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)

Conjugated linoleic acid (CLA) is a mixture of positional (e.g. 7,9; 9,11; 10,12; 11,13) and geometric (cis or trans) isomers of octadecadienoic acid. This compound was first shown to prevent mammary carcinogenesis in murine models. Later investigations uncovered a number of additional health benefits, including decreasing atherosclerosis and inflammation while enhancing immune function. The mechanisms of action underlying these biological properties are not clearly understood. The aim of this review is to highlight recent advances in CLA research related to experimental inflammatory bowel disease. In addition, two possible mechanisms of action (i.e. endoplasmic and nuclear) were discussed in detail in the context of enteric inflammatory disorders. Conjugated linoleic acid was first implicated in down-regulating the generation of inducible eicosanoids (i.e. PGE(2) and LTB(4)) involved in early micro-inflammatory events (endoplasmic). More recently, CLA has been shown to modulate the expression of genes regulated by peroxisome proliferator-activated receptors (PPARs; nuclear). In pigs, prolonged dietary CLA treatment stimulated the expression of PPAR-gamma in the muscle. Thus, evidence supporting both mechanistic theories of CLA acting through eicosanoid synthesis and PPAR activity is available. The further understanding of the anti-inflammatory mechanisms of action of CLA may yield novel nutritional therapies for enteric inflammation.
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PMID:Colonic anti-inflammatory mechanisms of conjugated linoleic acid. 1246 64

Leukotriene B(4) (LTB(4)) is a potent leukocyte chemoattractant recently implicated in the pathogenesis of atherosclerosis. The aim of this study was to assess the effects of LTB(4) on isolated aortic preparations. Rings of guinea pig aorta were challenged with LTB(4) for recording mechanical responses and measurements of mediator release, and LTB(4) receptor (BLT(1)) expression was assessed by RT-PCR. Single concentrations of LTB(4) induced concentration-dependent contractions that were inhibited by treatment with antihistamines, indomethacin, or the thromboxane receptor antagonist BAYu3405 as well as by denudation of endothelium. In addition, LTB(4) increased the release of histamine and thromboxane in the bath. The contractions induced by LTB(4) were inhibited by either the unselective BLT receptor antagonist ONO-4057 or the selective BLT(1) receptor antagonist U-75302. Pretreatment with all-trans-retinoic acid enhanced the contractions and the release of histamine induced by LTB(4), without affecting either the contractions induced by histamine or the histamine release evoked by calcium ionophore A23187. Analysis by RT-PCR indicated the expression of a BLT(1) receptor in the guinea pig aorta and that BLT(1) receptor mRNA was upregulated after treatment with retinoic acid. These results suggest that LTB(4) contracts the guinea pig aorta via an indirect mechanism involving the release of histamine and thromboxane and that this BLT(1) receptor-mediated response can be upregulated by all-trans-retinoic acid.
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PMID:Leukotriene B4 is an indirectly acting vasoconstrictor in guinea pig aorta via an inducible type of BLT receptor. 1501 29

Cigarette smoking is associated with increased atherosclerosis and intimal thickening, and has immune-suppressive effects. The immune system modulates atherosclerosis and intimal thickening. We hypothesized that detrimental effects of cigarette smoke (CS) involves modulation of the immune response to oxidized low-density lipoprotein (oxLDL). ApoE-/- mice fed Western diet were exposed to CS starting at 20 weeks of age. Control mice were exposed to air. After 5 weeks of CS, mice were subjected to carotid arterial cuffing for 21 days. Intimal thickening was significantly increased in CS mice compared to control (0.050 +/- 0.034 mm(2) versus 0.023 +/- 0.021 mm(2); P < 0.05). Spleen lymphocyte population, cytokine mRNA expression, and total IgM and IgG levels were similar. Anti-MDA oxLDL IgG was reduced by 40% (P < 0.05) in CS mice compared to control. Copper-oxidized LDL IgG antibodies remained unchanged but IgM increased in CS mice, associated with increased intimal thickening. Anti-phosphorylcholine (PC) IgM was also increased in the CS mice, associated with increased intimal thickening. Lymphocyte signaling molecule lymphotoxin beta (LTbeta) expression was significantly decreased in spleens of CS exposed mice. Our results suggest that immune modulation by CS characterized by aberrant antibody responses to oxLDL and reduced LTbeta mRNA expression is associated with increased intimal thickening after arterial cuffing.
Atherosclerosis 2004 Jul
PMID:Aberrant antibody responses to oxidized LDL and increased intimal thickening in apoE-/- mice exposed to cigarette smoke. 1518 41

Cardiovascular disease is the leading cause of morbidity in Westernized populations. Low levels of alpha-tocopherol (AT) are associated with increased incidence of atherosclerosis and increased intakes appear to be protective. AT supplementation decreases interleukin 1 and 6 release from human monocytes. Thus, the aim of this study was to examine the effect of AT on an important proinflammatory cytokine, tumor necrosis factor-alpha (TNF) release from human monocytes. AT supplementation (1200 IU/day for 3 months) significantly decreased TNF release from activated human monocytes. Mechanisms that were examined included its effect as a general antioxidant, its inhibitory effect on protein kinase C (PKC), and the cycloxygenase-lipoxygenase pathway. While AT decreased TNF release from activated monocytes, other antioxidants had no effect on TNF release. Specific PKC inhibitors had no effect on TNF release from activated monocytes. The inhibition of TNF release by AT in activated monocytes was reversed by leukotriene B(4) (LTB(4)), a major product of the 5-lipoxygenase (5-LO) pathway. Similar observations were seen with inhibitors of 5-lipoxygenase. Indomethacin, a COX inhibitor, in the presence and absence of AT failed to affect TNF activity. These findings suggest that AT decreases TNF release from activated human monocytes via inhibition of 5-lipoxygenase. Also, AT as well as a 5-LO inhibitor significantly decreased TNF mRNA. Furthermore, AT and the 5-LO inhibitor decreased NFkappab-binding activity. Thus, in activated human monocytes, AT appears to inhibit TNF mRNA and protein by inhibition of 5-LO.
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PMID:Alpha-tocopherol decreases tumor necrosis factor-alpha mRNA and protein from activated human monocytes by inhibition of 5-lipoxygenase. 1580 19

More than 30 lipid ligands, which express their biological activities through cognate G-protein-coupled receptors (GPCRs), have been reported. Among them, leukotriene B(4) (LTB(4)) is a potent lipid mediator involved in host defense, inflammation, and the immune responses. Two GPCRs for LTB(4) (BLT1 and BLT2) have been cloned and analyzed. Recent studies using genetically engineered mice suggest that BLT1 plays an important role in several inflammatory diseases including ischemic reperfusion tissue injury, atherosclerosis, and bronchial asthma. BLT1 is also a good tool to study the molecular mechanism of GPCR activation and inactivation in vitro. In this brief review, we focus on the biological and biochemical properties of BLT1 with special attention to the putative helix 8 of the receptor.
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PMID:Leukotriene B4 receptor and the function of its helix 8. 1604 89

High postprandial serum lipid concentrations are associated with increased oxidative stress which, in turn, increases the risk of atherosclerosis. Epidemiological studies correlate lower incidence of cardiovascular disease with adherence to the Mediterranean diet. The aim of this study was to evaluate changes in inflammatory (TXB(2) and LTB(4)) and oxidative stress markers (urinary hydrogen peroxide levels and serum antioxidant capacity), in addition to classic lipid parameters, after a fat-rich meal administered to 12 normolipemic, healthy subjects. Following a Latin square design, subjects were divided into three groups, each one receiving a different kind of oil (extra virgin olive oil; EVOO, olive oil; OO or corn oil; CO, together with 150g of potatoes), with 2-week washout periods between treatments. Blood samples were drawn at baseline and after 1, 2, and 6h after the meal. A significant decrease in inflammatory markers, namely TXB(2) and LTB(4), after 2 and 6h after EVOO (but not OO or CO) consumption and a concomitant increase of serum antioxidant capacity were recorded. These data reinforce the notion that the Mediterranean diet reduces the incidence of coronary heart disease partially due to the protective role of its phenolic components, including those of extra virgin olive oil.
Atherosclerosis 2007 Jan
PMID:Postprandial anti-inflammatory and antioxidant effects of extra virgin olive oil. 1648 19

Leukotriene B(4) (LTB(4)) mediates a variety of inflammatory diseases such as asthma, arthritis, atherosclerosis, and cancer through activation of the G-protein-coupled receptor, BLT1. Using in silico molecular dynamics simulations combined with site-directed mutagenesis we characterized the ligand binding site and activation mechanism for BLT1. Mutation of residues predicted as potential ligand contact points in transmembrane domains (TMs) III (H94A and Y102A), V (E185A), and VI (N241A) resulted in reduced binding affinity. Analysis of arginines in extracellular loop 2 revealed that mutating arginine 156 but not arginine 171 or 178 to alanine resulted in complete loss of LTB(4) binding to BLT1. Structural models for the ligand-free and ligand-bound states of BLT1 revealed an activation core formed around Asp-64, displaying multiple dynamic interactions with Asn-36, Ser-100, and Asn-281 and a triad of serines, Ser-276, Ser-277, and Ser-278. Mutagenesis of many of these residues in BLT1 resulted in loss of signaling capacity while retaining normal LTB(4) binding function. Thus, polar residues within TMs III, V, and VI and extracellular loop 2 are critical for ligand binding, whereas polar residues in TMs II, III, and VII play a central role in transducing the ligand-induced conformational change to activation. The delineation of a validated binding site and activation mechanism should facilitate structure-based design of inhibitors targeting BLT1.
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PMID:Critical role for polar residues in coupling leukotriene B4 binding to signal transduction in BLT1. 1723 98

Leukotrienes are potent inflammatory mediators synthesized locally within the cardiovascular system through the 5-lipoxygenase pathway of arachidonic acid metabolism. The leukotrienes, consisting of dihydroxy leukotriene LTB4 and the cysteinyl leukotrienes LTC4, LTD4 and LTE4, act by targeting cell surface receptors expressed on inflammatory cells and on structural cells of vessel walls. LTB, induces leukocyte activation and chemotaxis via high- and low-affinity receptor subtypes (BLT1 and BLT2), respectively. Recently, BLT, receptors were found on human vascular smooth muscle cells, inducing their migration and proliferation. Cysteinyl leukotrienes are vasoconstrictors and induce endothelium-dependent vascular responses through the CysLT, and CysLT2 receptor subtypes. There is also pharmacological evidence for the existence of further CysLT receptor subtypes. Taken together, experimental and genetic studies suggest a major role of leukotrienes in atherosclerosis and in its ischemic complications such as acute coronary syndromes and stroke. Furthermore, the effects on vascular smooth muscle cells suggest a role in the vascular remodeling observed after coronary angioplasty, as well as in aortic aneurysm. Further experimental and clinical studies are needed to determine the potential of therapeutic strategies targeting the leukotriene pathway in cardiovascular disease.
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PMID:[Leukotrienes: potential therapeutic targets in cardiovascular diseases]. 1745 Jun 83

Inflammatory eicosanoids generated by the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism are now known to have at least 6 receptors: OXE, which recognizes 5-HETE and 5-oxo-ETE; a putative receptor recognizing a potent 5-oxo-ETE metabolite, FOG(7); the LTB(4) receptors, BLT1 and BLT2; the cysteinyl leukotriene receptors, CysLT(1) and CysLT(2), which recognize leukotrienes LTC(4), LTD(4), LTE(4) and LTF(4). The 5-LO pathway is activated in many diseases and invokes inflammatory responses not affected by glucocorticoids, but therapy with selective BLT1 or CysLT(1) antagonists in asthma has met with variable success. Studies show that 5-LO pathway eicosanoids are not primary mediators in all cases of asthma, but may be especially important in severe persistent asthma, aspirin- and exercise-induced asthma, allergic rhinitis, COPD, idiopathic pulmonary fibrosis, atherosclerosis, atopic dermatitis, acne and ischemia-related organ injury. These disorders appear to involve multiple 5-LO pathway eicosanoids and receptor subtypes, suggesting that inhibition of the pathway at the level of 5-LO may be necessary for maximal efficacy.
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PMID:Pharmacotherapy of diseases mediated by 5-lipoxygenase pathway eicosanoids. 1748 54

Leukotriene B(4) (LTB(4)) is an inflammatory mediator derived from the 5-lipoxygenase pathway of arachidonic acid metabolism and has recently implicated in the pathogenesis of atherosclerosis. There are two membrane bound receptors for LTB(4): BLT(1) and BLT(2), which represent the high and low affinity receptors, respectively. BLT receptors are expressed on leukocytes, and LTB(4) is a potent chemoattractant for neutrophils, eosinophils, and T lymphocytes. Recent studies have in addition shown that LTB(4) is an indirectly acting vasoconstrictor of isolated vascular preparations. In the guinea pig aorta, the LTB(4)-induced contractions were inhibited by endothelium-denudation. In addition, pre-treatment with the NO synthase inhibitor, L-NOARG, significantly enhanced the contractions induced by LTB(4). The contractile response induced by LTB(4) in the guinea pig aorta was abolished by the selective BLT(1) receptor antagonist U75302 and the expression of BLT(1) receptor mRNA in the guinea pig aorta was established by RT-PCR. Taken together, these results suggest that LTB(4) activates BLT(1) receptors on the endothelium of the guinea pig aorta, associated with the release of both contractile factors and NO.
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PMID:Endothelium-dependent vascular responses induced by leukotriene B4. 1748 57


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