The Role of the Platelet in the Pathogenesis of Atherothrombosis

Steinhubl, Steven R.; Moliterno, David J.

doi:10.2165/00129784-200505060-00007

Cited by 125 publications

(71 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Again, high concentrations of oxidised, and especially glycated LDL, were very active in determining this effect, whereas the effect of native LDL was slower if still significant. Because the CD40/CD40 ligand complex, induced by LDL [33], leads to an upregulation of proinflammatory cytokines, adhesion molecules and reactive oxygen species [32,34], the current observations establish that LDL can directly affect the inflammatory process at the glomerular level.…”

Section: Discussionmentioning

confidence: 58%

Effects of different LDL particles on inflammatory molecules in human mesangial cells

et al. 2008

View full text Add to dashboard Cite

Aims/hypothesis Inflammation is a mechanism of glomerular damage in chronic glomerulopathies. LDL may increase the production of inflammatory cytokines in renal tissues. However, the relative role of native, oxidised and glycated LDL in promoting this process has been only partially elucidated. Methods We tested the inflammatory and proapoptotic effects of native, oxidised and glycated LDL in human mesangial cells (HMCs) by measuring levels of IL6, CD40 and macrophage migration inhibitory factor (MIF) genes, MIF protein, release of IL6, soluble CD40, fibronectin and laminin, early and late apoptosis, and extracellular regulated kinases (ERK) 1/2 and c-Jun N-terminal kinase (JNK) activation. Results IL6 and CD40 mRNA were dose-dependently upregulated by all three species; this was closely paralleled by their increased release. MIF mRNA was potently stimulated by modified LDL, as confirmed by immunostaining. Fibronectin and laminin release was stimulated by both oxidised and glycated, but not native, LDL. All LDL species induced some increase in late, but not early, apoptosis, and similarly activated JNK2/3 phosphorylation; in contrast, ERK1/2 phosphorylation was more strongly upregulated by oxidised than either native or glycated LDL.Conclusions In HMCs, the production and release of IL6 and CD40 is stimulated by both native and modified LDL, while MIF is more strongly stimulated by oxidised LDL. Regarding the pattern of mesangial expansion, fibronectin and laminin are upregulated by oxidised and glycated LDL. Apoptosis, if modest, is induced by all species. Intracellular signalling of native and modified LDL involves JNK2/3 and, perhaps more specifically, ERK1/2. Tight control of the lipid profile may be useful in preserving kidney function in patients with metabolic alterations.

show abstract

Section: Discussionmentioning

confidence: 58%

Effects of different LDL particles on inflammatory molecules in human mesangial cells

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Next, platelets are stimulated to release various molecules, such as thrombin, thromboxane A 2 , and ADP, to activate other platelets, and to increase the expression of glycoprotein IIb/IIIa receptors for fibrinogen binding. These processes lead to the formation of a platelet plug at the damaged endothelial site (20,21).…”

Section: Discussionmentioning

confidence: 99%

Antiplatelet, anticoagulant and fibrinolytic effects of Litchi chinensis Sonn. extract

2011

View full text Add to dashboard Cite

Abstract. Litchi chinensis Sonn. (lychee), which belongs to the family of Sapindaceae, is a subtropical evergreen tree that is cultivated throughout Southeast Asia, particularly in China. Litchi chinensis has been reported to have anti-inflammatory, antioxidant and antidiabetic activities. However, the antiplatelet and anticoagulant effects of Litchi chinensis have not been reported previously. In this study, we investigated the effects of a 70% ethanol extract from Litchi chinensis (LCE) on platelet aggregation, coagulation and fibrinolysis. LCE dose-dependently inhibited collagen-and ADP-induced platelet aggregation in rat platelet-rich plasma. LCE at 4 mg/ml had a maximal inhibitory effect on platelet aggregation. In particular, the LCE 4 mg/ml-treated group showed almost complete inhibition in the collagen-induced platelet aggregation assay. It also significantly prolonged coagulation times, such as the activated partial thromboplastin and prothrombin time, in rat platelet-poor plasma. We also investigated the fibrinolytic effects of LCE using the fibrin plate assay. LCE increased fibrinolytic activity in a dose-dependent manner. These results demonstrated the antithrombotic effects of LCE and suggest that Litchi chinensis may be a new natural source for the development of antiplatelet, anticoagulant and thrombolytic therapeutics for thrombotic and cardiovascular diseases. IntroductionPlatelets circulate in the blood and play essential roles in hemostasis and repair of the endothelial wall in a physiological state (1). This is achieved primarily by thrombus formation when damage occurs to the endothelial cell layer of blood vessels. However, excessive platelet aggregation produces a pathological thrombus and plays a major role in the initiation and pathogenesis of atherothrombotic diseases (2). An abnormal thrombus within the vascular system can obstruct the flow of blood and nutrients to important tissues. As a result, it can cause a variety of cardiovascular diseases, such as myocardial infarction, stroke and ischemic heart disease, and is a leading cause of death (3). Thus, inhibition of platelet aggregation is important in preventing the progression of atherosclerosis and arterial thromboses (4).A thrombus is composed of fibrin, which is produced from its precursor, fibrinogen, by thrombin. An inappropriate fibrin clot must be eliminated rapidly by fibrinolysis to maintain homeostasis (5). Dissolution of a fibrin clot is dependent on the action of plasmin, a serine protease that is activated by tissue plasminogen activator. In clinical therapy, thrombolytic agents (fibrinolytic enzymes), such as tissue plasminogen activator and urokinase, convert inactive plasminogen to active plasmin, allowing fibrinolysis to occur (6). Antiplatelet agents, such as aspirin and clopidogrel, are widely used and directly inhibit platelet aggregation. However, use of these agents is limited as they can lead to serious side effects, such as headache, vomiting, and gastric ulceration, and are costly (7,8).Litchi chinensis Son...

show abstract

“…The importance of control of intra-arterial thombosis is enhanced if this process proves crucial to the development of atherothrombosis as well as to the terminal stages [1,2]. It is commonly thought that thrombosis and haemostasis are always linked, leading to the concept that anti-thombotic therapy is inevitably associated with excess bleeding, also called 'bleeding risk' [3].…”

Section: Introductionmentioning

confidence: 99%

Preservation of Haemostasis with Anti-thrombotic Serotonin Antagonism

Mi¹

2017

J Hematol Clin Res

View full text Add to dashboard Cite

An enquiry into the lack of attention awarded to serotonin antagonism in the treatment of arterial thrombosis revealed that the mode of action of serotonin and its platelet receptor antagonists was an action upon thrombus growth, and not, as with other anti-platelet drugs upon the initiation of thrombosis. This lack of effect could explain why this approach has been considered not to be effective. However under conditions of arterial stenosis in which there is platelet activation by increased shear stress, and during the growth phase of arterial thrombi, serotonin 5HT 2A antagonism has been demonstrated to have great potentcy in dispersing thrombotic obstruction to blood fl ow. This mode of action, the lack of participation of serotonin in haemostasis, and the absence of serotonin in wounds accounts for the proven lack of effect of effect of pure specifi c 5HT 2A antagonists (i.e., not those with other actions) on operative bleeding and skin bleeding times. This lack of effect on haemostasis solves the dosing problem encountered with other anti-thrombotic drugs, with which drug concentration cannot be controlled with single fi xed doses, leading to the association between increased antithrombotic effi cacy and increased bleeding complications. Thus 5HT 2A antagonism appears to be the preferred approach, from the point of view of safety and lack of bleeding risk; this consideration applies particularly to thrombosis therapy in the context of traumatic accidents, surgical operations and invasive procedures such as angioplasty.

show abstract

The Role of the Platelet in the Pathogenesis of Atherothrombosis

Cited by 125 publications

References 89 publications

Effects of different LDL particles on inflammatory molecules in human mesangial cells

Effects of different LDL particles on inflammatory molecules in human mesangial cells

Antiplatelet, anticoagulant and fibrinolytic effects of Litchi chinensis Sonn. extract

Preservation of Haemostasis with Anti-thrombotic Serotonin Antagonism

Contact Info

Product

Resources

About