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Effect Of Diabetes On Endothelial And Plateletts Pdf

effect of diabetes on endothelial and plateletts pdf

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Oncotarget a primarily oncology-focused, peer-reviewed, open access, biweekly journal aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

Metrics details. The incidence and prevalence of diabetes mellitus is rapidly increasing worldwide at an alarming rate. Besides affecting the ability of body to use glucose, it is associated with micro-vascular and macro-vascular complications. Augmented atherosclerosis is documented to be the key factor leading to vascular complications in T2DM patients.

Interaction between platelets and endothelium: from pathophysiology to new therapeutic options

The reciprocal and often complex interactions with the endothelium and leucocytes are object of continuous studies and future targeted drug therapies.

Low-grade inflammation, endothelial dysfunction, and platelet hyper-reactivity are all independently associated with an increased risk of cardiovascular events. In this context, antiplatelet treatment for patients with coronary artery disease CAD , beyond its major treatment impact on the reduction of thrombotic events through platelet inhibition, seems to have an important role on platelet and endothelium interplay, by decreasing inflammation, improving endothelial function and decelerating atherosclerosis progression.

This review article describes the cross talk between platelets and endothelial cells ECs , in particular those who promote atherosclerosis. Moreover, we summarize the current knowledge about the influence of contemporary antiplatelet regimens with their individual characteristics on those complex processes.

Largest ones are alpha granules whom number is 50—60 per platelet 3. Platelet lysosomes, contain mainly acid hydrolases, cathepsin D and E which are able to degrade glycoproteins, glycolipids and glycosaminoglycans 4. They are implicated in the remodeling of the extracellular matrix and to thrombus regulation.

Dense granules count 4—8 per platelet, containing high concentrations of calcium and phosphates, serotonin and adenine nucleotides, substances that promote vasoconstriction and platelet aggregation 5. P-selectin, a large adhesion molecule of the selectin family, is expressed in elevated concentrations on platelets surface during platelets activation mediating interactions between ECs, leucocytes and other platelets 6 , 7.

Platelets actions are mediated through a variety of receptors and mediator molecules. GPVI and GPa2b1 integrin represent the main collagen receptors that mediate platelet interactions with subendothelial collagen during primary haemostasis 8. GPIba receptor is the principal platelet receptor for vWF 9. It is found on platelets surface in an inactive form and changes structure during platelets activation, having a central role in platelets aggregation 10 , Fibrinogen, fibronectin, vitronectin and vWF constitute the main ligands of this important receptor.

Protease activated receptors PAR which are members of G protein receptors, mediate the action of thrombin, one of the most important activators inducing platelet activation and granule release Thromboxane A2 TXA2 is an arachidonic acid product that induces potent platelet activation, aggregation and degranulation, in cooperation with other platelet agonists.

These actions are mediated via two isoforms of receptors, TPa which represents the prevalent form on human platelets and TPb, members of the G protein-coupled receptor family 13 , The stimulation of P2Y1 receptor results in increased intracellular calcium levels and initiation of platelet shape change and aggregation At the same time, the stimulation of the P2Y12 receptor inhibits adenylyl cyclase activity, resulting in reduction of the intracellular levels of CAMP and subsequent amplification and stabilization of platelets aggregation process, enhancing platelet response to other agonists 15 , The entire vascular system is covered by a single strut of ECs.

Endothelium which was originally considered as a simple passive barrier, is now viewed as an organ whose normal functioning is crucial for maintaining vascular health and whose dysfunction is crucial in the initiation, progression and clinical complications of vascular disease ECs play an important role in vascular tone, regulating thrombosis and thrombolysis, platelets adherence and activation in order to maintain an undisturbed blood flow under physiologic conditions.

At the same time endothelium is of paramount importance in body homeostasis as it regulates the transfer of different molecules through blood vessels The role of the endothelium as a semipermeable barrier is one of its most basic functions.

It regulates transport of macromolecules between the vascular lumen and vascular smooth muscle. Under physiologic conditions platelets circulate without adhering to intact and inactive endothelium.

A layer of proteoglycans and glycoproteins is present between ECs and blood, known as glycocalyx This structure regulates endothelium permeability and endothelium interactions with other cells such as platelets and leucocytes, mainly repelling them through its negative charge and limiting the endothelial exposure to adhesion molecules. In addition, prostacyclin, a product of arachidonic acid metabolism in endothelial cells with vasodilating properties, inhibits platelets aggregation by elevating intracellular levels of CAMP 19 , This substance has a synergistic action with nitric oxide NO.

NO is the most important endothelial derived relaxing factor and inhibits platelets activation by enhancing the production of guanosine monophosphate GMP. The endothelium is also producing substances with vasoconstrictive and pro-thrombotic behavior, like TXA2 22 which promotes platelet aggregation, expresses adhesive co-factors for platelets such as vWF, fibronectin and thrombospondin, and procoagulant factors such as factor V.

Endothelial-derived vasoconstrictors are opposing the action of the endothelial-derived vasodilators Endothelial dysfunction is a disturbance in normal endothelial function as a consequence of different stimuli or clinical conditions. This disturbed balance may lead to platelets aggregation and adhesion to the endothelium thereby activating it and encouraging leukocyte adhesion, as well as releasing platelet-derived growth factors PDGFs that stimulate intimal hyperplasia.

Atherosclerosis is characterized by two parallel operations: infiltration of inflammatory cells and lipid accumulation in the intima of the arterial wall Chronic inflammation defines the evolution of the atherosclerotic plaque, from the earliest stages till its rupture and atherothrombosis.

There is growing evidence that platelets, through complex interactions with endothelial and inflammatory cells, play a major role in the initiation and preservation of this process 28 - The initiation of atherosclerosis requires the presence of either activated platelets or activated endothelial cells or both A series of pathologic stimuli like hypertension, diabetes mellitus, smoking and dyslipidemia can lead to endothelial dysfunction and triggering of the atherosclerotic process.

Oxidant stress and in particular low-density lipoprotein LDL accumulation, results in reduced NO levels and triggering of inflammatory pathways 32 , The presence of integrins which are transmembrane receptors mediating cells adhesion on platelets surface, further enhances this binding, leading to a more stable adhesion between platelets and ECs 39 , Adhesion proteins, platelet endothelial cell adhesion molecule PECAM , P-selectin, fibronectin, vWF, vitronectin and fibrinogen, coagulation factors including plasminogen, protein S, factor V and matrix metalloproteinase are also released.

Other mediators participating in this activation state are serotonin, histamine and PDGF. In this way platelets promote inflammation in a self-sustaining way preparing the next step which is the formation of atherosclerotic plaque Figure 3. Activated platelets form aggregates with circulating leucocytes PLAs 57 - The initial binding of platelets to leukocytes is mediated by platelet P-selectin binding to leukocyte PSGL This is followed by further platelets activation by leucocytes, while platelets promote leucocytes transformation in more adhesive and migratory forms, in a continuous interaction.

These cells are involved in vascular repair processes after vascular injury or ischemia. They sustain reendothelialization and neovascularization, via their potential to proliferate and differentiate into endothelial-phenotype cells. The number of those cells in peripheral blood of patients with cardiovascular disease has been shown to predict cardiovascular outcomes. Platelets not only mediate EPCs recruitment at the site of vascular injury, but they also strongly support their proliferation, maturation, differentiation to endothelial-phenotype cells and the acquisition of functional properties such as NO production in vitro Those platelet actions are independent from direct contact between the two cell populations and seem to be mediated through PDGF and basic fibroblast growth factor BFGF.

Antiplatelet therapy is a cornerstone therapy for CAD patients as it prevents thrombotic events. Older antiplatelet agents like aspirin and clopidogrel and newer more potent agents like prasugrel and ticagrelor have been proven effective in all the clinical spectrum of CAD patients, especially those undergoing percutaneous coronary intervention PCI or suffering from acute coronary syndromes ACS.

Current antiplatelet medications offer clinical benefits not only due to their well-recognized antithrombotic effect, but also via the attenuation of platelet inflammatory action, impediment of P2Y12 activation effects in other cells and through other pathways.

Aspirin remains the basis of antiplatelet therapy for thrombotic events prevention. Aspirin is considered to prevent platelet aggregation by inhibition of platelet TXA2 synthesis due to irreversible inactivation of platelet cyclooxygenase-1 COX Since platelet-derived TXA2 increases vessel wall constriction and enhances proliferation of vascular cells 61 , inhibition of its synthesis by aspirin may have indirect effects on the interaction between platelets and vascular wall.

Hypercholesterolemic mice lacking the TXA2 receptor TP develop less atherosclerosis 62 , suggesting an anti-atherosclerotic activity of aspirin. Aspirin inhibits NO consumption by platelets from healthy subjects, but its beneficial effects on NO bioactivity may be compromised in some hypercholesterolemic patients In the clinical level, platelet inhibition with aspirin has been shown to modulate acetylcholine-induced peripheral vasodilation in patients with atherosclerosis, via inhibition of COX-dependent vasoconstrictors In addition, administration of low dose aspirin seems to improve the endothelium dependent vasodilation in patients with arterial hypertension Heitzer et al.

Finally, Warnholtz et al. Platelet P2Y12 inhibitors form a major part of the treatment strategy for patients with CAD due to the importance of the platelet P2Y12 receptor in mediating arterial thrombosis. The most commonly used agents are clopidogrel and the newer and more potent prasugrel and ticagrelor.

These agents are selective P2Y12 inhibitors, with different pharmacodynamic and pharmacokinetic properties. Prasugrel and ticagrelor with in vitro and in vivo stronger antiplatelet action than clopidogrel, have proven better clinical efficacy than clopidogrel, showing less thrombotic events in large ACS populations, with the cost of increased bleeding events.

ROS can further activate platelets, enhance platelets-leukocytes interactions and accelerate lipids oxidation and inflammation processes. P2Y12 receptors expression can be also found in other cells, such as leukocytes, dendritic cells, VSMC, endothelial cells and neurons In patients with stable CAD, clopidogrel treatment is associated with improvement of forearm blood flow and reduction in values of inflammation and oxidative stress biomarkers Warnholtz et al.

Consistently, Patti et al. Bonello et al. Muller et al. Fujisue et al. However, in another study Haynes et al. Those controversies might be explained due to the different methods used for endothelial function and platelet activation evaluation and the different study populations. Prasugrel, similar to clopidogrel, is a prodrug requiring hepatic metabolism to generate an active metabolite that acts as an irreversibly binding P2Y12 antagonist.

Prasugrel improves mid-term vascular dysfunction and inflammation in patients with unstable angina. It is also associated with a reduction of platelet-derived inflammatory markers and platelet-leukocyte interaction Ticagrelor seems to offer additional benefits than clopidogrel and prasugrel on endothelial function Ticagrelor beyond its profound platelet inhibition seems to enhance adenosine levels by blocking adenosine reuptake in blood cells 81 , resulting in vessels dilatation.

In addition, it causes ATP release from red blood cells 82 , enhancing the endothelium release of vasodilatory mediators such as prostacyclin, NO and endothelial hyperpolarizing factor. Brachial artery reactivity, as well as post treatment platelet inhibition with VerifyNow assay was evaluated in all patients.

The results of this study suggested that ticagrelor, besides a more potent platelet inhibition, caused a significant improvement of brachial artery vascular tone, both by endothelial function amelioration and with enhancement of nitroglycerin-mediated dilation, an endothelium independent mechanism.

Furthermore, Torngren et al. Rusnak et al. In other animal models ticagrelor seems to attenuate neointimal formation or hyperplasia 86 , Interestingly ticagrelor exerts beneficial effects on endothelium also through other pathways. This effect of ticagrelor was independent of platelet activity and may contribute to endothelial repair-regeneration processes.

Ticagrelor beyond P2Y12 reversible inhibition appears to have additional antithrombotic properties. Tissue factor TF is the molecule that promotes the extrinsic coagulation cascade and it is expressed in different cells, including endothelial cells. Reiner et al. These results showed that ticagrelor exhibits endothelial-specific antithrombotic properties independent from P2Y12 receptor inhibition.

Those findings were confirmed in ticagrelor-treated mice where attenuated endothelial TF expression levels were observed. A summary of all the clinical studies showing the impact of antiplatelet treatment on endothelial function is shown in the Table 1.

Mechanisms Involved in Diabetes-Associated Platelet Hyperactivation

Cardiovascular disease remains the main cause of morbidity and mortality in patients with diabetes. The risk of vascular ischemia is increased in this population and outcome following an event is inferior compared to individuals with normal glucose metabolism. The reasons for the adverse vascular profile in diabetes are related to a combination of more extensive atherosclerotic disease coupled with an enhanced thrombotic environment. Long-term measures to halt the accelerated atherosclerotic process in diabetes have only partially addressed vascular pathology, while long-term antithrombotic management remains largely similar to individuals without diabetes. We address in this review the pathophysiological mechanisms responsible for atherosclerosis with special emphasis on diabetes-related pathways.

Javascript is currently disabled in your browser. Several features of this site will not function whilst javascript is disabled. Authors He Y , Wu N. Received 24 December Published 3 March Volume Pages — Review by Single anonymous peer review.

The reciprocal and often complex interactions with the endothelium and leucocytes are object of continuous studies and future targeted drug therapies. Low-grade inflammation, endothelial dysfunction, and platelet hyper-reactivity are all independently associated with an increased risk of cardiovascular events. In this context, antiplatelet treatment for patients with coronary artery disease CAD , beyond its major treatment impact on the reduction of thrombotic events through platelet inhibition, seems to have an important role on platelet and endothelium interplay, by decreasing inflammation, improving endothelial function and decelerating atherosclerosis progression. This review article describes the cross talk between platelets and endothelial cells ECs , in particular those who promote atherosclerosis. Moreover, we summarize the current knowledge about the influence of contemporary antiplatelet regimens with their individual characteristics on those complex processes. Largest ones are alpha granules whom number is 50—60 per platelet 3.

Thrombosis and Vascular Inflammation in Diabetes: Mechanisms and Potential Therapeutic Targets

Address correspondence to John M. Harlan, MD. Phone: ; Fax: ; E-mail: jharlan u. The authors gratefully acknowledge Dr. Rothlein, Dr.

Introduction

This open-access and indexed, peer-reviewed journal publishes review articles ideal for the busy physician. The copyright in this work belongs to Radcliffe Medical Media. Permission is required for reuse of this content. Diabetes mellitus DM , characterised by chronic hyperglycaemia, is a rapidly growing worldwide health problem. The incidence of DM is increasing and will more than double within 15 years, mainly due to adverse lifestyle changes with excess caloric intake and reduced physical activity, which in turn will lead to obesity, insulin resistance and, consequently, impaired glucose tolerance and type 2 DM.

 Пустой номер. Наверное, уплыли на уик-энд с друзьями на яхте. Беккер заметил, что на ней дорогие вещи. - И у тебя нет кредитной карточки. - Есть, но отец ее заблокировал. Он думает, что я балуюсь наркотиками. - А это не так? - спросил Беккер холодно, глядя на ее припухший локоть.

Беккер долго вглядывался в текст и хмурил брови. И ради этого стоило убивать.

 Да? - Меган внезапно насторожилась. Беккер достал из кармана бумажник. - Конечно, я буду счастлив тебе заплатить.

Внезапно она вспомнила, зачем искала Стратмора, и повернулась к. - Коммандер. Северная Дакота - это Грег Хейл. Сьюзан едва ли не физически ощутила повисшее молчание.

Diabetic concentrations of metformin inhibit platelet-mediated ovarian cancer cell progression

Всякий раз, ступая на очередную ступеньку, она носком туфли первым делом старалась нащупать ее край. К ней снова вернулись страхи, связанные с новой попыткой найти ключ Хейла в Третьем узле. Коммандер был абсолютно убежден в том, что у Хейла не хватит духу на них напасть, но Сьюзан не была так уж уверена в .

Они двигались уже не по узкому боковому притоку, а по главному руслу. Когда улица сделала поворот, Беккер вдруг увидел прямо перед собой собор и вздымающуюся ввысь Гиральду. Звон колоколов оглушал, эхо многократно отражалось от высоких стен, окружающих площадь. Людские потоки из разных улиц сливались в одну черную реку, устремленную к распахнутым дверям Севильского собора. Беккер попробовал выбраться и свернуть на улицу Матеуса-Гаго, но понял, что находится в плену людского потока.

 Сейф Бигглмана, - протянула Сьюзан. Стратмор кивнул. Сейф Бигглмана представляет собой гипотетический сценарий, когда создатель сейфа прячет внутри его ключ, способный его открыть. Чтобы ключ никто не нашел, Танкадо проделал то же самое с Цифровой крепостью. Он спрятал свой ключ, зашифровав его формулой, содержащейся в этом ключе.

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