Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The liver X receptors alpha and beta (LXRalpha and LXRbeta) are members of the nuclear receptor family of proteins that are critical for the control of lipid homeostasis in vertebrates. The endogenous activators of these receptors are oxysterols and intermediates in the cholesterol biosynthetic pathway. LXRs serve as cholesterol sensors that regulate the expression of multiple genes involved in the efflux, transport, and excretion of cholesterol. Recent studies have outlined the importance of LXR signaling pathways in the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Synthetic LXR agonists inhibit the development of atherosclerosis in murine models, an effect that is likely to result from the modulation of both metabolic and inflammatory gene expression. These observations identify the LXR pathway as a potential target for therapeutic intervention in human cardiovascular disease.
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PMID:Liver X receptor signaling pathways in cardiovascular disease. 1269 94

Vascular endothelial cell activation and dysfunction are critical early events in atherosclerosis. Even though very low or high levels of cholesterol can compromise cellular functions, cholesterol is a critical membrane component and may protect the vascular endothelium from oxidative stress and polyunsaturated fatty acid-mediated inflammatory responses. We have previously shown that the parent omega-6 fatty acid linoleic acid can markedly activate vascular endothelial cells. We now propose that membrane cholesterol can modify and inhibit linoleic acid-mediated endothelial cell dysfunction. To test this hypothesis, pulmonary artery endothelial cells were incubated with cholesterol (0 to 100 micromol/L) for 24 hours and then treated with 90 micromol/L of linoleic acid (18:2n-6) for 6 to 24 hours. In control cells, treatment with linoleic acid reduced intracellular glutathione levels and induced the DNA binding activity of nuclear factor-kappaB (NF-kappaB) leading to the upregulation of interleukin-6 (IL-6). In addition, the expression of endothelial nitric oxide synthase (eNOS) was altered, with linoleic acid increasing eNOS activity. In contrast, enrichment with cholesterol enhanced glutathione levels and reduced the linoleic acid-induced activation of NF-kappaBand the production of IL-6. Prior exposure to 50 micromol/L cholesterol also prevented the fatty acid-induced increase in eNOS activation. Cholesterol loading activated peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor that can decrease inflammatory responses. Furthermore, the PPAR-gamma agonist thiazolidinedione markedly downregulated the NF-kappaB activation mediated by linoleic acid. Our data suggest that signaling pathways linked to endothelial cell activation by prooxidant and proinflammatory insults may be influenced by cellular cholesterol levels.
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PMID:Cholesterol attenuates linoleic acid-induced endothelial cell activation. 1270 Oct 65

Lipid mediators can exert their effects by interactions with well-characterised cell surface G-protein-linked receptors. Recently, a group of intracellular receptors have been identified that are activated by a large variety of lipid-derived mediators. Amongst these novel targets, the peroxisome proliferator-activated receptors (PPARs), a family of three (PPARalpha, beta/delta and gamma) nuclear receptor/transcription factors have become a major area for investigation. PPARs are found throughout the body, where they have diverse roles regulating lipid homeostasis, cellular differentiation, proliferation and the immune response. There is a great interest, therefore, in the roles of PPARs in a variety of pathological conditions, including diabetes, atherosclerosis, cancer and chronic inflammation. Although, a number of naturally occurring compounds can activate PPARs, it has been difficult, as yet, to characterise any of these mediators as truly endogenous ligands. These findings have lead to the suggestion that PPARs may act just as general lipid sensors. Acting as lipid sensors, PPARs may take changes in lipid/fatty acid balance in the diet or local metabolism and translate them to tissue-specific ligands, exerting tissue-specific effects. Using classical pharmacological criteria for endogenous mediator classification we will critically discuss the variety of pathways for putative ligand generation.
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PMID:Peroxisome proliferator-activated receptors: a critical review on endogenous pathways for ligand generation. 1274 90

Retinoid X Receptors (RXRs) consist of a family of nuclear receptors that target and regulate multiple signalling pathways. The early evolutionary emergence of RXRs in comparison to other nuclear receptors may have allowed for the development of unique properties as transcriptional regulators. Indeed, the complexity of these receptors is derived from their ability to activate transcription as homodimers or as obligate heterodimeric partners of a multitude of other nuclear receptors. In addition, RXRs can regulate gene expression in a ligand-dependent (forming permissive heterodimeric complexes) or - independent (forming non-permissive heterodimeric complexes) manner. Given that ligand binding is a critical component of RXR function, this review will focus on the ligand dependent functions of RXR. The remarkably conserved ligand binding domain of RXR is a multi-functional structure that in addition to ligand binding, serves as a homo- and heterodimeric interface, and a region to bind coactivactor and corepressor molecules. RXRs have a small ligand binding pocket and therefore bind their ligands (such as 9-cis RA) with both high affinity and specificity. In the presence of ligand, permissive RXR heterodimers bind coactivators, but nonpermissive complexes can bind coactivators or corepressors depending on the activation of the RXR's heterodimeric partner. Physiologically, the temporal and tissue specific pattern of RXRs as well as the presence of phenotypic abnormalities in receptor knockout studies (most severe in RXRa -/- animals) demonstrate the important role for these receptors both during development (morphogenesis) and in adult differentiated tissues (cell proliferation, cell differentiation, cell death). These receptors also play an important regulatory role metabolic signaling pathways (glucose, fatty acid and cholesterol metabolism), including metabolic disorders such as type 2 diabetes, hyperlipidemia and atherosclerosis. RXRs function as master regulators producing diverse physiological effects through the activation of multiple nuclear receptor complexes. RXRs represent important targets for pharmacologic interventions and therapeutic applications.
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PMID:The retinoid X receptor and its ligands: versatile regulators of metabolic function, cell differentiation and cell death. 1275 20

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. PPARs have three isoforms, alpha, beta (or delta) and gamma. It has been conceived that PPARgamma is expressed predominantly in adipose tissue and promotes adipocyte differentiation and glucose homeostasis. Recently, synthetic antidiabetic thiazolidinediones and natural prostaglandin D(2) (PGD(2)) metabolite, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), have been identified as ligands for PPARgamma. Following demonstration that PPARgamma is present in a variety of cell types, further study of PPARgamma has been conducted. Although activation of PPARgamma appears to have beneficial effects on atherosclerosis and heart failure, it is still largely uncertain whether PPARgamma ligands prevent the development of cardiovascular diseases. Recent evidence suggests that some benefit from the antidiabetic agents known as thiazolidinediones may occur through PPARgamma-independent mechanisms. In this review, we report on the latest developments concerning the study of PPARs and summarize the roles of the PPARgamma-dependent pathway in cardiovascular diseases.
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PMID:The role of PPARgamma-dependent pathway in the development of cardiac hypertrophy. 1286 48

Diabetes, obesity, atherosclerosis and cancer are the principal contributors to morbidity and mortality in Western society. Emerging evidence indicates that a nuclear receptor, the peroxisome proliferator-activated receptor gamma (PPARgamma), plays a role in these pathological processes. Furthermore, modulation of receptor action in these diseases may be of therapeutic value, as exemplified by the recent introduction of the thiazolidinediones, a novel class of insulin-sensitizing agent for the treatment of type 2 diabetes mellitus. The availability of such high-affinity ligands has facilitated the study of signalling pathways through which PPARgamma regulates metabolic processes; these analyses have been complemented by the study of human subjects harbouring (naturally occurring) mutations and polymorphisms within the receptor. The latter have provided unique genetic evidence for a link between PPARgamma and mammalian glucose homeostasis, lipid metabolism and regulation of fat mass. This review highlights recent studies which have advanced our understanding of the pivotal role that this receptor plays in metabolism, with particular reference to the consequences of inherited variation in the human receptor gene.
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PMID:PPARgamma and metabolism: insights from the study of human genetic variants. 1291 47

Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the ligand-activated nuclear receptor superfamily, plays a key role in mediating differentiation of adipocytes and regulating fat metabolism. PPARgamma has been implicated in the pathophysiology of atherosclerosis, inflammation, obesity, diabetes, immune response, and ageing. Recently, it has been shown that activation of PPARgamma by J(2) series cyclopentenone prostaglandins (cyPGs), especially 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) or synthetic agents, such as antidiabetic thiazolidinediones, causes anti-proliferation, apoptosis, differentiation, and anti-inflammation of certain types of cancer cells. The anti-proliferative effects of PPARgamma activators are associated with de novo synthesis of proteins involved in regulating the cell cycle and cell survival/death. Anti-inflammatory effects of 15d-PGJ(2) are associated with interruption of nuclear factor-kappaB and subsequent blockade of inflammatory gene expression. Furthermore, 15d-PGJ(2) at nontoxic doses induce expression of phase II detoxification or stress-responding enzymes, which may confer cellular resistance or adaptation to oxidative stress. The presence of a reactive alpha,beta-unsaturated carbonyl moiety in the cyclopentenone ring of 15d-PGJ(2) is important for part of biological functions this cyPG has. Recently, attention has been focused on the anti-proliferative activity of nonsteroidal anti-inflammatory drugs (NSAIDs) in cancerous or transformed cells, which is mediated through interaction with PPARgamma irrespective of their ability to inhibit COX-2. Despite the fact that abnormally elevated COX-2 is associated with resistance to cell death, induction of apoptosis by certain NSAIDs is accompanied by up-regulation of COX-2 expression. This commentary focuses on dual effects of the typical PPARgamma agonist 15d-PGJ(2) on cell proliferation and growth, and its possible involvement in the NSAID-induced COX-2 expression and apoptosis.
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PMID:Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands as bifunctional regulators of cell proliferation. 1455 12

Macrophages play essential roles in immunity and homeostasis. As professional scavengers, macrophages phagocytose microbes and apoptotic and necrotic cells and take up modified lipoprotein particles. These functions require tightly regulated mechanisms for the processing and disposal of cellular lipids. Under pathological conditions, arterial wall macrophages become foam cells by accumulating large amounts of cholesterol, contributing to the development of atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs) are members of the nuclear receptor superfamily of transcription factors that have emerged as key regulators of macrophage homeostasis. PPARs and LXRs control transcriptional programs involved in processes of lipid uptake and efflux, lipogenesis, and lipoprotein metabolism. In addition, PPARs and LXRs negatively regulate transcriptional programs involved in the development of inflammatory responses. This review summarizes recent efforts to decode the differential and overlapping roles of PPARs and LXRs in the context of macrophage lipid homeostasis and the control of inflammation.
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PMID:Decoding transcriptional programs regulated by PPARs and LXRs in the macrophage: effects on lipid homeostasis, inflammation, and atherosclerosis. 1459 55

Atherosclerosis remains a major complication of type 2 diabetes mellitus. Increasing data suggest insulin resistance, and its associated metabolic abnormalities, may underlie many of the cardiovascular complications seen among patients with insulin resistance and/or diabetes mellitus. This insight has also suggested that therapeutic approaches targeting insulin resistance may not only improve metabolism but also limit complications like atherosclerosis and the inflammation that contributes to it. Thiazolidinediones, agonists of the nuclear receptor peroxisome proliferator activated receptor gamma, are one such insulin-sensitizing therapeutic intervention in current use among patients with type 2 diabetes mellitus. The existing data regarding thiazolidinedione effects on the cardiovascular system are reviewed and considered, along with the future prospects for this emerging drug class.
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PMID:Peroxisome proliferator activated receptor gamma and its activation in the treatment of insulin resistance and atherosclerosis: issues and opportunities. 1459 89

Macrophages play diverse roles in host defense and in maintenance of homeostasis. Based on their ability to promote inflammatory responses, inappropriate macrophage function also contributes to numerous pathological processes, including atherosclerosis, rheumatoid arthritis and inflammatory bowel disease. Members of the nuclear receptor superfamily of ligand-dependent transcriptions factors have emerged as key regulators of inflammation and lipid homeostasis in macrophages. These include the glucocorticoid receptor (GR), which inhibits inflammatory programs of gene expression in response to natural corticosteroids and synthetic anti-inflammatory ligands such as dexamethasone. Also, in response to endogenous eicosanoids and oxysterols, respectively, peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs) regulate transcriptional programs involved in inflammatory responses and lipid homeostasis. Identification of their mechanisms of action should help guide the development of new therapeutic agents useful in the treatment of diseases in which macrophages play critical pathogenic roles.
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PMID:Nuclear receptor signaling in macrophages. 1469 33


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