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 development of atherosclerosis is often associated with altered concentrations of systemic lipoproteins, which are determined by the concentration and/or activity of three groups of different proteins, i.e. apolipoproteins (apo), enzymes, and receptors. The effects of diet or therapeutic interventions on lipid metabolism are mediated by changes in activity or concentrations of these three components. Fibrates have been shown to activate nuclear receptors belonging to the steroid hormone receptor super-family, termed peroxisome proliferator activated receptor (PPAR). These activated PPARs are potent transcription factors which influence the expression of several target genes implicated in lipoprotein homeostasis, e.g. LPL, apo C-III and apo A-1. Fibrates decrease apo C-III transcription and increase LPL production via these PPARs resulting in a profound hypotriglyceridaemic effect. Apolipoproteins and enzymes are important in governing lipid metabolism, thus therapeutically altering the expression of these genes constitutes an efficient therapeutic option.
Atherosclerosis 1996 Jul
PMID:Transcriptional control of triglyceride metabolism: fibrates and fatty acids change the expression of the LPL and apo C-III genes by activating the nuclear receptor PPAR. 883 13

CD36, an 88 kD transmembrane glycoprotein, is an important receptor for oxidized lipoproteins. Unlike the LDL receptor, expression of CD36 is upregulated by this pro-atherogenic particle, and binding and uptake perpetuates a cycle of lipid accumulation and receptor expression. This effect is, in part, mediated by the transcription factor, peroxisome proliferator activated receptor-gamma (PPAR gamma), and its ligands. We have found that specific inhibitors of protein kinase C (PKC) reduce basal mRNA expression of CD36 and block induction of CD36 mRNA and protein by oxidized LDL (OxLDL) and a PPAR gamma ligand. In addition, PKC inhibitors block both PPAR gamma mRNA and protein expression. These results suggest that activation of CD36 gene expression by OxLDL involves activation and translocation of PKC with subsequent PPAR gamma activation. More recently, we have generated a mouse null for CD36, and crossed it with the atherogenic Apo E null strain. Evaluation of lesion development in these animals will allow us to assess the in vivo contribution of CD36 to the pathogenesis of atherosclerosis.
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PMID:CD36 in atherosclerosis. The role of a class B macrophage scavenger receptor. 1086 32

Orphan nuclear receptors of the peroxisome proliferator activated receptor (PPAR) and liver X receptor (LXR) subfamilies have been shown to play critical roles in both local and systemic lipid metabolism. The PPARs control fatty acid metabolism in various cell types, including adipocytes, liver, and macrophages. The LXRs have been implicated in the regulation of cholesterol metabolism in the liver, intestines, and macrophages. The importance of these receptors in physiologic lipid metabolism suggests that they may influence the development of metabolic disorders such as obesity, diabetes, and atherosclerosis. Furthermore, the ability of these receptors to be modulated pharmacologically makes them attractive therapeutic targets. This review focuses on the role of PPAR and LXR signaling pathways in macrophage lipid metabolism and the potential of these pathways to modulate the development of atherosclerosis.
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PMID:Orphan nuclear receptors find a home in the arterial wall. 1193 19

Members of the peroxisome proliferator activated receptor (PPAR) family of transcription factors are under investigation as molecular targets for the treatment of numerous diseases including Alzheimer's, asthma, atherosclerosis, inflammation, multiple sclerosis, cancer, and diabetes. We employed the X-ray crystal structure of the PPARgamma subtype complexed with the potent small molecule agonist GI262570 (farglitazar) to design and synthesize a novel fluorescent and high-affinity probe for homogeneous and high-throughput fluorescent polarization (FP) assays. Examination of this X-ray structure revealed that the phenyl carbon atom meta to the oxazole moiety of GI262570 is exposed to solvent at the bottom of a narrow protein cavity. A derivative of GI262570 was synthesized bearing a linear phenylacetylene-derived side chain comprising propargylamine coupled to fluorescein. This fluorescent analogue was designed to project the fluorophore into the adjacent protein cavity with minimal effects on receptor affinity and maximal effects on fluorescence polarization properties. The recombinant PPARgamma ligand binding domain protein bound tightly and specifically to this probe with Kd=61+/-14 nM as determined by FP measurements. Competition binding assays with known PPARgamma ligands provided Ki values that were highly correlated with analogous values obtained by scintillation proximity (SP) assays. This fluorescent PPARgamma probe enables high-throughput and homogenous FP assays for the identification of novel endogenous and exogenous PPARgamma ligands, and this rational ligand design approach may be applied to other therapeutically important members of the nuclear hormone receptor superfamily.
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PMID:Synthesis of a high-affinity fluorescent PPARgamma ligand for high-throughput fluorescence polarization assays. 1312 68

Insulin resistance is a key metabolic defect in type 2 diabetes that is exacerbated by obesity, especially if the excess adiposity is located intra-abdominally/centrally. Insulin resistance underpins many metabolic abnormalities-collectively known as the insulin resistance syndrome-that accelerate the development of cardiovascular disease. Thiazolidinedione anti-diabetic agents improve glycaemic control by activating the nuclear receptor peroxisome proliferator activated receptor-gamma (PPARgamma). This receptor is highly expressed in adipose tissues. In insulin resistant fat depots, thiazolidinediones increase pre-adipocyte differentiation and oppose the actions of pro-inflammatory cytokines such as tumour necrosis factor-alpha. The metabolic consequences are enhanced insulin signalling, resulting in increased glucose uptake and lipid storage coupled with reduced release of free fatty acids (FFA) into the circulation. Metabolic effects of PPARgamma activation are depot specific-in people with type 2 diabetes central fat mass is reduced and subcutaneous depots are increased. Thiazolidinediones increase insulin sensitivity in liver and skeletal muscle as well as in fat, but they do not express high levels of PPARgamma, suggesting that improvement in insulin action is indirect. Reduced FFA availability from adipose tissues to liver and skeletal muscle is a pivotal component of the insulin-sensitising mechanism in these latter two tissues. Adipocytes secrete multiple proteins that may both regulate insulin signalling and impact on abnormalities of the insulin resistance syndrome--this may explain the link between central obesity and cardiovascular disease. Of these proteins, low plasma adiponectin is associated with insulin resistance and atherosclerosis--thiazolidinediones increase adipocyte adiponectin production. Like FFA, adiponectin is probably an important signalling molecule regulating insulin sensitivity in muscle and liver. Adipocyte production of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, and angiotensin II secretion are partially corrected by PPARgamma activation. The favourable modification of adipocyte-derived cardiovascular risk factors by thiazolidinediones suggests that these agents may reduce cardiovascular disease as well as provide durable glycaemic control in type 2 diabetes.
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PMID:Central role of the adipocyte in the insulin-sensitising and cardiovascular risk modifying actions of the thiazolidinediones. 1473 74

At a time when the lipid management guidelines give more and more emphasis to the identification and treatment of high-risk patients with the metabolic syndrome and diabetes, there is an obvious need to balance the known effects of low-density lipoprotein (LDL) lowering with the new evidence of clinical efficacy derived from the adjustment of high-density lipoprotein (HDL) and triglyceride levels. Whereas the statins remain the drug of choice for patients who need to reach the LDL goal, fibrate therapy may represent the best intervention for subjects with atherogenic dyslipidemia and an LDL already close to goal. In addition, the concomitant use of fibrates may significantly reduce cardiovascular risk in patients whose LDL is controlled by statin therapy. In this review, we evaluate the pharmacologic properties of the fibrate drugs, with particular attention to the effects of peroxisome proliferator activated receptor a activation in the control of dyslipidemia as well as in the attenuation of arterial inflammation. Clinical trials of fibrates, such as the Helsinki Heart Study, Veterans Affairs High-density lipoprotein Intervention Trial, Diabetes Atherosclerosis Intervention Study, and Bezafibrate Infarction Prevention trial, have conjured up a scenario for the clinical utility of fibrates and their possible superiority to statins in the management of obese, insulin-resistant, and diabetic patients presenting with near-goal LDL and inappropriate HDL and triglyceride levels.
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PMID:The role of fibrates in managing hyperlipidemia: mechanisms of action and clinical efficacy. 1502

Current treatments for non-insulin-dependent diabetes mellitus (NIDDM) remain far from ideal. The presence of both hyperinsulinaemia and resistance to insulin action in NIDDM challenges the rationale of treatments which primarily boost insulin secretion. Novel therapeutic strategies focus mainly on increasing peripheral sensitivity to endogenous insulin, an approach which has the potential not only to treat, but also to prevent NIDDM in high-risk individuals. The most promising new agents are the thiazolidinedione derivatives, in particular troglitazone. Thiazolidinediones are ligands for a specific subtype of the peroxisome proliferator activated receptor (PPAR), and decrease plasma glucose levels in both obesity and NIDDM, while at the same time reducing circulating insulin and free fatty acid levels. The current development status of these agents is reviewed, along with an assessment of their potential in the prevention and treatment of diverse pathophysiological states characterised by insulin resistance, including atherosclerosis and polycystic ovarian disease. Reference is made to the current status of other experimental agents including hydantoin derivatives, (3)-adrenoceptor agonists, and inhibitors of lipolysis.
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PMID:Insulin and lipid metabolism: new developments in drug therapy. 1598 34

Thiazolidinediones (TZDs), which are synthetic ligands for peroxisome proliferator activated receptor g (PPARg) activation, have been introduced in clinical medicine to improve insulin resistance and glycemic control in patients with type 2 diabetes. The metabolic effects of TZDs are mediated by receptor-dependent activation of the PPARg-retinoid X receptor (RXR) complex and subsequent transcriptional activation of target genes. The PPARg1 isoform is also expressed in endothelial cells, vascular smooth muscle cells, and monocytes/macrophages in the vasculature. TZDs have been shown to have anti-atherosclerotic effects on these cells in vitro, which appear to be partially independent of the PPARg-RXR-mediated transcriptional effects. Direct anti-atherosclerotic effects of TZDs include increased nitric oxide bioavailability, decreased leukocyte/endothelial cell interaction, reduced vascular smooth muscle cell migration and proliferation, and cholesterol efflux from macrophages. So far, there are no data on the effects of TZDs on cardiovascular events, but studies using surrogate markers of vascular disease provide preliminary evidence that TZDs delay progression of atherosclerosis in different patient groups. TZDs interfere with key processes in atherogenesis and may, therefore, offer additional opportunities to improve cardiovascular risk beyond treatment of glycemic control in patients with type 2 diabetes.
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PMID:Impact of thiazolidinedione therapy on atherogenesis. 1610 80

Metabolic syndrome is characterized by the clustering of a number of metabolic abnormalities in the presence of underlying insulin resistance with a strong association with diabetes and cardiovascular disease morbidity and mortality. The disorder is defined in different ways, but the pathophysiology is attributable to insulin resistance. An increased release of free fatty acids (FFAs) from adipocytes block insulin signal transduction pathway, induce endothelial dysfunction due to increased reactive oxygen species (ROS) generation and oxidative stress. Dyslipidemia, associated with high levels of triglycerides and low concentrations of high density lipoproteins (HDLs), contributes to a proinflammatory state. Inflammation, the key pathogenic component of atherosclerosis, promotes thrombosis, a process that underlies acute coronary event and stroke. Tissue factor, a potent trigger of the coagulation cascade, is increased in diabetes with poor glycemic control. Therapeutic lifestyle changes (weight loss and physical activity) along with pharmacological interventions are recommended to prevent the complications of metabolic syndrome. In addition to statins, metformin, blood pressure lowering medications, interventions to increase HDLs are other important approaches to decrease the risk of cardiovascular disease. Furthermore, the peroxisome proliferator activated receptor (PPAR)-alpha and gamma agonists are potent anti-inflammatory and anti-atherogenic agents that could both improve insulin sensitivity and the long-term cardiovascular risk. In this review we focus on the molecular and pathophysiological basis of metabolic syndrome, which augments diabetes (insulin resistance) and the contribution of neovascularization in the plaque progression in diabetes, leading to rupture and coronary thrombosis.
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PMID:Metabolic syndrome and diabetic atherothrombosis: implications in vascular complications. 1691 71

Despite significant progress in the management of atherosclerosis and its resultant complications, cardiovascular disease remains the principal cause of death in the world. The National Cholesterol Education Project Adult Treatment Panel III (NCEP ATP III) recognizes low levels of high-density lipoprotein cholesterol (HDL) as a risk factor for coronary heart disease (CHD) and high levels of HDL as a risk-reducing factor; however, the elevation of HDL as a specific therapeutic target for the prevention and treatment of CHD has yet to be accepted on the same level as low-density lipoprotein (LDL)-reducing therapies. Current HDL elevators including nicotinic acid, fibric acid derivatives, peroxisome proliferator activated receptor (PPAR) agonists and statins also affect other lipid constituents which make interpretation of the clinical trials of these drugs difficult in teasing out the independent effect of HDL elevation. Ample laboratory investigation suggests that HDL elevation would reduce atherosclerotic burden through multiple independent mechanisms. In this review, we explore HDL biology, its potential mechanisms in the treatment of atherosclerotic disease, and promising new drugs with HDL-raising activity.
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PMID:The role of high-density lipoprotein cholesterol in the prevention and possible treatment of cardiovascular diseases. 1691 77


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