Abstract 187: Paraoxonase-2 Regulates Blood Coagulation through Endothelial Redox-Signaling and Inflammation

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Julia Ebert ◽  
Petra Wilgenbus ◽  
Sven Horke
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Blood Coagulation ◽  
Coagulation Factors ◽  
Vascular Wall ◽  
Inflammatory Processes ◽  
Gene Expression Studies ◽  
Underlying Mechanisms ◽  
Membrane Exposure ◽  
Bone Marrow Chimeras

Background: Enhanced coagulation increases the risk for cardiovascular diseases (CVDs) such as stroke, myocardial infarction or atherosclerosis. Increased oxidative stress and inflammation, predominantly in the vascular wall and platelets, are important underlying mechanisms of a pro-coagulant state. Paraoxonase-2 (PON2), an anti-oxidative protein with anti-inflammatory properties, has an emergent role in CVDs, as it counter-acts atherosclerosis. Previous studies revealed enhanced atherosclerosis in PON2-/- mice and diminished PON2 expression in human atherosclerotic endothelium. We hypothesized that PON2 affects coagulation by controlling redox-mediated inflammatory processes provoking atherosclerosis. Methods and Results: In several coagulation tests, PON2-/- mice showed significantly shortened clotting times (8.58±0.09 sec) compared to WT (9.32±0.16 sec prothrombin time; p<0.001; n=42). Confocal microscopy, flow cytometry and gene expression studies revealed enhanced vascular oxidative stress (p<0.001; n=6) and a pro-inflammatory endothelium in PON2-/- mice. In line with this, the endogenous interleukin-6 plasma level was increased compared to WT (2-fold) as disclosed by cytokine profiling. Additionally, plasmatic coagulation factors VIII, IX and XI displayed significantly elevated activities in PON2-/- mice (p<0.05; n=10). Further, PON2-/- platelets showed a pro-coagulant activity, due to increased endogenous thrombin potentials triggered by an enhanced phosphatidylserine plasma membrane exposure (p<0.01; n=7). To locate PON2’s dominant effect to either endothelial cells, plasma or platelets, we established bone marrow chimeras and transgenic mice with exclusively endothelial and hematopoietic PON2 expression (Tie2cre-PON2-/-). Coagulation time analyses revealed that the pro-coagulant effect was attenuated in WT chimera with PON2-/- bone marrow (9.22±0.15 sec; n=12) and in Tie2cre-PON2-/- (10.02±0.3 sec; n=23), indicating that much of the effects originates from PON2 functions in the endothelium. Conclusion: We found that PON2 regulates specific pathways of blood coagulation based on a redox-mediated endothelial-dependent modulation of important players in inflammation and hemostasis.

scholarly journals Novel Insights into the Vasoprotective Role of Heme Oxygenase-1

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Emanuela Marcantoni ◽  
Luigia Di Francesco ◽  
Melania Dovizio ◽  
Annalisa Bruno ◽  
Paola Patrignani
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Vascular Wall ◽  
Heme Oxygenase 1 ◽  
Antiinflammatory Effect ◽  
Atherosclerotic Lesions ◽  
Inflammatory Processes ◽  
Cox 2 ◽  
Endogenous Antioxidant

Cardiovascular risk factors contribute to enhanced oxidative stress which leads to endothelial dysfunction. These events trigger platelet activation and their interaction with leukocytes and endothelial cells, thus contributing to the induction of chronic inflammatory processes at the vascular wall and to the development of atherosclerotic lesions and atherothrombosis. In this scenario, endogenous antioxidant pathways are induced to restrain the development of vascular disease. In the present paper, we will discuss the role of heme oxygenase (HO)-1 which is an enzyme of the heme catabolism and cleaves heme to form biliverdin and carbon monoxide (CO). Biliverdin is reduced enzymatically to the potent antioxidant bilirubin. Recent evidence supports the involvement of HO-1 in the antioxidant and antiinflammatory effect of cyclooxygenase(COX)-2-dependent prostacyclin in the vasculature. Moreover, the role of HO-1 in estrogen vasoprotection is emerging. Finally, possible strategies to develop novel therapeutics against cardiovascular disease by targeting the induction of HO-1 will be discussed.

Angiotensin II type 1 receptors and the intestinal microvascular dysfunction induced by ischemia and reperfusion

2006 ◽  
Vol 290 (6) ◽  
pp. G1203-G1210 ◽  
Author(s):  
Thomas Petnehazy ◽  
Dianne Cooper ◽  
Karen Y. Stokes ◽  
Janice Russell ◽  
Katherine C. Wood ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Angiotensin Ii ◽  
Blood Cell ◽  
Blood Cells ◽  
Platelet Adhesion ◽  
Sham Operation ◽  
Cell Recruitment ◽  
Bone Marrow Chimeras

The acute phase of intestinal ischemia-reperfusion (I/R) injury is mediated by leukocytes and is characterized by oxidative stress and blood cell recruitment. Upregulation of angiotensin II type 1 receptors (AT1-R) has been implicated in the pathogenesis of conditions associated with oxidative stress. The AT1-R-antagonist Losartan (Los) attenuates leukocyte recruitment following I/R. However, the role of AT1-R in intestinal I/R injury and the associated platelet-leukocyte interactions remains unclear. The objective of this study was to define the contribution of AT1-R to I/R-induced blood cell recruitment in intestinal venules. Leukocyte and platelet adhesion were quantified by intravital microscopy in the small bowel of C57Bl/6 [wild-type (WT)] mice exposed to sham operation or 45 min of ischemia and 4 h of reperfusion. A separate WT group received Los for 7 days before gut I/R (WT-I/R + Los). AT1-R bone marrow chimeras that express AT1-R on the vessel wall but not blood cells also underwent I/R. Platelet and leukocyte adhesion as well as AT1-R expression in the gut microvasculature were significantly elevated after I/R. All of these responses were attenuated in the WT-I/R + Los group, compared with untreated I/R mice. A comparable abrogation of I/R-induced blood cell adhesion was noted in AT1-R bone marrow chimeras. I/R-induced platelet adhesion was unaltered in mice overexpressing Cu,Zn-SOD or mice deficient in NAD(P)H oxidase. These data suggest that although gut I/R upregulates endothelial expression of AT1-R, engagement of these angiotensin II receptors on blood cells is more important in eliciting the prothrombogenic and proinflammatory state observed in postischemic gut venules, through a superoxide-independent pathway.

Natural Oestrogen in the Female Climacteric - Influence on Blood Coagulation and Fibrinolysis

1978 ◽  
Vol 40 (02) ◽  
pp. 532-541 ◽  
Author(s):  
Anders Lagrelius ◽  
Nils-Olov Lunell ◽  
Margareta Blombäck
Keyword(s):  
Blood Coagulation ◽  
Antithrombin Iii ◽  
Coagulation Factors ◽  
Control Group ◽  
Blood Coagulation Factors ◽  
Excessive Bleeding ◽  
Oestrone Sulphate ◽  
Menopausal Women ◽  
History Of ◽  
Coagulation And Fibrinolysis

SummaryThe aim of the present study was to investigate the effect on blood coagulation and fibrinolysis of a natural oestrogen preparation, piperazine oestrone sulphate, prospectively in menopausal women. Scopolamine was given to the control group.The women were investigated before and during treatment with regard to factors VIII, VII, X, V, fibrinopeptide A, antithrombin III, plasminogen, rapid antiplasmin and α1-antitrypsin. There was no significant change towards hypercoagulability or decreased fibrinolysis in any group. In the oestrogen group, however, a tendency towards an increased level of plasminogen and a decreased level of antiplasmin was demonstrated. In the scopolamine group there was an unexpected fall in factors X and V and also in plasminogen and α1,-antitrypsin. A low level of some blood coagulation factors in some of the women before treatment is somewhat astonishing; none of them had any history of excessive bleeding.

Changes in Blood Coagulation and Fibrinolysis in Rats Fed Atherogenic Diets

1963 ◽  
Vol 10 (02) ◽  
pp. 295-308 ◽  
Author(s):  
Clarence Merskey ◽  
Herbert Wohl
Keyword(s):  
Blood Coagulation ◽  
Blood Platelets ◽  
Coagulation Factors ◽  
Atherogenic Diet ◽  
Normal Serum ◽  
Significant Prolongation ◽  
Lysis Time ◽  
Factor Ii ◽  
Euglobulin Lysis Time ◽  
Coagulation And Fibrinolysis

Summary1. Groups of rats were fed thrombogenic diets and the effects on blood coagulation and fibrinolysis assessed.2. Animals fed a diet containing cholesterol, thiouracil and cholic acid developed high levels of coagulation factors I, II, V, VII—X, VIII, IX and X.3. Animals fed a similar diet with additional 40% beef fat developed even greater elevation of V, VII—X, VIII and X, similar elevation of factor II, and lesser (but still significant) elevation of factors I and IX. In addition marked elevation of blood platelets occurred.4. Euglobulin lysis time of the group not fed the additional fat was longer than in controls. Significant prolongation of euglobulin lysis time was not found in the group fed additional fat.5. If the increased levels of plasma fibrinogen were taken into account, it was found that a larger amount of fibrin was lysed per unit time in the euglobulin lysis test with plasma from rats fed either atherogenic diet compared with controls.6. Defective thromboplastin generation was present in both groups of rats fed an atherogenic diet. The defect was present in the serum and was not due to lack of a factor required for thromboplastin generation. An inhibitor was present in the serum which was capable of preventing the action of normal serum.7. No good correlation was found between the occurrence of changes in blood coagulation or fibrinolysis and the presence or absence of thrombosis and infarction.8. The exact cause of these anomalies remains unexplained, as does the cause of the thrombosis in these animals. Starvation per se does not account for these abnormal findings. They could not adequately be explained on the basis of “hypercoagulability” of the blood.

Exercise-Induced Fibrinolysis – Fact or Fiction?

1982 ◽  
Vol 48 (02) ◽  
pp. 201-203 ◽  
Author(s):  
N A Marsh ◽  
P J Gaffney
Keyword(s):  
Plasminogen Activator ◽  
Degradation Products ◽  
Coagulation Factors ◽  
Vascular Wall ◽  
Strenuous Exercise ◽  
Fibrin Degradation Products ◽  
Real Increase ◽  
Exercise Induced ◽  
Male Subjects

SummaryThe effect of strenuous exercise on the fibrinolytic and coagulation mechanisms was examined in six healthy male subjects. Five min bicycle exercise at a work-rate of 800 to 1200 kpm. min−1 produced an abrupt increase in plasma plasminogen activator levels which disappeared after 90 min. However, there was no change in early or late fibrin degradation products nor was there a change in fibrinopeptide A levels or βthromboglobulin levels after exercise although activated partial thromboplastin times were significantly shortened. It is concluded that strenuous exercise does not produce any real increase in fibrinogen-fibrin conversion nor any real increase in the breakdown of these proteins. The role of exercise-induced release of plasminogen activator remains unclear, but probably helps to maintain plasma levels in a discontinuous manner concurrently with the continuous low-level secretion from the vascular wall. The shortening of partial thromboplastin time may be due to the raised levels of plasminogen activator changing the activation state of other coagulation factors.

STEROIDSTRUKTUR UND LEBERTOXIZITÄT

1967 ◽  
Vol 54 (1) ◽  
pp. 73-84 ◽  
Author(s):  
H. L. Krüskemper ◽  
G. Noell
Keyword(s):  
Alkaline Phosphatase ◽  
Liver Function ◽  
Blood Coagulation ◽  
Electrophoretic Pattern ◽  
Coagulation Factors ◽  
Blood Coagulation Factors ◽  
Methyl Group ◽  
Liver Functions ◽  
Male Subjects ◽  
Androstane Derivatives

ABSTRACT In male subjects investigations have been carried out regarding the effect of C1- and C17-methylated androstane derivatives (20 mg per day, orally, two weeks) on liver functions (parameters: activities of GPT, GOT, alkaline phosphatase and cholinesterase in serum; electrophoretic pattern; blood coagulation factors V, VII, X and prothrombin; BSP-retention). In addition to the well known hepatotropic action of 17α-alkylated C-19-steroids a quasi-axial 1α-methyl configuration (in 1α-methylandrost-2-en-17β-ol) definitely increased BSP-retention and several coagulation factors. These steroid effects decreased gradually when a methyl group was introduced in C1 equatorially (1-methylandrost-1-en-17β-ol-3-one) or quasi-equatorially (1β-methylandrost-2-en-17β-ol), the latter compound completely lacking from any influence on parameters of liver function under investigation.

Phytosomal Curcumin Elicits Anti-tumor Properties Through Suppression of Angiogenesis, Cell Proliferation and Induction of Oxidative Stress in Colorectal Cancer

2019 ◽  
Vol 24 (39) ◽  
pp. 4626-4638 ◽  
Author(s):  
Reyhaneh Moradi-Marjaneh ◽  
Seyed M. Hassanian ◽  
Farzad Rahmani ◽  
Seyed H. Aghaee-Bakhtiari ◽  
Amir Avan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Therapeutic Potential ◽  
Vegf Signaling ◽  
Anticancer Effects ◽  
Inhibition Of Angiogenesis ◽  
Underlying Mechanisms ◽  
Apoptotic Activity

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-associated mortality in the world. Anti-tumor effect of curcumin has been shown in different cancers; however, the therapeutic potential of novel phytosomal curcumin, as well as the underlying molecular mechanism in CRC, has not yet been explored. Methods: The anti-proliferative, anti-migratory and apoptotic activity of phytosomal curcumin in CT26 cells was assessed by MTT assay, wound healing assay and Flow cytometry, respectively. Phytosomal curcumin was also tested for its in-vivo activity in a xenograft mouse model of CRC. In addition, oxidant/antioxidant activity was examined by DCFH-DA assay in vitro, measurement of malondialdehyde (MDA), Thiol and superoxidedismutase (SOD) and catalase (CAT) activity and also evaluation of expression levels of Nrf2 and GCLM by qRT-PCR in tumor tissues. In addition, the effect of phytosomal curcumin on angiogenesis was assessed by the measurement of VEGF-A and VEGFR-1 and VEGF signaling regulatory microRNAs (miRNAs) in tumor tissue. Results: Phytosomal curcumin exerts anti-proliferative, anti-migratory and apoptotic activity in-vitro. It also decreases tumor growth and augmented 5-fluorouracil (5-FU) anti-tumor effect in-vivo. In addition, our data showed that induction of oxidative stress and inhibition of angiogenesis through modulation of VEGF signaling regulatory miRNAs might be underlying mechanisms by which phytosomal curcumin exerted its antitumor effect. Conclusion: Our data confirmed this notion that phytosomal curcumin administrates anticancer effects and can be used as a complementary treatment in clinical settings.

Could Antioxidant Supplementation Delay Progression of Cardiovascular Disease in End-Stage Renal Disease Patients?

2020 ◽  
Vol 19 (1) ◽  
pp. 41-54 ◽  
Author(s):  
Stefanos Roumeliotis ◽  
Athanasios Roumeliotis ◽  
Xenia Gorny ◽  
Peter R. Mertens
Keyword(s):  
Oxidative Stress ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Close Association ◽  
Omega 3 ◽  
Endstage Renal Disease ◽  
Increased Risk ◽  
Underlying Mechanisms ◽  
Stage Renal Disease ◽  
End Stage

In end-stage renal disease patients, the leading causes of mortality are of cardiovascular (CV) origin. The underlying mechanisms are complex, given that sudden heart failure is more common than acute myocardial infarction. A contributing role of oxidative stress is postulated, which is increased even at early stages of chronic kidney disease, is gradually augmented in parallel to progression to endstage renal disease and is further accelerated by renal replacement therapy. Oxidative stress ensues when there is an imbalance between reactive pro-oxidants and physiologically occurring electron donating antioxidant defence systems. During the last decade, a close association of oxidative stress with accelerated atherosclerosis and increased risk for CV and all-cause mortality has been established. Lipid peroxidation has been identified as a trigger for endothelial dysfunction, the first step towards atherogenesis. In order to counteract the deleterious effects of free radicals and thereby ameliorate, or delay, CV disease, exogenous administration of antioxidants has been proposed. Here, we attempt to summarize existing data from studies that test antioxidants for CV protection, such as vitamins E and C, statins, omega-3 fatty acids and N-acetylcysteine.

Exercise and Stevia Rebaudiana (R) Extracts Attenuate Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms

2020 ◽  
Vol 20 (7) ◽  
pp. 1117-1132
Author(s):  
Abdelaziz M. Hussein ◽  
Elsayed A. Eid ◽  
Ismaeel Bin-Jaliah ◽  
Medhat Taha ◽  
Lashin S. Lashin
Keyword(s):  
Oxidative Stress ◽  
Blood Glucose ◽  
Diabetic Cardiomyopathy ◽  
Caspase 3 ◽  
Stevia Rebaudiana ◽  
Diabetic Rats ◽  
Control Group ◽  
Underlying Mechanisms ◽  
Type 2 Diabetic

Background and Aims: In the current work, we studied the effects of exercise and stevia rebaudiana (R) extracts on diabetic cardiomyopathy (DCM) in type 2 diabetic rats and their possible underlying mechanisms. Methods: : Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group, b) DM group, type 2 diabetic rats received 2 ml oral saline daily for 4 weeks, c) DM+ Exercise, type 2 diabetic rats were treated with exercise for 4 weeks and d) DM+ stevia R extracts: type 2 diabetic rats received methanolic stevia R extracts. By the end of the experiment, serum blood glucose, HOMA-IR, insulin and cardiac enzymes (LDH, CK-MB), cardiac histopathology, oxidative stress markers (MDA, GSH and CAT), myocardial fibrosis by Masson trichrome, the expression of p53, caspase-3, α-SMA and tyrosine hydroxylase (TH) by immunostaining in myocardial tissues were measured. Results: T2DM caused a significant increase in blood glucose, HOMA-IR index, serum CK-MB and LDH, myocardial damage and fibrosis, myocardial MDA, myocardial α-SMA, p53, caspase-3, Nrf2 and TH density with a significant decrease in serum insulin and myocardial GSH and CAT (p< 0.05). On the other hand, treatment with either exercise or stevia R extracts significantly improved all studied parameters (p< 0.05). Moreover, the effects of stevia R was more significant than exercise (p< 0.05). Conclusion: Both exercise and methanolic stevia R extracts showed cardioprotective effects against DCM and Stevia R offered more cardioprotective than exercise. This cardioprotective effect of these lines of treatment might be due to attenuation of oxidative stress, apoptosis, sympathetic nerve density and fibrosis and upregulation of the antioxidant transcription factor, Nrf2.

scholarly journals The Contribution of Microglia to Neuroinflammation in Parkinson’s Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 4676
Author(s):  
Katja Badanjak ◽  
Sonja Fixemer ◽  
Semra Smajić ◽  
Alexander Skupin ◽  
Anne Grünewald
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inflammatory Cytokine ◽  
Population Ageing ◽  
Future Research ◽  
Cytokine Release ◽  
Vicious Cycle ◽  
Inflammatory Processes ◽  
Great Evidence

With the world’s population ageing, the incidence of Parkinson’s disease (PD) is on the rise. In recent years, inflammatory processes have emerged as prominent contributors to the pathology of PD. There is great evidence that microglia have a significant neuroprotective role, and that impaired and over activated microglial phenotypes are present in brains of PD patients. Thereby, PD progression is potentially driven by a vicious cycle between dying neurons and microglia through the instigation of oxidative stress, mitophagy and autophagy dysfunctions, a-synuclein accumulation, and pro-inflammatory cytokine release. Hence, investigating the involvement of microglia is of great importance for future research and treatment of PD. The purpose of this review is to highlight recent findings concerning the microglia-neuronal interplay in PD with a focus on human postmortem immunohistochemistry and single-cell studies, their relation to animal and iPSC-derived models, newly emerging technologies, and the resulting potential of new anti-inflammatory therapies for PD.

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