UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interactions of blood cells (platelets and leukocytes) with the components of the vessel wall (endothelial cells, extracellular subendothelial matrix and smooth muscle cells) play an important role in the initiation of thrombosis and the development of atherosclerosis. These cellular interactions are partially regulated by the formation of pharmacologically active lipids (PAL): prostaglandins, leukotrienes, PAF-acether and related compounds. These biochemical mediators are produced from the phospholipids of the cell membrane in response to external stimulation. The metabolic precursors, such as arachidonic acid, are common. The subsequent enzymatic differentiation leads to the formation of different terminal products according to the cells, thromboxane A2 in the platelets and prostacyclin in the endothelial cells.
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PMID:[Physiology of the interactions of blood and the blood vessel wall. Role of pharmacologically active lipids]. 393 41

Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent phospholipid mediator of numerous inflammatory and thrombotic responses. The purpose of this study was to determine if PAF synthesis is elevated in damaged coronary arteries after a sustained period of cyclic flow variation (CFV), a phenomenon caused by alternating periods of thrombosis and reperfusion at sites of endothelial injury. Cyclic flow was established and maintained in the left anterior descending coronary arteries (LADs) of 10 dogs. After 8 hours of CFV, the section of damaged LAD containing the thrombus and control sections of the circumflex artery, carotid artery, and saphenous vein was excised, and the total lipids were extracted. The PAF was then purified by silica column chromatography and high-performance liquid chromatography and assayed by both a rabbit platelet bioassay and a PAF radioimmunoassay. With the platelet bioassay, PAF levels of 8.9 +/- 4.0 (range, 4.8 to 15.5) pg/mg wet wt were found in the damaged LADs from the 10 dogs. This PAF bioactivity was completely inhibited by a PAF receptor antagonist. When the radioimmunoassay was used, slightly higher PAF levels of 16.3 +/- 12.9 (range, 4.5 to 41.8) pg/mg wet wt were observed in the LADs. Overall, these PAF levels were 3- to 64-fold higher than in the control vessels when either assay method was used. Although increases in PAF were observed in the damaged LADs, measurements of PAF in blood samples taken from the LAD and the aorta (control) failed to demonstrate any site-specific increase of PAF in the blood. In related experiments, PAF was also measured in 23 endarterectomy samples taken from the coronary arteries of 16 patients with severe atherosclerosis. The PAF levels in these samples were highly variable (2.9 +/- 2.2 [range, 0.3 to 8.5] pg/mg wet wt) and showed no correlation with tissue mass, suggesting that PAF is affected by factors other than the simple presence of atherosclerotic tissue in the vessel. These findings provide direct evidence that PAF is synthesized locally at the site of endothelial injury during thrombosis and that PAF accumulates in the atherosclerotic plaque of some patients with advanced coronary artery disease.
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PMID:Measurement of platelet-activating factor in a canine model of coronary thrombosis and in endarterectomy samples from patients with advanced coronary artery disease. 778 82

Monocytes were prepared from healthy human volunteers and were allowed to differentiate into macrophages by adhesion to plastic surface and cultured over 7 days in presence of either 10% fetal calf serum (FCS), human control serum or serum from hyperlipaemic patients. Hyperlipaemic serum stimulated the differentiation (measured as an increase in cellular protein and DNA content) to a higher extent when compared to control serum and FCS. With all sera a marked increase of the cellular activity of the enzyme platelet-activating factor acetylhydrolase (PAF-AH) and a tremendous decrease in the capacity of cells to generate reactive oxygen species (ROS) was observed. After seven days of culture the increase in PAH-AH activity was about 19-fold with hyperlipaemic serum, 11-fold with control serum and 6-fold with FCS. During the same period of time ROS generation measured as zymosan-induced chemiluminescence decreased by about 98% and no significant differences between the three types of serum were found. The results indicate that the activity of PAF-AH and the capacity of ROS generation which are both assumed to play an important role in the oxidation of low-density lipoproteins (LDL) and thus in the development of atherosclerosis, change in opposite direction during the differentiation of blood monocytes into macrophages, and that hyperlipaemic serum stimulates PAF-AH activity but not ROS generation.
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PMID:Generation of reactive oxygen species and activity of platelet-activating factor acetylhydrolase in human monocyte-derived macrophages. 808 51

Both platelets and macrophages play a role in the pathogenesis of atherosclerosis. To examine whether they may interact and, if they do, to elucidate the mechanisms of such an interaction, suspensions of the two cell types from rabbits were mixed together, then subjected to Stractan density-gradient centrifugation and transmission electron microscopy. Suspensions of only one cell type served as controls. When otherwise unstimulated platelets and macrophages came into contact with each other, the platelets became less dense. Ultrastructurally, the platelets underwent shape changes without losing their granules, and were often arranged around the macrophages like a rosette. The processes of the macrophages became elongated. ADP caused a similar shift in platelet density and, when the cell types were together, increased this shift. With ADP the rosetting was abolished, but platelet aggregates were found to be in superficial contact with the macrophages. With thrombin the contact between the platelet aggregates and macrophages was close. Addition of platelet antagonists showed that the shift in platelet density and the rosetting upon contact with macrophages are dependent on divalent cations. Neither ADP, nor thrombin, nor PAF seem to be involved in the reactions.
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PMID:Rabbit lung macrophages stimulate platelets in vitro as observed by density-gradient centrifugation and transmission electron microscopy. 827 58

The reactivity and the structure as well as the growth of the vascular wall depend on a variety of locally synthetised factors in a process of a permanent structure-function adaptation. These substances exert their inhibitory or stimulatory growth effects by paracrine or autocrine mechanisms. These factors command the reorganisation of the structure of existing blood vessel or the creation of new vessels. They are synthetised and secreted form either endothelial and smooth muscle cells or circulating cells (in particular macrophages, platelets). The growth factors are multiple and interactive insuring a role of physiological vascular modeling in normal conditions but they may participate and even induce dramatic structural dysfunctions that are observed in pathologies such as venous diseases, atherosclerosis or hypertension. Among them, the polypeptides PDGF (platelet derived growth factor), FGF (fibroblast growth factor) and TGF beta (transforming growth factor beta) play a major role. Other factors like cytokines, IGFs (insulin like growth factors), PAF (platelet activating factor) endothelins or nitric oxide have also to be considered. Thus, the vascular wall structure is under the influence of a complex group of growth factors which become to be identified and may be the targets of new therapies of the vessels.
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PMID:Growth factors and vascular wall. 880 32

In human plasma with no detectable lipoprotein (a) (Lp(a)) levels, platelet-activating factor acetylhydrolase (PAF-AH) is associated with low density lipoprotein (LDL) and high density lipoprotein (HDL) with a distribution of 70 and 30%, respectively. We used a density gradient ultracentrifugation procedure to study the distribution of PAF-AH among lipoproteins in plasma containing Lp(a). Lp(a) was migrated as a broad band in the density region of d = 1.050-1.100 g/ml, independently of its isoform size. In plasma with Lp(a) levels 30-40 mg/dl or 80-100 mg/dl the PAF-AH activity migrated in this density region was 4 or 9% higher as compared to plasma having Lp(a) levels < 8 mg/dl (P < 0.05 or P < 0.02, respectively). Enrichment of plasma with the dense LDL5 subfraction, significantly increased the enzyme activity distributed in this density region. The physicochemical properties of the Lp(a)-associated PAF-AH activity were similar to those reported for the LDL-associated enzyme. However, the kinetic constants in small Lp(a) isoforms were significantly higher compared to large ones. Isoform F had apparent Km = 117 +/- 9 mumol/l and Vmax = 94 +/- 5 nmol/mg protein per min, and isoform S2/S3 had apparent Km = 36 +/- 9 mumol/l and Vmax = 25 +/- 5 nmol/mg protein per min. Removal of apolipoprotein (a) (apo(a)) from Lp(a) by reductive cleavage with dithiothreitol, slightly affected the amount of PAF-AH existing on Lp(a) since, only 15 +/- 5% of the total enzyme activity dissociated from its particle after density gradient ultracentrifugation. During Cu(2+)-induced Lp(a) oxidation, the PAF-AH activity decreased from 10.90 +/- 2.30 nmol/mg per min to 2.57 +/- 0.56 nmol/mg per min 4 h after the initiation of the oxidation (P < 0.001). The apparent Km of the enzyme remained essentially unchanged during oxidation, whereas Vmax was significantly decreased from 58.6 +/- 7.8 nmol/mg protein per min to 38.2 +/- 8.7 nmol/mg protein per min (P < 0.03). An extensive hydrolysis of the endogenous phosphatidylcholine (PC) to lysophosphatidylcholine (lyso-PC) was observed during Lp(a) oxidation, since the Lyso-PC/sphingomyelin molar ratio at the end of oxidation (0.55 +/- 0.09) was significantly higher than that before oxidation (0.19 +/- 0.01, P < 0.001). Our results show that the existence of Lp(a) in plasma alters the distribution of PAF-AH among the other lipoproteins. Apo(a) seems to affect the association of the enzyme with Lp(a) but does not bind itself to PAF-AH. During Lp(a) oxidation, the PAF-AH activity decreases whereas an extensive hydrolysis of the endogenous PC to Lyso-PC is observed which is possibly due to the PAF-AH activity.
Atherosclerosis 1996 Aug 23
PMID:PAF-acetylhydrolase activity of Lp(a) before and during Cu(2+)-induced oxidative modification in vitro. 883 34

Blood platelets are capable of interacting with monocytes and macrophages and of enhancing various functions of these cells, which are believed to play a role in thrombosis and inflammation. An increase in the uptake of oxidised low density lipoprotein (LDL), in the synthesis of procoagulant tissue factor, thrombospondin and leukotrienes, as well as stimulation of oxygen radical production by platelets has been described (1-5). In circulating blood, a substantial proportion of monocytes was found to be associated with platelets, but the pathophysiological significance of such platelet-monocyte conjugates is not yet clear (6,7). Immigration of monocytes into the arterial intima and their differentiation into macrophages are initial steps in the development of an atherosclerotic lesion (8). During differentiation, there is a tremendous increase in the activity and secretion of the enzyme PAF acetylhydrolase (PAF = platelet-activating factor = 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) (9,10), and there is some evidence that this enzyme may contribute to the development of atherosclerosis. It cleaves PAF, and the remaining lyso-PAF is chemotactic for monocytes (11). Furthermore it also acts on oxidised low density lipoproteins and enhances their uptake into macrophages (12,13). We were therefore interested in investigating whether platelets may modulate the differentiation of monocytes into macrophages and the activity of PAF acetylhydrolase.
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PMID:Platelets inhibit the activity of platelet-activating factor acetylhydrolase in monocyte-derived macrophages. 921 35

Patients with heterozygous familial hypercholesterolaemia (FH) have elevated plasma concentrations of low-density lipoprotein (LDL) and develop premature atherosclerosis. There is increasing evidence that oxidative modification of LDL is important for the pathogenesis of atherosclerosis, and the LDL-associated platelet-activating factor acetylhydrolase (PAF-AH) seems to play a key role in LDL oxidation by hydrolysing the oxidized phospholipids of phosphatidylcholine (PC) and producing lysophosphatidylcholine (lyso-PC). We measured the total serum and high-density lipoprotein (HDL) levels of PAF-AH activity and studied the distribution of PAF-AH activity among three LDL subfractions isolated by gradient ultracentrifugation in 15 patients with heterozygous FH and 13 normolipidaemic control subjects. We also determined the lyso-PC production in each LDL subfraction during Cu2(+)-induced oxidation in vitro. The total serum PAF-AH activity in heterozygous FH patients was significantly higher than in control subjects, whereas the HDL-associated PAF-AH activity, expressed as a percentage of total serum PAF-AH activity, was significantly lower in the FH patients than in control subjects (13.9 +/- 6.6% vs. 30.6 +/- 4.4%, P < 0.001). Among the LDL subfractions, the PAF-AH activity in both normolipidaemic control subjects and FH patients, expressed as nmol mg-1 protein min-1, was significantly higher in the LDL3 subfraction (33.1 +/- 4.8 and 53.4 +/- 11.5 respectively) than in the LDL2 (18.6 +/- 5.3 and 26.8 +/- 10.4 respectively, P < 0.0001 for both comparisons) and LDL1 subfractions (5.1 +/- 1.5 and 7.8 +/- 2.6, respectively, P < 0.0001 for both comparisons). Additionally, the enzyme activity in each LDL subfraction of the heterozygous FH patients was significantly higher than in control subjects (P < 0.02 for LDL1, P < 0.03 for LDL2 and P < 0.0001 for LDL3). No difference was observed in the susceptibility to oxidation of each LDL subfraction among the heterozygous FH patients and the normolipidaemic control subjects. During oxidation, the PAF-AH activity decreased, whereas the lyso-PC levels significantly increased in all subfractions of both groups. The lyso-PC/sphingomyelin molar ratio in each LDL subfraction of the FH patients 3 h after the onset of the oxidation was significantly higher than in control subjects [0.38 +/- 0.05 and 0.27 +/- 0.04, respectively, for LDL1 (P < 0.006), 0.47 +/- 0.08 and 0.39 +/- 0.03, respectively, for LDL2 (P < 0.04), 0.55 +/- 0.11 and 0.42 +/- 0.06, respectively, for LDL3 (P < 0.02)]. Our results show that heterozygous FH patients exhibit higher PAF-AH activity than control subjects in all LDL subfractions, resulting in higher lyso-PC production during oxidation, which confers on these subfractions higher biological potency. This phenomenon, in combination with the diminished anti-atherogenic and antioxidant capability of HDL in these patients due to the relatively low HDL-cholesterol levels compared with LDL-cholesterol levels and, consequently, the relatively low HDL-associated PAF-AH activity, could contribute to the higher atherogenicity and incidence of coronary artery disease observed in FH patients.
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PMID:Increased activity of platelet-activating factor acetylhydrolase in low-density lipoprotein subfractions induces enhanced lysophosphatidylcholine production during oxidation in patients with heterozygous familial hypercholesterolaemia. 969 45

Since the classical studies by Furchgott and Zawadski (Nature, 1980, 286, 373-376), the vascular endothelium is known to play a fundamental role in the regulation of haemostasis and vasomotor activity. This is primarily due to its strategic interface position between the circulating blood and smooth muscle cells of the media. Due to the presence of specific receptors to mediators released during platelet aggregation (thrombin, ATP, serotonin, PAF, etc.), and the presence of mechanoreceptors sensitive to shearing forces generated by blood flow along the vessel wall, the endothelium is able to release, at the two poles of the cell, vasodilator and antiaggregant substances called "endothelium derived relaxing factors" (EDRFs), the best known for which are nitric oxide (NO) ans prostacyclin (PGl2). In the absence of endothelium (angioplasty), or in the case of endothelium dysfunction related to cardiovascular diseases such as hypertension, heart failure, atherosclerosis or diabetes, EDRF synthesis is absent or defective and its oxidative catabolism in increased (particularity by superoxide anion), resulting in varying degrees of disorders of haemostasis (thrombosis) and/or arterial and venous vasomotor activity. The only known effective treatment to palliate these dysfunctions is exogenous NO, supplied in the form of nitrate (nitroglycerin, isosorbide dinitrate, 5-mononitrate) or "NO donors" (Sin1, nitroprussate). The advantage of these substances is that their vasodilator effects (and, in some cases, their antiaggregant effects) are strictly endothelium-independent and they remain effective regardless of the causes and severity of endothelial dysfunction.
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PMID:[Nitrates and coronary vascular endothelium dysfunction]. 945 72

In health, the vascular endothelium forms a multifunctional interface between the circulating blood and various tissues and organs of the body. It constitutes a selectively permeable barrier for macromolecules, as well as a nonthrombogenic and nonadhesive container that actively maintains the fluidity of blood. It is a metabolically active endocrine organ, serving as the source of multiple factors and mediators that are critical for normal homeostasis. These include vasodilators (nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor), vasoconstrictors (endothelin-1, thromboxane A2, prostaglandin H2 and components of the renin angiotensin system), various pro- and antithrombotic factors (e.g. tissue factor, platelet activating factor--PAF, von Willebrand factor), fibrinolytic activators and inhibitors (e.g. tissue plasminogen activator, plasminogen activator inhibitor-1), potent arachidonate metabolites (prostanoids), leukocyte adhesion molecules (e.g. E-selectin, P-selectin, intercellular adhesion molecule-1--ICAM-1, vascular cell adhesion molecule-1--VCAM-1), and multiple cytokines with activities of growth stimulators and inhibitors, transforming growth factors, proinflammatory and antiinflammatory mediators, tumour necrosis factors and chemotactic factors (chemokines). Besides these essential activities controlling the cardiovascular system, the endothelial cells represent an important part of the immune system as well. They have a pivotal role in the initiation and development of defensive and damaging inflammatory responses. Therefore endothelium can be considered as being the central equipment for the mutual exchange of life important information between the cardiovascular and immune systems. This in turn is leading to rapid advances in understanding the pathogenesis of some of the most serious and most common diseases, including inflammation, atherosclerosis and hypertension. (Tab. 7, Ref. 89.)
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PMID:[Vascular endothelium as a factor in information transfer between the cardiovascular and immune systems]. 958 73

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