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 peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that regulates fat-cell development and glucose homeostasis and is the molecular target of a class of insulin-sensitizing agents used for the management of type 2 diabetes mellitus. PPARgamma is highly expressed in macrophage foam cells of atherosclerotic lesions and has been demonstrated in cultured macrophages to both positively and negatively regulate genes implicated in the development of atherosclerosis. We report here that the PPARgamma-specific agonists rosiglitazone and GW7845 strongly inhibited the development of atherosclerosis in LDL receptor-deficient male mice, despite increased expression of the CD36 scavenger receptor in the arterial wall. The antiatherogenic effect in male mice was correlated with improved insulin sensitivity and decreased tissue expression of TNF-alpha and gelatinase B, indicating both systemic and local actions of PPARgamma. These findings suggest that PPARgamma agonists may exert antiatherogenic effects in diabetic patients and provide impetus for efforts to develop PPARgamma ligands that separate proatherogenic activities from antidiabetic and antiatherogenic activities.
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PMID:Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. 1097 14

The CCR2-mediated recruitment of monocytes into the vessel wall plays an important role in all stages of atherosclerosis. In recent studies, we have shown that lipoproteins can modulate CCR2 expression and have identified native LDL as a positive regulator. In contrast, oxidized LDL (OxLDL), which is mainly formed in the aortic intima, reduces CCR2 expression, promotes monocyte retention, and may cause pathological accumulation of monocytes in the vessel wall. We now provide evidence that OxLDL reduces monocyte CCR2 expression by activating intracellular signaling pathways that may involve peroxisome proliferator-activated receptor gamma (PPARgamma). Receptor-mediated uptake of the lipoprotein particle was required and allows for delivery of the exogenous ligand to the nuclear receptor. The suppression of CCR2 expression by OxLDL was mediated by lipid components of OxLDL, such as the oxidized linoleic acid metabolites 9-HODE and 13-HODE, known activators of PPARgamma. Modified apoB had no such effect. Consistent with a participation of the PPARgamma signaling pathway, BRL49653 reduced CCR2 expression in freshly isolated human monocytes ex vivo and in circulating mouse monocytes in vivo. These results implicate PPARgamma in the inhibition of CCR2 gene expression by oxidized lipids, which may help retain monocytes at sites of inflammation, such as the atherosclerotic lesion.
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PMID:Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator-activated receptor gamma. 1099 90

This study investigated whether the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) gene is associated with glucose and lipid metabolism in young healthy subjects participating in the European Atherosclerosis Research Study II. Men aged 18-28 years (n=675) were recruited from 14 university student populations in 11 European countries. At their first visit subjects had an oral glucose tolerance test and 1 week later an oral fat tolerance test. Lipid variables and genotype were measured centrally. The Ala allele frequency exhibited a clearcut north-to-south gradient through Europe, decreasing from 0.21 in Baltic countries to 0.07 in Mediterranean countries. There was no significant effect of the Pro12Ala polymorphism on fasting lipid, glucose, or insulin levels, nor on the postprandial changes in these variables after glucose and fat tolerance tests. Neither was the Pro12Ala polymorphism associated with body mass index. This study provides no evidence for a major effect of the Pro12Ala polymorphism on glucose and lipid metabolism in young healthy subjects. Since PPARgamma has a major role in adipogenesis, the differential effect of its polymorphism on weight and related metabolic disorders may become apparent only later in life.
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PMID:The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma2 gene is not associated with postprandial responses to glucose or fat tolerance tests in young healthy subjects: the European Atherosclerosis Research Study II. 1100 32

Peroxisome proliferator-activated (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family. PPARs function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPARalpha is highly expressed in tissues such as liver, muscle, kidney and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPARgamma is predominantly expressed in intestine and adipose tissue. PPARgamma triggers adipocyte differentiation and promotes lipid storage. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPARalpha and PPARgamma, respectively. Furthermore, fatty acids and eicosanoids are natural PPAR ligands: PPARalpha is activated by leukotriene B4, whereas prostaglandin J2 is a PPARgamma ligand. These observations suggested a potential role for PPARs not only in metabolic but also in inflammation control. The first evidence for a role of PPARalpha in inflammation control came from the demonstration that PPARalpha deficient mice display a prolonged response to inflammatory stimuli. It was suggested that PPARalpha deficiency results in a reduced beta-oxidative degradation of these inflammatory fatty acid derivatives. More recently, PPAR activators were shown to inhibit the activation of inflammatory response genes (such as IL-2, IL-6, IL-8, TNFalpha and metalloproteases) by negatively interfering with the NF- kappaB, STAT and AP-1 signalling pathways. PPAR activators exert these anti-inflammatory activities in different immunological and vascular wall cell types such as monocyte/macrophages, endothelial, epithelial and smooth muscle cells in which PPARs are expressed. These recent findings indicate a modulatory role for PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases, such as atherosclerosis and inflammatory bowel disease.
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PMID:Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. 1108

The discovery of peroxisome proliferator-activated receptor gamma (PPARgamma) as the molecular target for antidiabetic thiazolidinediones has heralded a new era in the approach to understanding the pathophysiology of insulin resistance and its relationship to cardiovascular disease. However, the subsequent discovery of PPARgamma-dependent modulation of immune function and the cell cycle has led to a new paradigm in the approach to treating proliferative, inflammatory diseases. Moreover, PPARgamma agonists can promote apoptosis, block angiogenesis and inhibit pathological remodelling in a variety of malignant and non-malignant pathological states. These findings imply that the pharmacological modulation of this key nuclear transcription factor and its co-factors could be important tools in understanding the relationships between multigenic diseases, and pave the way to a focused interventional approach in their treatment. With the availability of the PPARgamma protein crystal structure, the ligand binding domain co-ordinates and a better knowledge of the interaction of PPARgamma with co-factor assemblies, libraries of simple synthetic organic PPARgamma ligands can be constructed. High throughput screening can identify the best candidates for targeting cellular phenotypic transition, cell cycle control, inflammation and apoptosis. Instead of single agents for single pathologies, one can envisage the development of multifunctional therapeutic agents that target the multiple cellular processes that contribute to multifactorial diseases such as diabetes, hypertension, atherosclerosis, psoriasis and other inflammatory diseases, and carcinogenesis. The considerable potential of PPARgamma ligands in the treatment of diseases other than diabetes is the subject of this review.
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PMID:Pharmacological peroxisome proliferator-activated receptorgamma ligands: emerging clinical indications beyond diabetes. 1113 30

alpha1-Antitrypsin (AAT) serine proteinase inhibitor is found in most biological fluids, diffuses into most tissues, and is an important factor in controlling tissue damage by proteases in inflammatory diseases such as atherosclerosis. We have previously reported that the C-terminal fragment (C-36) generated during the cleavage of AAT by proteinases forms amyloid fibrils which have biological effects unrelated to precursor functions. Here we show that the C-36 fragment is present in atherosclerotic plaques, particularly within the fibrous cap at the base of the lipid core. We also found that human monocyte stimulation with C-36 fibrils led to a strong activation of both peroxisome proliferator-activated receptors alpha and gamma (PPARalpha and PPARgamma) at 1, 2, and 18 h of cell culture. A parallel increase in the intracellular lipid accumulation was also observed. Furthermore, stimulation of monocytes with C-36 for 18 h led to activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) activation. These data for the first time demonstrate the peptide of AAT as a component of atherosclerotic plaques and as a novel activator of PPARalpha, PPARgamma, NF-kappaB, and AP-1 in cultured monocytes. Taken together, the effects of the peptide represent a new mechanism of monocyte activation that may be of importance not only in atherogenesis, but also in other inflammatory processes.
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PMID:The carboxyl-terminal fragment of alpha1-antitrypsin is present in atherosclerotic plaques and regulates inflammatory transcription factors in primary human monocytes. 1115 28

A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. Dysregulation of such metabolic pathways can lead to the development of atherosclerosis, a disease influenced by both systemic and local factors. Here we analyzed the effects of activation of RXR and some of its heterodimers in apolipoprotein E -/- mice, a well established animal model of atherosclerosis. An RXR agonist drastically reduced the development of atherosclerosis. In addition, a ligand for the peroxisome proliferator-activated receptor (PPAR)gamma and a dual agonist of both PPARalpha and PPARgamma had moderate inhibitory effects. Both RXR and liver X receptor (LXR) agonists induced ATP-binding cassette protein 1 (ABC-1) expression and stimulated ABC-1-mediated cholesterol efflux from macrophages from wild-type, but not from LXRalpha and beta double -/-, mice. Hence, activation of ABC-1-mediated cholesterol efflux by the RXR/LXR heterodimer might contribute to the beneficial effects of rexinoids on atherosclerosis and warrant further evaluation of RXR/LXR agonists in prevention and treatment of atherosclerosis.
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PMID:Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor. 1122 87

Coronary heart disease (CHD), whose primary aetiology is atherosclerosis, is the leading cause of mortality and a major cause of morbidity in the industrialised world [1]. Serum lipoprotein levels are aetiologically related to the risk of atherosclerosis and CHD [2]. The liver and the gastrointestinal system are the major protagonists involved in regulation of lipoprotein biochemical-physiological mechanisms and the development of hypercholesterolaemia. Furthermore, specific lipoprotein receptors are being discovered as targets for pharmacological intervention to correct lipoprotein disorders. Agents that target lipoprotein regulation in the liver, gastrointestinal-biliary and atherosclerotic tissues resulting in improved serum lipoprotein levels and/or control of primary and secondary dyslipidaemic disorders including diabetes, are currently undergoing clinical trials. The most novel promising compounds, after the greatly effective newest HMG-CoA reductase inhibitors, are drugs that affect peroxisome proliferator-activated receptors, PPARalpha and PPARgamma receptors, bile acid transport mechanisms, cholesterol absorption and cholesterol acyltransferase and other biochemical targets of lipoprotein regulation. Current knowledge and ongoing trials with these agents are described here within the boundaries of investigator confidentiality agreements.
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PMID:New pharmacological agents under clinical investigation for treating disorders of lipoprotein regulation leading to atherosclerosis. 1122 51

The peroxisome proliferator-activated receptors (PPARalpha, gamma, delta) are members of the nuclear receptor superfamily of ligand-activated transcription factors that have central roles in the storage and catabolism of fatty acids. Although the three PPAR subtypes are closely related and bind to similar DNA response elements as heterodimers with the 9-cis retinoic acid receptor RXR, each subserves a distinct physiology. PPARalpha (NR1C1) is the receptor for the fibrate drugs, which are widely used to lower triglycerides and raise high-density lipoprotein cholesterol levels in the treatment and prevention of coronary artery disease. In rodents, PPARalpha agonists induce hepatomegaly and stimulate a dramatic proliferation of peroxisomes as part of a coordinated physiological response to lipid overload. PPARgamma (NR1C3) plays a critical role in adipocyte differentiation and serves as the receptor for the glitazone class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. In contrast to PPARalpha and PPARgamma, relatively little is known about the biology of PPARdelta (NR1C2), although recent findings suggest that this subtype also has a role in lipid homeostasis. All three PPARs are activated by naturally occurring fatty acids and fatty acid metabolites, indicating that they function as the body's fatty acid sensors. Three-dimensional crystal structures reveal that the ligand-binding pockets of the PPARs are much larger and more accessible than those of other nuclear receptors, providing a molecular basis for the promiscuous ligand-binding properties of these receptors. Given the fundamental roles that the PPARs play in energy balance, drugs that modulate PPAR activity are likely to be useful for treating a wide range of metabolic disorders, including atherosclerosis, dyslipidemia, obesity, and type 2 diabetes.
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PMID:Peroxisome proliferator-activated receptors: from genes to physiology. 1123 16

Atherosclerosis is a major complication of type 2 diabetes. The pathogenesis of this complication is poorly understood, but it clearly involves production in the vascular wall of macrophage (Mo) lipoprotein lipase (LPL). Mo LPL is increased in human diabetes. Peripheral factors dysregulated in diabetes, including glucose and free fatty acids (FAs), may contribute to this alteration. We previously reported that high glucose stimulates LPL production in both J774 murine and human Mo. In the present study, we evaluated the direct effect of FAs on murine Mo LPL expression and examined the involvement of peroxisome proliferator-activated receptors (PPARs) in this effect. J774 Mo were cultured for 24 h with 0.2 mmol/l unsaturated FAs (arachidonic [AA], eicosapentaenoic [EPA], and linoleic acids [LA]) and monounsaturated (oleic acid [OA]) and saturated FAs (palmitic acid [PA] and stearic acid [SA]) bound to 2% bovine serum albumin. At the end of this incubation period, Mo LPL mRNA expression, immunoreactive mass, activity, and synthetic rate were measured. Incubation of J774 cells with LA, PA, and SA significantly increased Mo LPL mRNA expression. In contrast, exposure of these cells to AA and EPA dramatically decreased this parameter. All FAs, with the exception of EPA and OA, increased extra- and intracellular LPL immunoreactive mass and activity. Intracellular LPL mass and activity paralleled extracellular LPL mass and activity in all FA-treated cells. In Mo exposed to AA, LA, and PA, an increase in Mo LPL synthetic rate was observed. To evaluate the role of PPARs in the modulatory effect of FAs on Mo LPL gene expression, DNA binding assays were performed. Results of these experiments demonstrate an enhanced binding of nuclear proteins extracted from all FA-treated Mo to the peroxisome proliferator-response element (PPRE) consensus sequence of the LPL promoter. PA-, SA-, and OA-stimulated binding activity was effectively diminished by immunoprecipitation of the nuclear proteins with anti-PPAR-alpha antibodies. In contrast, anti-PPAR-gamma antibodies only significantly decreased AA-induced binding activity. Overall, these results provide the first evidence for a direct regulatory effect of FAs on Mo LPL and suggest a potential role of PPARs in the regulation of Mo LPL gene expression by FAs.
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PMID:Direct regulatory effect of fatty acids on macrophage lipoprotein lipase: potential role of PPARs. 1124 88

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