Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An adhesive interaction between activated platelets and mononuclear phagocytes may contribute to the role these cells play in regulating inflammation, thrombosis, and atherosclerosis. We have previously shown that this adhesive interaction is mediated by the expression of the glycoprotein thrombospondin (TSP) on the surface of activated platelets. We now show that TSP-dependent platelet-monocyte interactions are mediated by glycoprotein IV (GPIV), an intrinsic membrane protein recently identified as a cell surface TSP receptor. Monoclonal antibodies to GPIV bound to cells of the human monocytoid line U937 as assessed by flow cytometry and inhibited the binding of 125I-TSP to the cell surface by 83%. U937 cells preincubated with anti-GPIV were not rosetted by thrombin-stimulated platelets (72% inhibition compared with control anti-monocyte antibodies). In addition, when platelets were stimulated in the presence of saturating concentrations of monoclonal antibodies to GPIV, only 18% of U937 cells were rosetted (78% inhibition). Control antibodies including anti-GPIb did not inhibit rosette formation. These data suggest that TSP can cross-link platelets and monocytes via an interaction with GPIV on the surface of both cells. This molecular bridge may mediate platelet-macrophage communication in various pathophysiologic settings.
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PMID:Glycoprotein IV mediates thrombospondin-dependent platelet-monocyte and platelet-U937 cell adhesion. 247 71

The interaction of blood platelets with collagen is generally considered to be of primary importance in the arrest of bleeding and to have a role in the pathogenesis of thrombosis and atherosclerosis. Following damage to the vascular endothelium, circulating platelets come into contact with exposed collagen fibrils in the subendothelium and spread along it; this is followed by the secretion of several biologically active substances and by aggregation of platelets. The glycoproteins of the platelet plasma membrane have an important role in the mechanisms underlying these processes. So far, two specific defects of platelet function in patients with a bleeding disorder are known to be associated with a glycoprotein defect and the study of these patients has contributed significantly to present concepts of platelet function. The glycoprotein (GP) IIB-III complex, absent or deleted in the aggregation-defective Glanzmann's thrombasthenia, has been identified as the platelet fibrinogen receptor. GPIb, which is absent in the adhesion-defective Bernard-Soulier syndrome, has been identified as the von Willebrand factor receptor on platelets. We now report a defect of the platelet plasma membrane glycoprotein composition in a patient whose platelets are totally unresponsive to collagen.
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PMID:Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia. 293 89

Platelets are activated by contact with vascular lesions in high flow arteries and are involved in the development of thrombosis, atherosclerosis and the complications of transluminal angioplasty. Hence platelets are one the targets of pharmacological intervention in the prevention and treatment of arterial thrombosis. Understanding of the mechanisms of activation of platelet has enabled the development of new antiplatelet agents and the improvement of their therapeutic usage. The most recent clinical drugs and those currently under development belong to two main families: antagonists of the membrane receptors of activation coupled to signal transducting G proteins which fix circulating stimuli such as ADP, thrombin and TXA2 and inhibitors of the binding of adhesive proteins such as fibrinogen to the GPIIb-IIIa integrin or of von Willebrand factor to the leucine-rich glycoprotein complex GPIb-V-IX.
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PMID:[Mechanisms of platelet activation and development of antiplatelet agents]. 909 10

Platelet activation state and responsiveness to physiological agonists were measured in 65 patients with documented coronary artery disease (54 male and 11 female; mean age, 58 years). Twelve patients (mean age, 52 years), selected at random from the male cohort, were compared with 12 age-matched male control subjects (mean age, 52 years) and with 10 normal, young male subjects (mean age, 25 years). Whole-blood flow cytometry was used to measure platelet activation status ex vivo and platelet responsiveness to physiological agonists in vitro. Peripheral blood samples were analyzed for bound fibrinogen and expression of P-selectin, GPIb, and GPIIb-IIIa at rest and in response to ADP (0.1 to 10 mumol/L) and thrombin (0.02 to 0.32 mu/mL). No significant differences were seen in the basal levels of fibrinogen binding between any of the groups, but P-selectin expression was significantly lower in patients compared with age-matched control subjects (P = .0005). When stimulated with agonists, patients' platelets had significantly decreased fibrinogen binding (P < .03) but no difference in P-selectin expression compared with the age-matched group. Both agonist-induced fibrinogen binding and P-selectin expression were, however, higher in the young subjects compared with either the older control group or the patients (P < .05). GPIb and GPIIb-IIIa expression were lowest in the patients with angina and highest in the young control subjects, with levels in the age-matched control subjects falling between these values. Data from the total patient cohort (n = 65) were identical to those in the smaller cohort (n = 12). In conclusion, atherosclerosis impairs platelet aggregatory responses (fibrinogen binding) over and above the decreased response seen with age. Platelet degranulation (P-selectin expression) is also impaired in patients with coronary artery disease, but only in comparison with younger subjects, not age-matched controls.
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PMID:Altered platelet function detected by flow cytometry. Effects of coronary artery disease and age. 935 70

Cigarette smoking is a well-known risk factor for atherosclerotic disorders. Several authors have suggested that platelet aggregability is important in smoking-induced vascular injury. When platelet-rich plasma is stirred at 37 degrees C in the absence of chemical stimulants, small aggregates of platelets may be formed, but it was difficult to detect small aggregates by conventional aggregometer using optical density. Recent technological advances have made it possible to detect small aggregates by using a newly developed assay system that employs laser light scattering. In the present study, we attempted to measure platelet aggregation by this method, using laser light scattering in 54 nonsmoking healthy males and 51 healthy male habitual smokers who were age matched. In smokers, blood was obtained after 10 hours of smoking abstinence. No significant difference in platelet aggregation was induced by 1 microM or 5 microM of ADP between smokers and nonsmokers. In smokers, plasma fibrinogen levels and the number of small aggregates formed in the absence of chemical stimulants was significantly higher than in nonsmokers. Small aggregates formed in the absence of stimulants correlated positively with the concentrations of von Willebrand factor (vWF) antigen (r=0.2654, p<0.01) and of fibrinogen (r=0.2834, p<0.01). The formation of these small aggregates was inhibited by monoclonal antibody against GPIIb/IIIa blocking fibrinogen binding to GPIIb/IIIa but not inhibited at all by monoclonal antibody against GPIb blocking vWF binding to GPIb. From these results, enhanced platelet aggregability in smokers was confirmed, and it was suggested that GPIIb/IIIa is concerned in platelet spontaneous aggregation, although vWF may not directly influence on the platelet spontaneous aggregation. Since the mechanism of spontaneous aggregation and the effect of increased spontaneous aggregability on the progression of atherosclerosis remains unclear, further study was considered necessary.
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PMID:Platelet spontaneous aggregation in platelet-rich plasma is increased in habitual smokers. 1009 68

Diabetes mellitus (DM) type 2 is a very strong risk factor for atherosclerosis. The final event of atherosclerosis is the vessels occlusion by platelet riche thrombus. Platelets adhesion and aggregation is mediated by interaction between platelets glycoproteins: GPIb-IX, GPIIb-IIIa and adhesive proteins: von Willebrand factor or fibrinogen. The expression of platelets GPIb-IX, GPIIb-IIIa, plasma vWF, fibrinogen concentrations were evaluated in 40 patients with diabetes type 2 (22 patients with PAOD stage II and IV according to Fontain, 18 diabetics without paod) and 32 healthy individuals. The expression of platelets glycoproteins GPIIb-IIIa and GPIb-IX was estimated by ELISA using monoclonal antibody against GPIIb-IIIa (CD41a) and GPIb-IX (CD 42a Immunotech). Plasma vWf (189.7 +/- 53.6%), fibrinogen (4.5 +/- +/- 1.3 g/l) level and expression of platelets GPIb-IX (63.2 +/- 19.6% in platelets concentration 125,000/mm3, 104.5 +/- 28.1% in platelets concentrations 250,000/mm3) and GPIIb-IIIa 50.8 +/- 10.1% in platelets concentrations 125,000/mm3, 95.3 +/- 21.3% in platelets concentrations 250,000/mm3 were statistically higher in patients with diabetes type 2 than in controls (vWf: 94.9 +/- 27.1%, fibrinogen: 2.8 +/- 0.4 g/l, GPIb-IX in platelets concentration 125,000/mm3: 43.8 +/- 9.3%, in concentration 250,000/mm3: 83.9 +/- 18.3%, GPIIb-IIIa in platelets concentration 125,000/mm3: 33.7 +/- 10.1%, in platelets concentration 250,000/mm3: 63.2 +/- 15.4%). We found significant correlation between the expression of GPIIb-IIIa, GPIb-IIIa, GPIb-IX and plasma adhesive proteins: vWF, fibrinogen in controls and both subgroups of diabetic patients. The correlation between plasma vWF and fibrinogen level and degree of arterial insufficiency in diabetic patients was also found. We can assume that higher vWf, fibrinogen plasma level in diabetic patients with and without PAOD could account for high expression of platelets GPIIb-IIIa and GPIb-IX.
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PMID:[Chronic peripheral arterial occlusive disease, platelet glycoproteins GPIIb-IIIa and GP Ib-IX, plasma von Willebrand factor and plasma fibrinogen concentrations in patients with type 2 diabetes mellitus]. 1123 40

Atherosclerosis and its complications are the result of complex interactions between the environment and genetic factors. Platelets play an important role in this disease process and antiplatelet agents are an essential part of its treatment. However, individual response to antiplatelet therapy is variable and agents that are safe and effective in one individual may be ineffective or harmful in another. It is likely that genetic factors are involved in this variance as platelet, and platelet-associated proteins are highly polymorphic. Up to 30% of natural variation in platelet reactivity is related to genetic inheritance. Rare inherited defects of platelet function due to the absence or reduced surface expression of platelet adhesion receptors have long been recognised. These cause minor bleeding defects and are usually clinically apparent. Antiplatelet agents should be avoided in these situations. The importance of the more common genetic variations or polymorphisms, which result in minor changes in the expressed protein and are often clinically silent, is unknown. Investigations are ongoing into the role of this variation in platelet physiology. A number of polymorphisms in platelet surface glycoproteins have received particular attention; the (A1/2) polymorphism resulting in conformational change at the amino terminus of the beta-3 chain of the platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa and polymorphisms in the platelet collagen (GPIa/IIa and GPVI) and von Willebrand receptors (GPIb-IX). The (A2) allele has been associated with resistance to the antiplatelet agent aspirin and increased platelet responsiveness. The GPIa polymorphism has been associated with increased surface expression of GPIa and increased platelet adhesion to collagen. Recently, conflicting reports of the association of these polymorphisms with coronary artery disease (CAD) and its complications have been described. Mutations have also been identified in other platelet surface receptors including the recently identified G(i)-linked platelet adenosine diphosphate (ADP) receptor (P2Y(12)), targeted by the antiplatelet agents ticlopidine and clopidogrel. These discoveries have stimulated interest in the role of genetic factors in platelet physiology. In this article, the current knowledge of the influence of genetic make-up on antiplatelet therapy is discussed.
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PMID:Common variations in platelet glycoproteins: pharmacogenomic implications. 1172 84

Accumulating evidence suggests that several polymorphisms in factors regulating blood coagulation, platelet function, and lipid metabolism are relevant for susceptibility to ischemic cerebrovascular diseases (CVD). The present study analyzed 15 genetic polymorphisms possibly associated with atherosclerosis and thrombosis in a case-control study involving a total of 200 genetically unrelated Japanese patients with ischemic CVD (mean age 58.3 +/- 7.6 y) and 281 age- and gender-matched control subjects (59.0 +/- 4.1 y). Control subjects were randomly selected from unrelated donors with no history of documented CVD or any type of cardiovascular disease with normal resting electrocardiograms. Among the factors genotyped, two factors, platelet glycoprotein (GP) Ib alpha (Thr145Met) and NADPH oxidase p22phox (His72Tyr), were significantly associated with CVD after adjustment for acquired risk factors including hypertension, diabetes mellitus, hyperlipidemia, and smoking. For those with age < 60 y, 10.6% of the CVD patients and 2.9% of the control subjects had both of the two risk genotypes (GPIb alpha 145Met and p22phox 72Tyr, p < 0.05). The mean onset-age of CVD was 58.6 +/- 7.7 y for those having no or only one risk genotype, while 53.3 +/- 5.5 y for those having both of the risk genotypes (p < 0.05). Thus, GPIb alpha 145Met and p22phox 72 Tyr are the genetic factors associated with the risk of ischemic CVD in the Japanese. Carrying both of the two mutations might be associated with developing CVD at a younger age.
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PMID:[Genetic risk factors for ischemic cerebrovascular disease--analysis on fifteen candidate prothrombotic gene polymorphisms in the Japanese population]. 1496 55

Platelets have important roles in atherosclerosis and thrombosis and their inhibition reduces the risk of these disorders. There is still a need for platelet inhibitors affecting pathways that reduce thrombosis and atherosclerosis while leaving normal hemostasis relatively unaffected, thus reducing possible bleeding complications. Although combinations show progress in achieving these goals none of the present inhibitors completely fulfill these requirements. Collagen receptors offer attractive possibilities as alternative targets at early stages in platelet activation. Three major collagen receptors are assessed in this review; the alpha2beta1 integrin, responsible primarily for platelet adhesion to collagen; GPVI, the major signaling receptor for collagen; and GPIb-V-IX, which is indirectly a collagen receptor via von Willebrand factor. Several thrombosis models and experimental approaches suggest that all three are interesting targets and merit further investigation.
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PMID:Collagen receptors as potential targets for novel anti-platelet agents. 1789 11

Platelets play a complex role in hemostasis and thrombosis. The expression of multiple membrane receptors, both constitutive and activation-dependent, mediates platelet adhesion and aggregation at sites of vascular lesion. Platelet activation leads to exocytosis of granular constituents, release of newly synthesized mediators, and discharge of membrane-bound transcellular signaling molecules. Many of the same mechanisms that play a role in hemostasis and thrombosis facilitate platelet participation in other physiological or pathological processes including inflammation, malignancy and the immune response. Platelet receptors such as GPIb/IX/V, P-selectin, P-selectin glycoprotein ligand 1, CD40 and the alphaIIbbeta3 integrin, crucial to hemostasis, have been implicated in the progression of such inflammatory conditions as atherosclerosis, rheumatoid arthritis and inflammatory bowel disease, in the progression and metastatic spread of malignancies, and in the immune response to bacterial challenge. The release of platelet granular contents, including adhesive proteins, growth factors and chemokines/cytokines, that serve to facilitate hemostasis and wound repair, also function in acute and chronic inflammatory disease and in tumor cell activation and growth. Platelets contribute to host defence as they recognise bacteria, recruit traditional immune cells to the site of infection and secrete bactericidal mediators. The primary focus of this review is the "non-haemostatic" functions of platelets in physiological and pathological states.
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PMID:Beyond hemostasis: the role of platelets in inflammation, malignancy and infection. 1853 97


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