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)

Traditional risk factors for coronary artery disease (CAD) predict about 50% of the risk of developing CAD. The Adult Treatment Panel (ATP) III has defined emerging risk factors for CAD, including small, dense low-density lipoprotein (LDL). Small, dense LDL is often accompanied by increased triglycerides (TGs) and low high-density lipoprotein (HDL). An increased number of small, dense LDL particles is often missed when the LDL cholesterol level is normal or borderline elevated. Small, dense LDL particles are present in families with premature CAD and hyperapobetalipoproteinemia, familial combined hyperlipidemia, LDL subclass pattern B, familial dyslipidemic hypertension, and syndrome X. The metabolic syndrome, as defined by ATP III, incorporates a number of the components of these syndromes, including insulin resistance and intra-abdominal fat. Subclinical inflammation and elevated procoagulants also appear to be part of this atherogenic syndrome. Overproduction of very low-density lipoproteins (VLDLs) by the liver and increased secretion of large, apolipoprotein (apo) B-100-containing VLDL is the primary metabolic characteristic of most of these patients. The TG in VLDL is hydrolyzed by lipoprotein lipase (LPL) which produces intermediate-density lipoprotein. The TG in intermediate-density lipoprotein is hydrolyzed further, resulting in the generation of LDL. The cholesterol esters in LDL are exchanged for TG in VLDL by the cholesterol ester tranfer proteins, followed by hydrolysis of TG in LDL by hepatic lipase which produces small, dense LDL. Cholesterol ester transfer protein mediates a similar lipid exchange between VLDL and HDL, producing a cholesterol ester-poor HDL. In adipocytes, reduced fatty acid trapping and retention by adipose tissue may result from a primary defect in the incorporation of free fatty acids into TGs. Alternatively, insulin resistance may promote reduced retention of free fatty acids by adipocytes. Both these abnormalities lead to increased levels of free fatty acids in plasma, increased flux of free fatty acids back to the liver, enhanced production of TGs, decreased proteolysis of apo B-100, and increased VLDL production. Decreased removal of postprandial TGs often accompanies these metabolic abnormalities. Genes regulating the expression of the major players in this metabolic cascade, such as LPL, cholesterol ester transfer protein, and hepatic lipase, can modulate the expression of small, dense LDL but these are not the major defects. New candidates for major gene effects have been identified on chromosome 1. Regardless of their fundamental causes, small, dense LDL (compared with normal LDL) particles have a prolonged residence time in plasma, are more susceptible to oxidation because of decreased interaction with the LDL receptor, and enter the arterial wall more easily, where they are retained more readily. Small, dense LDL promotes endothelial dysfunction and enhanced production of procoagulants by endothelial cells. Both in animal models of atherosclerosis and in most human epidemiologic studies and clinical trials, small, dense LDL (particularly when present in increased numbers) appears more atherogenic than normal LDL. Treatment of patients with small, dense LDL particles (particularly when accompanied by low HDL and hypertriglyceridemia) often requires the use of combined lipid-altering drugs to decrease the number of particles and to convert them to larger, more buoyant LDL. The next critical step in further reduction of CAD will be the correct diagnosis and treatment of patients with small, dense LDL and the dyslipidemia that accompanies it.
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PMID:Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density lipoprotein heterogeneity. 1241 79

Cardiovascular magnetic resonance (CMR) is a rapidly developing new field in cardiology. It is beginning to contribute to greater understanding of diagnosis and management of hitherto difficult clinical conditions and is invaluable for research programmes, where its resolution, accuracy and reproducibility allow studies to be performed more quickly and cheaply than in the past. This article emphasises the use of CMR in preventing cardiovascular disease, such as ventricular remodelling after infarction, the genetic control of left ventricular hypertrophy, cardiomyopathies, high resolution myocardial perfusion in cardiac syndrome X, and detection of early stage atherosclerosis.
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PMID:Cardiovascular magnetic resonance: twenty-first century solutions in cardiology. 1284 66

Insulin resistance syndrome (also called syndrome X) includes obesity, diabetes, hypertension, and dyslipidemia and is a complex phenotype of metabolic abnormalities. The disorder poses a major public health problem by predisposing individuals to coronary heart disease and stroke, the leading causes of mortality in Western countries. Given that hypertension, diabetes, dyslipidemia, and obesity exhibit a substantial heritable component, it is postulated that certain genes may predispose some individuals to this cluster of cardiovascular risk factors. Emerging data suggest that peroxisome proliferator-activated receptors (PPARs), including alpha, gamma, and delta, are important determinants that may provide a functional link between obesity, hypertension, and diabetes. It has been well documented that hypolipidemic fibrates and antidiabetic thiazolidinediones are synthetic ligands for PPAR alpha and PPAR gamma, respectively. In addition, PPAR natural ligands, such as leukotriene B4 for PPAR alpha, 15-deoxy-delta 12,14-prostaglandin J2 for PPAR gamma, and prostacyclin for PPAR delta, are known to be eicosanoids and fatty acids. Studies have documented that PPARs are present in all critical vascular cells: endothelial cells, vascular smooth muscle cells, and monocyte-macrophages. These observations suggest that PPARs not only control lipid metabolism but also regulate vascular diseases such as atherosclerosis and hypertension. In this review, we present structure and tissue distribution of PPAR nuclear receptors, discuss the mechanisms of action and regulation, and summarize the rapid progress made in this area of study and its impact on the cardiovascular system.
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PMID:Peroxisome proliferator-activated receptors and the cardiovascular system. 1285 55

Normal metabolic balance is maintained by a complex homeostatic system involving multiple tissues and organs. Acquired or inherited defects associated to environmental factors in any part of this system can lead to metabolic disorders such as the syndrome X which is presently a frequent syndrome in industrialized countries. It is characterized by a cluster of risk factors of atherosclerosis including insulin resistance, hyperinsulinemia, impaired glucose tolerance or type 2 diabetes, hypertension, dyslipidemia, and coagulation abnormalities. Its pathophysiology is likely to involve insulin resistance at the level of both skeletal muscle and visceral adipose tissue and altered fluxes of metabolic substrates between these tissues that in turn impair liver metabolism. Therapeutic intervention favours at present diet and exercise prescriptions. In addition, if necessary, specific treatment of the metabolic disorders is required. In the treatment of insulin resistance, new promising drugs are likely to be used in the next future. In this regard, adipose tissue, once thought to function primarily as a passive depot for the storage of excess lipid, is now understood to play a much more active role in metabolic regulation, secreting a variety of metabolic hormones and actively functioning to prevent deleterious lipid accumulation in other tissues and to modulate the insulin resistance. Here, we review new advances in our understanding of mechanisms leading to insulin resistance and type 2 diabetes from the perspective of the role and interactions of recently identified adipocyte-specific chemical messengers, the adipocytokines, such as adiponectin, tumor necrosis factor-alpha, interleukin 6, and resistin.
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PMID:[Adipocytokins, obesity and development of type 2 diabetes]. 1459 11

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependant nuclear transcription factors, consisting of three isoforms: alpha,beta/delta and gamma, which form a subfamily of the nuclear receptors superfamily. PPARs play an important role in adipocyte differentiation, energy metabolism, and inflammation. PPARs' effect goes beyond the improvement of insulin resistance in syndrome X (diabetes mellitus, hypertension, obesity and so on). Through recent years' study, it has been demonstrated that PPARs regulate vascular wall directly, which, therefore, decelerate the development of atherosclerosis. In this review, we will look at current trends of PPARs research in their structure, function, and molecular mechanism related to pathogenesis and therapy of atherosclerosis.
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PMID:[Peroxisome proliferator-activated receptors and atherosclerosis]. 1512 91

The insulin resistance syndrome (syndrome X, metabolic syndrome) has become the major health problem of our times. Associated obesity, dyslipidemia, atherosclerosis, hypertension, and type 2 diabetes conspire to shorten life spans, while hyperandrogenism with polycystic ovarian syndrome affect the quality of life and fertility of increasing numbers of women. Whereas a growing number of single genetic diseases affecting satiety or energy metabolism have been found to produce the clinical phenotype, strong familial occurrences, especially in racially prone groups such as those from the Indian subcontinent, or individuals of African, Hispanic, and American Indian descents, together with emerging genetic findings, are revealing the polygenetic nature of the syndrome. However, the strong lifestyle factors of excessive carbohydrate and fat consumption and lack of exercise are important keys to the phenotypic expression of the syndrome. The natural history includes small for gestational age birth weight, excessive weight gains during childhood, premature pubarche, an allergic diathesis, acanthosis nigricans, striae compounded by gynecomastia, hypertriglyceridemia, hepatic steatosis, premature atherosclerosis, hypertension, polycystic ovarian syndrome, and focal glomerulonephritis appearing increasingly through adolescence into adulthood. Type 2 diabetes, which develops because of an inherent and/or an acquired failure of an insulin compensatory response, is increasingly seen from early puberty onward, as is atheromatous disease leading to coronary heart disease and stroke. A predisposition to certain cancers and Alzheimer's disease is also now recognized. The looming tragedy from growing numbers of individuals affected by obesity/insulin resistance syndrome requires urgent public health approaches directed at their early identification and intervention during childhood. Such measures include educating the public on the topic, limiting the consumption of sucrose-containing drinks and foods with high carbohydrate and fat contents, and promoting exercise programs in our nation's homes and schools.
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PMID:Insulin resistance syndrome in children. 1518 Oct 20

Type 2 Diabetes Mellitus (DM) or Non-Insulin Dependent Diabetes Mellitus (NIDDM) accounts for 90-95% of all diabetes cases and has become a major health concern over the years. This disease has assumed frightening proportions due to unhealthy food habits and sedentary life style. About a decade ago, due to the absence of defined molecular targets or an understanding of disease pathophysiology, treatment of this disease was mostly focused on insulin secretion or administration of external insulin. During the past decade however, advent of genomics and proteomics has helped in understanding the molecular alteration characteristics of NIDDM. Untreated type 2 diabetes leads to several complications such as hyperlipidemia, hypertension and atherosclerosis--collectively known as Syndrome X. Though United Kingdom Prospective Diabetes Study (UKPDS) showed that normalization of hyperglycemia could prevent majority of diabetes complications, the available treatment regime does not adequately normalize the blood glucose level in type 2 diabetic patients. Currently, four distinct classes of oral hypoglycemic agents are available, some of which can act as lipid lowering agents as well. The efficacy and side effect profiles of these drugs are still to be optimized, so there is an unmet need for better candidates. Several new targets as well as better drugs for old targets are under investigation across the world. Availability of such drugs, based on the validated targets, may lead to a new therapeutic paradigm for the prevention of diabetes as well as complications arising out of it. The current review will deal with existing oral therapies for type 2 diabetes as well as the emerging therapeutic targets.
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PMID:Non-insulin dependent diabetes mellitus: present therapies and new drug targets. 1630 31

Fenofibrate, a selective (1)PPAR-alpha activator, is prescribed to treat human dyslipidemia. The aim of this study was to delineate the mechanism of fenofibrate-mediated reductions in adiposity, improvements in insulin sensitivity, and lowering of triglycerides (TG) and free fatty acids (FFA) and to investigate if these favorable changes are related to the inhibition of lipid deposition in the aorta. To test this hypothesis we used male LDLr deficient mice that exhibit the clinical features of metabolic syndrome X when fed a high fat high cholesterol (HF) diet. LDLr deficient mice fed HF diet and simultaneously treated with fenofibrate (100 mg/kg body weight) prevented development of obesity, lowered serum triglycerides and cholesterol, improved insulin sensitivity, and prevented accumulation of lipids in the aorta. Lowering of circulating lipids occurred via down-regulation of lipogenic genes, including fatty acid synthase, acetyl CoA carboxylase and diacyl glycerol acyl transferase-2, concomitant with decreased liver TG and cholesterol, and TG output rate. Fenofibrate also suppressed liver apoCIII mRNA levels and markedly increased lipoprotein lipase mRNA levels, known to enhance serum TG catabolism. In addition, fenofibrate profoundly reduced epididymal fat and mesenteric fat mass to the levels seen in lean mice. The reductions in body weight were associated with elevation of hepatic uncoupling protein 2 (UCP2) mRNA, a concomitant increase in the ketone body formation, and improved insulin sensitivity associated with tumor necrosis factor-alpha reductions and phosphoenol pyruvate carboxykinase down-regulation. These results demonstrate that fenofibrate improves lipid abnormalities partly via inhibition of TG production and partly via clearance of TG-rich apoB particles by elevating LPL and reduced apoCIII. The prevention of obesity development occurred via energy expenditure. Fenofibrate-mediated hypolipidemic effects together with improved insulin sensitivity and loss of adiposity led to the reductions in the aortic lipid deposition by inhibiting early stages of atherosclerosis possibly via vascular cell adhesion molecule-1 (VCAM-1) modulation. These results suggest that potent PPAR-alpha activators may be useful in the treatment of syndrome X.
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PMID:Peroxisome proliferator-activated receptor-alpha selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice. 1647 80

Platelets are rich sources of growth factors and enzymes that are implicated in a number of diseases including obesity, atherosclerosis, heart disease, syndrome X, liver and kidney diseases and certain types of cancers. In this research we investigated, if platelets in Zucker obese rats differ from their lean counterparts with respect to the levels of TGF-beta and COX isoforms, implicated in the pathogenesis of chronic diseases. In addition, we investigated if energy intake of the animals affects the platelet physiology. Platelets were isolated from obese and lean rats bearing preneoplastic lesions in their colon. Prior to platelet isolation these rats were fed either ad libitum (Ob or Ln) or energy restricted (Ob-ER or Ln-ER) diets for 8 weeks (n = 8/group). The levels of TGF-beta1/-beta2 and COX-1/-2 proteins in platelets were analyzed by Western blot. The platelets of the Ob rats had significantly higher levels of TGF-beta1, COX-1/-2 (p < 0.001) than did the platelets of the Ln rats and were not affected by moderate energy restriction. There were no significant differences in the protein expression of platelet TGF-beta2 among any of the groups. These results demonstrate that cytokines and candidates playing a role in the pathogenesis of chronic diseases, such as TGF-beta1 and COX-1/-2, are over-expressed in platelets of Zucker obese rats by comparison to their lean counterparts. These findings also demonstrate that the genotype of the animals exerts a significant effect on the biochemical composition of the platelets and could contribute to the pathogenesis of colon cancer and other metabolic abnormalities associated with obesity.
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PMID:Obese state leads to elevated levels of TGF-beta and COX isoforms in platelets of Zucker rats. 1647 87

Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARalpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARdelta has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARdelta in the treatment of metabolic disease. PPARdelta enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis.
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PMID:PPAR delta: a dagger in the heart of the metabolic syndrome. 1651 91


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