inappropriate ADH Syndrome/drug therapy , Male , Middle Aged , Mutation , Pedigree , Receptors, Vasopressin/drug effects , Receptors, Vasopressin/genetics , Water-Electrolyte Imbalance/drug therapy , Water-Electrolyte Imbalance/genetics , Young Adult , von Willebrand Factor/drug effects , von Willebrand Factor/genetics
18.
Ginekol Pol ; 82(4): 259-64, 2011 Apr.
Article in Polish | MEDLINE | ID: mdl-21735693

ABSTRACT

OBJECTIVES: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and oligo-/anovulation and is associated with risk factors for cardiovascular disorders, such as insulin resistance and central adiposity. All these factors can lead to endothelial dysfunction and impaired coagulation processes. Metformin effectively treats hyperinsulinemia in women with PCOS. However, clinical trials assessing influence of metformin on endothelium and fibrinolysis are limited. Therefore, the objective of this study was to prospectively assess the effects of a 6-month metformin therapy on body mass index (BMI), insulin sensitivity and coagulation/fibrinolysis markers in hyperinsulinemic women with PCOS. MATERIALS AND METHODS: Thirty hyperinsulinemic PCOS women (aged 26.0 +/- 3.7 [mean +/- SD]) without any additional disorders were included into the study. Metformin was administered at a dose of 1700 mg daily for 6 months. Serum plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) concentrations and von Willebrand factor (vWf) levels were measured with specific assays, together with glucose and insulin concentrations. Insulin sensitivity index (ISI) and BMI were calculated. RESULTS: All patients completed the study and no side effects were reported. BMI decreased significantly (by 8.5%, p < 0.0001). The metformin therapy improved insulin sensitivity as evidenced by an increase in ISI by 41.5% (p = 0.0005). A marked reduction in PAI-1 (by 26%, p < 0.005) concentrations was observed. No significant changes were noted for t-PA and vWf. CONCLUSIONS: Metformin administration decreases the circulating PAI-1 concentration and simultaneously improves insulin sensitivity and BMI in PCOS women with hyperinsulinemia. Long-term metformin administration may be a new prophylactic measure for the prevention of cardiovascular disorders in such patients.


Subject(s)
Blood Coagulation Factors/drug effects , Hyperinsulinism/drug therapy , Hypoglycemic Agents/administration & dosage , Insulin Resistance , Metformin/administration & dosage , Polycystic Ovary Syndrome/drug therapy , Adult , Body Mass Index , Female , Humans , Hyperinsulinism/complications , Plasminogen Activator Inhibitor 1/blood , Poland , Polycystic Ovary Syndrome/complications , Tissue Plasminogen Activator/drug effects , Treatment Outcome , Young Adult , von Willebrand Factor/drug effects
19.
Pediatr Blood Cancer ; 54(7): 963-9, 2010 Jul 01.
Article in English | MEDLINE | ID: mdl-20405515

ABSTRACT

BACKGROUND: The pathogenesis and the impact of therapy on thrombin activation in children with acute lymphoblastic leukemia (ALL) are unknown. Steroids may contribute to ALL-associated thrombosis. We explored the hemostatic effects of methylprednisolone monotherapy (MpMT) (32 mg/m2/day IV x 3 days) in children with newly diagnosed ALL. METHODS: Children (>1 to < or = 18 years of age) enrolled on DFCI ALL05-01 protocol (n = 30; mean age 6.3 years), without prior steroid therapy, were eligible for study. Overnight fasting pre- and post-MpMT samples were analyzed for coagulation factors [FVIII:C, von Willebrand factor antigen (vWF:Ag) and fibrinogen] and parameters of thrombin generation [prothrombin fragments 1.2 (F1.2), thrombin-antithrombin complex (TAT), and D-dimer]. RESULTS: At diagnosis F1.2 (1.5 nmol/L), TAT (10.9 microg/L), and D-dimers (2,766 ng/ml) levels were increased indicating endogenous thrombin activation. Patients with peripheral blasts (n = 17) had higher levels of vWF:Ag (1.89 vs. 1.14 P = 0.001), TAT (15.39 vs. 5.02 P = 0.038), and D-dimer (3,640 vs. 1,623 P = 0.019) compared to those without peripheral blasts. Following MpMT the blast count decreased significantly from 24% to 3.5% (P < 0.001) with reduction in level of vWF:Ag (1.5, P < 0.01), TAT (8.9, P = 0.42), and D-dimer (P = 0.018) despite 30% increase in FVIII:C levels (P = 0.005). However, patients without peripheral blasts had no significant change in vWF:Ag levels (1.14 vs. 1.25; P = 0.142) and had an increase in thrombin generation parameters. CONCLUSIONS: We postulate that peripheral blasts through endothelial activation stimulate vWF:Ag production/secretion causing coagulation activation. Methylprednisolone therapy reduces the blast count and indirectly suppresses the coagulation activation. Future studies are required to confirm these findings.


Subject(s)
Glucocorticoids/adverse effects , Methylprednisolone/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Thrombin/drug effects , von Willebrand Factor/drug effects , Adolescent , Child , Child, Preschool , Clinical Trials as Topic , Female , Humans , Male , Thrombosis/chemically induced
20.
Thromb Res ; 125(6): e275-80, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20156642

ABSTRACT

INTRODUCTION: The cortisol-induced increase in von Willebrand factor (VWF) in Cushing's syndrome (CS) seems to depend on single nucleotide polymorphisms (SNPs) of the VWF promoter, haplotype 1 (-3268G/-2709C/-2661A/-2527G) being the susceptible pattern. MATERIALS AND METHODS: This study focused on a new variable region of the VWF promoter, the -2144(GT)(n) locus, to establish whether different GT-repeat lengths are also involved in modulating the cortisol-induced increase in VWF. Sixty-nine CS patients were investigated, divided into groups A (high VWF) and B (normal VWF). RESULTS: Analysing the (GT)(n) locus revealed a similar allele distribution in CS patients and normal subjects, (GT)(n) variants ranging from 15 to 24 repeats and (GT)(19) and (GT)(21) being the two most represented. However, when groups A and B were analysed separately, a different allele distribution was observed: short GT-repeats (15-19, GT(S)) were more frequent in group A, long GT-repeats (20-24, GT(L)) in group B (p=0.01). About genotype distributions, (GT)(S)/(GT)(S) was higher in group A and rare in group B (22.5% and 3.4%, respectively), whereas (GT)(L)/(GT)(L) was higher in group B than in group A (55.2%, 27.5%) (p=0.021). Odds-ratio analysis revealed a risk of a cortisol-dependent increase in VWF three times higher for alleles (GT)(S) than for (GT)(L), and 13-fold for genotype (GT)(S)/(GT)(S) respect to (GT)(L)/(GT)(L). CONCLUSIONS: In conclusion, not only the SNPs haplotypes in the VWF gene promoter, but also the variable-length (GT)(n) locus predict the risk of developing high VWF levels under conditions of glucocorticoid excess; the combination of (GT)(S) and haplotype 1 represents the susceptible pattern.


Subject(s)
Cushing Syndrome/genetics , Glucocorticoids/pharmacology , Microsatellite Repeats , Promoter Regions, Genetic , von Willebrand Factor/genetics , Adult , Case-Control Studies , Cushing Syndrome/diagnosis , Cushing Syndrome/metabolism , Female , Genetic Predisposition to Disease , Haplotypes , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , von Willebrand Factor/drug effects
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