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)

Platelets and their interaction with the vessel wall play a role in atherogenesis and in the formation of the coronary thrombus. Supplementation of the diet with n-3 PUFA shifts the platelet-vessel wall interaction in anti-thrombotic direction in healthy persons and in patients with IHD. This is in part caused by an inhibition of Tx synthesis and also by an increased synthesis of PGI2 and PGI3 in the vessel wall. However, the clinical significance of these findings needs to be elucidated in clinical trials. Large, dense platelets are more reactive than small ones. Platelet size and density are determined at thrombopoiesis. Large, reactive platelets have in states with an increased platelet demand been shown to be produced from large, high-ploidy megakaryocytes. In patients with thrombopoiesis in steady-state an inverse relation between the bleeding time and both the DNA content and the size of the bone marrow megakaryocytes has been demonstrated. The bone marrow megakaryocytes in these patients were larger in men than in women, which may explain the sex difference in bleeding time observed by others. In experimental atherosclerosis changes in megakaryocyte size have been demonstrated. The significance of these changes are still unclear. In a single study stimulation of the platelet-megakaryocyte axis was associated with an acceleration of experimental atherosclerosis. This study suggests that large, high ploidy megakaryocytes may produce a large amount of atherogenic platelets that may be responsible for the increased formation of atheroma in this model. However, due to the complexity of the study design this hypothesis needs verification in other experimental and clinical studies. In patients suffering from an AMI the mean platelet volume is increased. The bleeding time is shortened at the time of infarction in these patients probably due to increased synthesis of TxA2, but an increased production of adrenaline may also be of importance. These large, reactive platelets present in AMI may be a reflection of an altered thrombopoiesis in these patients. It remains to be established whether these changes in platelet reactivity are present before the time of coronary thrombus formation.
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PMID:The platelet-vessel wall interaction in experimental atherosclerosis and ischaemic heart disease with special reference to thrombopoiesis. 161 18

The effect of a short-term high cholesterol diet on thrombopoiesis and vascular ultrastructure was evaluated in rabbits. Six pairs of male litter-mate rabbits were randomized pairwise to feeding with either 2 g of cholesterol daily in addition to their normal diet or normal diet alone for 7 days. A significant 12-fold increase in median serum cholesterol (P less than 0.035) and an insignificant decrease in platelet count (P = 0.07) were found in the animals fed a high cholesterol diet. In these animals the total and cytoplasmic megakaryocyte size measured as planimetric areas in bone marrow sections were significantly decreased (P less than 0.035). No statistically significant difference in the megakaryocyte DNA content measured by flow cytometry in marrow suspensions enriched for megakaryocytes by density gradient centrifugation and centrifugal elutriation was observed between the cholesterol-fed animals and controls. Light microscopic, transmission and scanning electron microscopic examination of the aorta in both groups of animals showed a morphologically intact endothelium without any adhesion of blood-borne cells to the luminal surface. Transmission electron microscopic studies showed that cells with ultrastructural features resembling smooth muscle cells were present in the intima of the aortas of the animals on the high cholesterol diet, but not in control animals. A decrease in the size of bone marrow megakaryocytes and the occurrence of intimal smooth muscle cells are found in rabbits fed a high cholesterol diet for 7 days. These cellular events may be important features in early atherogenesis.
Atherosclerosis 1988 Jun
PMID:Megakaryocyte and vascular changes in rabbits on a short-term high cholesterol diet. 340 Dec 85

Rabbits given a hypercholesterolemic diet (500 mg/day) for 6 months and then maintained for another 6 months on a normal diet were found to have developed fibrous lipidic lesions in the aorta. Although circulating platelet levels in these animals were normal there was a reduction in mean megakaryocyte ploidy. The high concentrations of megakaryoblasts in all the sedimentation fractions collected by the 'STAPUT' system suggested an increase in megakaryocyte turnover with activation of committed stem cells. In addition, other defects in maturation of megakaryocytes were observed, such as abnormalities in the demarcation membrane system and granule number. These data reveal that defects in megakaryocyte maturation and turnover may occur during the process of reparative fibrosis of the arterial tree following a period of moderate hypercholesterolemic diet in the rabbit.
Atherosclerosis 1987 Jan
PMID:Megakaryopoiesis disturbances in atherosclerotic rabbits. 382 67

Rabbits were fed either 2 g cholesterol in 10 ml olive oil daily with normal diet (n = 5) or normal diet alone (n = 5). After 12 weeks, the cholesterol-fed animals had developed fatty plaques involving 24% +/- 4% of the surface area of the aorta; the control animals had none. Mean platelet volume was significantly smaller (p less than 0.04) in the cholesterol-fed animals (4.1 +/- 0.3 fl) compared with the controls (4.8 +/- 0.4 fl). The heterogeneity of the average volume distributions of the two groups, characterized by the statistical parameters of the coefficient of variation, skewness, and kurtosis, was also significantly different. Platelet count was significantly higher (p less than 0.001) in the cholesterol-fed group (7.48 +/- 1.06 x 10(11) platelets/liter blood) compared to the control group (4.86 +/- 0.60 x 10(11) platelets/liter blood). Mean megakaryocyte cytoplasmic volume was significantly larger (p less than 0.001) in the cholesterol-fed rabbits (12,262 +/- 1485 fl) compared with controls (6,814 +/- 761 fl). The range of cytoplasmic volumes was also significantly increased in the cholesterol-fed rabbits. A significant (p less than 0.01) increase in mean megakaryocyte nuclear volume in the cholesterol-fed animals was accompanied by a nonsignificant increase in mean nuclear DNA content: 30.2 +/- 3.7 N compared with a control value of 23.6 +/- 4.0 N. This evidence indicates that a high cholesterol diet in rabbits is associated with changes in platelet production from megakaryocytes as well with as the development of atherosclerosis.
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PMID:Platelet and megakaryocyte changes in cholesterol-induced experimental atherosclerosis. 407 94

Endothelial and platelet generation of nitric oxide (NO) plays an important role in the regulation of hemostasis. Alterations in NO biosynthesis are described in atherosclerosis. We have investigated the NO pathway in megakaryocytes and platelets from patients with atherosclerosis and age-matched control subjects. Megakaryocytes and platelets were isolated from patients with severe coronary atherosclerosis (n = 19) and normal coronary arteries (n = 9) as demonstrated by selective angiography. Constitutive (Ca(2+)-dependent) and inducible (Ca(2+)-independent) NO synthase (cNOS and iNOS, respectively) activities were measured by using the citrulline assay and by immunostaining techniques using an anti-peptide antibody to iNOS. Megakaryocytes from patients with atherosclerosis expressed significantly greater amounts of iNOS (1.28 +/- 0.46 pmol citrulline.mg-1.min-1) than cNOS (0.29 +/- 0.40 pmol.mg-1.min-1). In contrast, megakaryocytes from patients with normal coronary arteries expressed significantly more cNOS (1.48 +/- 0.23 pmol.mg-1.min-1) than iNOS (0.49 +/- 0.40 pmol.mg-1.min-1). Platelets isolated from both groups showed no significant difference in cNOS expression, and no iNOS was seen in either group. Immunostaining confirmed the presence of the iNOS in megakaryocytes. These results suggest there is a link between the expression of iNOS in the megakaryocyte and atherosclerosis.
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PMID:Megakaryocytes from patients with coronary atherosclerosis express the inducible nitric oxide synthase. 753 28

Thrombocytes of lower vertebrates are nucleated diploid cells, which differentiate directly from stem cells without an interposed megakaryocytic maturation program. With increased complexity of circulatory systems and higher blood pressures, more efficient haemostasis was required. In higher vertebrates and man, megakaryocytes developed which, by way of endomitotic polyploidization, can amplify genes relevant for haemostasis and adapt platelets to different haemostatic demands. As endomitotic polyploidization is regulated by cytokines, it is also influenced by inflammatory or malignant cell growth. The responsiveness of the megakaryocyte system to various stimuli is a possible explanation for the high incidence of thrombohaemorrhagic and thromboembolic disorders in man. For example, thrombotic complications in tumour patients are due to pathologic overstimulation of megakaryocytes. Atherosclerosis is another process which may be caused by inappropriate stimulation of the megakaryocyte system. As this complication does not manifest itself during reproductive ages, it is not going to be corrected by evolution.
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PMID:Megakaryocytes: origin of bleeding and thrombotic disorders. 801 27

Platelets form a heterogeneous population of cells produced from the uniquely large polyploid cell found in the bone marrow, the megakaryocyte. The platelet megakaryocyte axis forms a dynamic equilibrium varying in normal biology and in disease. Prolonged platelet destruction leads to the production of large platelets from large, high ploidy megakaryocytes. In vivo and ex vivo studies show that such platelets have more haemostatic potential than smaller less dense platelets. The evidence suggesting that prothrombotic changes in the megakaryocyte platelet axis precede coronary artery thrombosis and the importance of platelet reactivity in atherosclerosis will be reviewed.
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PMID:The megakaryocyte platelet system and vascular disease. 801 33

Platelet-derived growth factor (PDGF) is a potent mitogen consisting of heterodimers of two distinct but homologous polypeptide chains, denoted A and B. PDGF-like homodimers of the A- and B-chains have been isolated, as well as two distinct receptor types (alpha and beta), which discriminate among the PDGF isoforms. The PDGF A- and B-chains are encoded by distinct genes located on human chromosomes 7 and 22, respectively. Although PDGF has been implicated as an important participant in development, tissue repair, and numerous pathologic states including tumorigenesis, atherosclerosis and inflammation, the mechanisms which determine the rate of its synthesis are only beginning to be understood. Basal expression of the PDGF A- and B-chain genes has been characterized in a number of cell types and is directed in part by elements in the respective proximal promoter-regulatory regions of the two genes. In addition, the first intron of PDGF-B has been shown to contain both positive and negative regulatory elements. Transcription of the PDGF subunit genes is inducible by a wide variety of mitogenic growth factors, cytokines and other agonists. These agents produce a rapid increase in steady-state concentrations of PDGF A- and B-chain mRNAs, peaking within 4-8 h of stimulation. The inductive effects of protein kinase C-activating phorbol 12-myristate 13-acetate (PMA), thrombin and transforming growth factor-beta (TGF-beta) are mediated through increases in the transcription rates of both genes. In addition, cAMP blocks the increases in transcription of the B-chain gene induced by thrombin and TGF-beta. Studies have demonstrated the importance of sequences immediately upstream of the B-chain transcription start site for induction in response to PMA-initiated megakaryocyte differentiation, an effect which is dependent on protein synthesis. However, cis-acting elements which mediate more rapid transcriptional induction seen in endothelial cells and astrocytes have yet to be identified in the proximal 5'-flanking sequences of either the A- or B-chain genes, suggesting that such events may be mediated by elements located outside of this region.
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PMID:Transcriptional control of the platelet-derived growth factor subunit genes. 834 77

Platelets contain a vast number of biologically active molecules within cytoplasmic granules which are classified according to their respective distinct ultrastructures, densities and content. The alpha-granule is a unique secretory organelle in that it exhibits further compartmentalization and acquires its protein content via two distinct mechanisms: (1) biosynthesis predominantly at the megakaryocyte (MK) level (with some vestigial platelet synthesis) (e.g. platelet factor 4) and (2) endocytosis and pinocytosis at both the MK and circulating platelet levels (e.g. fibrinogen (Fg) and IgG). The currently known list of alpha-granular proteins continues to enlarge and includes many adhesive proteins (e.g. Fg, von Willebrand factor (vWf) and thrombospodin (TSP)), plasma proteins (e.g. IgG and albumin), cellular mitogens (e.g. platelet derived growth factor and TGF beta), coagulation factors (e.g. factor V) and protease inhibitors (e.g. alpha 2-macroglobulin and alpha 2-antiplasmin). More recently the inner lining of the alpha-granule unit membrane has been demonstrated to contain a number of physiologically important receptors including glycoprotein IIb/IIIa (alpha IIb beta 3) and P-selectin. The alpha-granules originate from small precursor granules which can be observed budding from the trans-Golgi network within the platelet precursor cell the MK. During MK maturation the alpha-granules become very prominent and are ultimately packaged into platelets during thrombopoiesis. The alpha-granular contents are destined for release during platelet activation at sites of vessel wall injury and thus play an important role in haemostasis, inflammation, ultimate wound repair and in the pathogenesis of atherosclerosis.
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PMID:Platelet alpha-granules. 846 33

Altered platelet morphology and function have been reported in patients with diabetes. They are likely to be associated with the pathological processes and increased risk of vascular disease seen in these patients. Mean platelet volume (MPV), platelet count, and megakaryocyte (MK) ploidy (DNA content) were measured in (1) nondiabetics with normal coronary arteries, (2) nondiabetics with coronary artery atherosclerosis, (3) diabetics without evidence of vascular complications, and (4) diabetics with vascular disease. The platelet count (+/- SD) was increased in all groups but only significantly in the diabetics with vascular disease (236 +/- 65 versus 250 +/- 54 versus 257 +/- 64 versus 295 +/- 90 [P < or = .05] x 10(9)/L, for groups, I, II, II, and IV, respectively). The MPV was significantly increased in patients with atherosclerosis (7.0 +/- 0.4 versus 8.0 +/- 1.2 [P < or = .05] versus 7.2 +/- 0.9 versus 8.1 +/- 0.9 [P < or = .05] IL). Geometric mean MK ploidy was significantly increased in all groups compared with controls (16 +/- 1.5 versus 18.7 +/- 1.8 [P < or = .05] versus 19.8 +/- 1.6 [P < or = .05] versus 20.1 +/- 2.7 [P < or = .05]). Furthermore, some patients with vascular disease and/or diabetes had a modal ploidy shift from 16 (the normal mammalian modal ploidy) to 32, with a concomitant reduction of MKs in the 8 and 16 ploidy classes. This shift was seen particularly in the diabetics with vascular disease (P = .007). Interleukin-6 (IL-6) levels were measured and were elevated in patients with atherosclerosis; the highest levels were found in the diabetic patients (0.7 +/- 0.9 versus 5.3 +/- 5.5 [P < or = .05] versus 2.5 +/- 2.8 versus 6.7 +/- 5.5 [P < or = .05] ng/L). In the diabetic patients with atherosclerosis, fibrinogen levels were also increased (2.85 +/- 0.76 versus 3.34 +/- 1.32 versus 2.43 +/- 1.50 versus 5.59 +/- 1.72 [P < or = .05] g/L). Furthermore, IL-6 levels correlated with MK ploidy (r = .45, P = .009) and fibrinogen levels (r = .5, P = .0001). This study demonstrates that patients with vascular disease, particularly diabetics, have an altered MK ploidy distribution, showing a shift toward higher ploidy in association with an increased platelet mass (count x volume). Changes in platelets in diabetes probably reflect MK changes, which themselves are a response to systemic change.
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PMID:Megakaryocyte ploidy and platelet changes in human diabetes and atherosclerosis. 910 97


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