leukotriene-b4 and Arteriosclerosis

Traditional approaches to prophylaxis of atherosclerosis have focused on one aspect of the pathogenesis of this multifactorial disease, such as platelet function or blood lipids, and therefore have had limited success. Epidemiologic studies show a striking inverse correlation of consumption of fish rich in the two omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, and mortality from cardiovascular disease. In studies of volunteers and patients, reductions in platelet responsiveness, lowering of blood lipids, and improvements of blood flow, as well as improvements in other values implicated in the pathogenesis of atherosclerosis, were induced with eicosapentaenoic and docosahexaenoic acids. These findings indicate that these omega-3 fatty acids have a larger prophylactic potential than traditional approaches. This potential must be scrutinized in meticulously designed and conducted trials with clinical endpoints.

Topics: Animals; Arteriosclerosis; Docosahexaenoic Acids; Eicosapentaenoic Acid; Epoprostenol; Erythrocytes; Fish Oils; Humans; Leukocytes; Leukotriene B4; Lipids; Platelet Aggregation Inhibitors

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Diabetes Mellitus; Glucocorticoids; Humans; Hypertension; Leukotriene B4; Lipoxygenase; Membrane Lipids; Organ Specificity; Phospholipases; Plants; Prostaglandin-Endoperoxide Synthases; Prostaglandins; SRS-A; Thrombosis; Thromboxanes

Leukotriene B4 (LTB4), a potent leukocyte chemoattractant, is known to promote several inflammatory diseases, including atherosclerosis. We sought to determine mechanisms through which LTB4 modulates atherosclerosis in cell lines expressing LTB4 receptors, BLT-1, and in mice deficient in BLT-1 as well as macrophage cell lines derived from BLT-1+/+ and BLT-1-/- mice.. Analysis of global changes in gene expression induced by LTB4 in rat basophilic leukemia cells (RBL-2H3) expressing the human BLT-1 showed highest-fold increase in expression of fatty acid translocase/CD36 and the chemokine MCP1/JE/CCL2, which are critical in atherogenesis. To determine the importance of BLT-1 in atherogenesis, we crossed BLT-1-null mice with apolipoprotein (apo)-E-deficient mice, which develop severe atherosclerosis. Deletion of BLT-1 significantly reduced the lesion formation in apo-E-/- mice only during initiating stages (4 and 8 weeks) but had no effect on the lesion size in mice fed atherogenic diet for 19 weeks. Macrophage cell lines from BLT-1-deficient mice expressed the low-affinity LTB4 receptor, BLT-2, and exhibited chemotaxis to LTB4.. The effects of LTB4 in atherosclerosis are likely mediated through the high-affinity BLT-1 and the low-affinity BLT-2 receptors. LTB4 promotes atherosclerosis by chemo-attracting monocytes, by providing an amplification loop of monocyte chemotaxis via CCL2 production, and by converting monocytes to foam cells by enhanced expression of CD36 and fatty acid accumulation.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Cells, Cultured; Chemotaxis; Crosses, Genetic; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Leukotriene B4; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Oligonucleotide Array Sequence Analysis; Rats; Receptors, Leukotriene; Receptors, Leukotriene B4; RNA, Messenger

Topics: Animals; Arteriosclerosis; Cell Adhesion Molecules; Chemokine CCL2; Chemotaxis, Leukocyte; Inflammation; Leukocytes; Leukotriene Antagonists; Leukotriene B4; Macrophage-1 Antigen; Mice; Monocytes; Receptors, Leukotriene B4

Leukotriene B4 (LTB4) is a potent chemotactic agent that activates monocytes through the LTB4 receptor (BLTR). We tested the hypothesis that LTB4 receptor blockade would slow atherosclerotic progression by inhibiting monocyte recruitment. Homozygous low-density receptor knockout (LDLr(-/-)) mice and apolipoprotein E deficient (apoE(-/-)) mice were treated with a specific LTB4 receptor antagonist, CP-105,696, for 35 days. In apoE(-/-)mice, treatment with the LTB4 antagonist did not affect plasma lipid concentrations but significantly reduced CD11b levels both in vascular lesions and whole blood. Compared with age-matched controls, lipid accumulation and monocyte infiltration were significantly reduced in treated apoE(-/-) mice at all time points tested. Lesion area reduction was also demonstrated in LDLr(-/-) mice maintained on a high-fat diet. LTB4 antagonism had no significant effect on lesion size in mice possessing the null alleles for another chemotactic agent, monocyte chemoattractant protein-1 (MCP-1(-/-)xapoE(-/-)), suggesting MCP-1 and LTB4 may either interact or exert their effects by a common mechanism. These results demonstrate that in a preclinical model of atherosclerosis LTB4 receptor blockade reduces lesion progression and further suggest a previously unrecognized role for LTB4 or other oxidized lipids recognized by the BLTR receptor in the pathogenesis of this disease.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Benzopyrans; Carboxylic Acids; Chemokine CCL2; Disease Progression; Foam Cells; Immunohistochemistry; Leukotriene Antagonists; Leukotriene B4; Lipids; Macrophage-1 Antigen; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Receptors, CCR2; Receptors, Chemokine; Receptors, LDL; Receptors, Leukotriene B4

Topics: Animals; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Epoprostenol; Fish Oils; Leukotriene B4; Lipoproteins; Macrophages; Monocytes; Platelet Aggregation; Platelet Count; Swine; Thromboxanes

The Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model for familial hypercholesterolemia, has a deficiency in low density lipoprotein (LDL) receptor binding and exhibits elevated plasma lipoprotein levels and spontaneous atherosclerosis. Since atherosclerotic plaque formation has a number of features in common with the inflammatory process, we have investigated the effect of dietary supplementation with an anti-inflammatory steroid (cortisone acetate, 5 mg daily for 3 months) on atherosclerosis using the WHHL rabbit as a model. Atherosclerotic plaque formation in cortisone-fed animals was reduced by about 60% compared to control WHHL rabbits. Steroid administration increased circulating cholesterol levels modestly and triglycerides were increased about 6-fold. While very low density lipoprotein (VLDL)-cholesterol was increased, LDL-cholesterol levels were decreased and the particle was more triglyceride-enriched as well as less dense. Steroid-fed animals also exhibited decreased platelet aggregation and increased aortic 15-lipoxygenase activity. The histological observations showed typical fibrous plaques in aortas of both control and cortisone-fed rabbits, with intima thickened by foamy macrophages and subcellular lipoproteinaceous debris covered by a fibrous cap. These findings thus indicate that steroids reduce the rate of plaque initiation or progression but do not significantly change the histological appearance of the lesion.

Topics: Animals; Arteriosclerosis; Cholesterol; Cortisone; Disease Models, Animal; Leukotriene B4; Rabbits

We evaluated the hypothesis that leukotriene (LT) B4, a potent chemotactic and endothelium-permeabilizing autacoid, may be a factor in the progression of the atherosclerotic lesion. Human vascular fragments, freshly obtained at vascular surgery from saphenous veins, atrial appendages, normal aortas and atherosclerotic lesions (histologically classified as fibrous plaques, fatty plaques and complicated lesions) were incubated at 37 degree C with mechanical agitation, for various times ranging between 5 and 60 minutes, sequentially, with buffer (basal), ionophore A23187 (IONO), and arachidonic acid (AA). After each step medium was assayed for LTB4 production by radioimmunoassay. Incubations were also performed in a chamber allowing selective exposure of the endothelial surface to the medium. Basal production (15 minute incubation, ng/g, mean +/- SD) was lowest for fibrous plaques (0.9 +/- 0.2, n = 38) and saphenous veins (1.0 +/- 0.3, n = 32) and much higher (P less than 0.01) for fatty plaques (7.3 +/- 2.2, n = 35) and complicated lesions (5.3 +/- 3.0, n = 28). A virtual abolition of production was observed after boiling of the vascular fragment. Production was increased in the presence of AA and IONO (in atheromas: 11.5 +/- 4.2 AND 14.3 +/- 5.3, respectively, with 15 minutes incubation), and decreased after incubation with 5-lipooxigenase inhibitors. Peak of ionophore or arachidonic acid-stimulated production in kinetic studies was reached at 20 minutes. LTB4 production was able to reach the luminal surface in both basal and stimulated conditions. There was no relationship with concomitantly measured prostacyclin production (mainly endothelial), while a correlation was found between LTB4 levels and degree of white cell infiltration in the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Arachidonic Acid; Arachidonic Acids; Arteries; Arteriosclerosis; Calcimycin; Humans; In Vitro Techniques; Leukotriene B4; Muscle, Smooth, Vascular; Reference Values; Veins

Topics: Arteriosclerosis; Blood Platelets; Coronary Disease; Eicosapentaenoic Acid; Fish Oils; Forecasting; Humans; Leukocytes; Leukotriene B4; Prostaglandins; SRS-A

(n-3) diets rich in polyunsaturated fatty acids (PUFA) reduce the atherogenic lipoproteins, especially the VLDL (very low density lipoproteins) rich in triglycerides but also the LDL, more effectively than (n-6) PUFA-rich diets. Moreover also other parameters such as high blood pressure and aggregation of thrombocytes are positively influenced, similarly like after (n-6) PUFA-rich diet. Eicosapentaenoic acid (20:5, n-3) has a triglyceride- and cholesterol-reducing effect by inhibition of the VLDL-synthesis (apolipoprotein B, triglycerides) in the liver, inhibition of lipogenic liver enzymes, accelerated elimination of VLDL from the circulation, increased excretion of steroids and bile acids into the stools and amelioration of the fat tolerance. The prolongation of the period of haemorrhage and the decrease of the aggregation of thrombocytes is associated with the enrichment of EPA in the platelet membrane. In these cases the decreased thrombocyte-vascular vessel-interaction shall be caused by a changed metabolism of the eicosanoids (secondary products of unsaturated fatty acids with 20 carbon atoms) and eicosanoid-independent mechanisms.

Topics: Arteriosclerosis; Blood Pressure; Coronary Disease; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Humans; Leukotriene B4; Lipids; Lipoproteins; Platelet Aggregation; Risk

A survey is given of the biochemistry and importance of the prostaglandins, the thromboxanes, the prostacyclins and the leukotrienes. The formation of these compounds takes place from poly-unsaturated fatty acids and is regulated: here the phospholipase A2 plays a role. Among others the prostaglandins take part in the regulation of the blood supply of various tissues (heart, kidneys), in the regulation of the reproduction and in the evokation of labour. The thromboxanes and prostacyclins influence the aggregation and the desaggregation of the thrombocytes, respectively. The leukotrienes take part in the regulation of the permeability of the capillaries, in the migration of the leucocytes, the formation of inflammatory processes and in the evokation of asthma bronchiale. The insufficient intake leads to functional disturbances in various tissues, which partly are to be traced back to a decrease of the formation of the tissue hormones mentioned. An intake transgressing the demand has a favourable effect in various diseases: thus the inclination to aggregation of the thrombocytes is decreased and the development of arteriosclerotic changes is inhibited.

Topics: Animals; Arteriosclerosis; Epoprostenol; Fatty Acids, Essential; Hemodynamics; Humans; Hypertension; Leukotriene B4; Phospholipases A; Phospholipases A2; Platelet Aggregation; Prostaglandins; SRS-A; Thromboxanes

Icosanoides (prostaglandins, leukotrienes) seem to play an essential part in cardiovascular pathology. A range of experimental data obtained both in vitro and in vivo has resulted in a rapid progression of our understanding of their biochemical and functional properties and has opened up new fields of pharmacological research. However, a clear cut demonstration of their clinical relevance remains difficult. Improved methodology will no doubt provide more information about the importance of these compounds. For the present, we recommend reexamination of previously reported results.

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Blood Vessels; Cells, Cultured; Endothelium; Humans; Leukotriene B4; Muscle, Smooth, Vascular; Prostaglandins; Rabbits; SRS-A; Thromboxane A2