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)

Enhanced macrophage cholesterol accumulation is associated with foam cell formation in the atherosclerotic lesion. Since platelet activation plays an important role in atherogenesis, we questioned whether products released from activated platelets could affect macrophage cholesterol metabolism. The addition of platelet-conditioned medium (PCM, obtained from collagen activated platelets) to a J-774 macrophage cell line, enhanced cellular cholesteryl ester content by 32%. The cholesterol esterification rate was also increased by 29%. Pre-loading the macrophages with cholesterol by incubation with acetyl-LDL, resulted in a further elevation of 48% in PCM-mediated cholesterol esterification. Possible mechanisms for the enhanced cholesterol esterification by J-774 macrophages following incubation with PCM include increased cholesterol influx and/or decreased cholesterol efflux (These cells were recently shown not to synthesize cholesterol). However, both increased uptake of PCM cholesterol by the macrophages as well as increased cellular cholesterol efflux (by 22%) were noted. The enhancement of cholesterol esterification by PCM was competitively inhibited by fucoidin and polyinosinic acid, implicating PCM binding to the scavenger receptor. This was further evidenced by the observations that apolipoprotein E which reduces cellular uptake via the scavenger receptor but not via the LDL receptor, also inhibited the effect of PCM, whereas IgG C-7, the LDL receptor antibody, did not alter the effect of PCM. Lysosomal involvement in the cellular processing of PCM was observed since PCM activity was inhibited by the lysosomal inhibitor, chloroquine. Partial purification of PCM by gel filtration revealed that the cholesterol component was associated with both phospholipids and proteins in a lipoprotein-like particle. Delipidation of PCM resulted in its inactivation but both heat treatment and tryptic digestion of PCM, revealed that the protein (and not only the cholesterol) component was also essential for the effect of PCM on cellular cholesterol esterification. Furthermore, PCM prepared from platelets of a patient with Gray Platelet Syndrome that lack platelet alfa granules (which contain platelet specific proteins), failed to enhance cholesterol esterification. These results demonstrate that lipoprotein-like particles released during platelet activation can interact with the macrophage scavenger receptor thus leading to enhanced cellular cholesterol accumulation.
Atherosclerosis 1991 Jun
PMID:Platelet secreted lipoprotein-like particle is taken up by the macrophage scavenger receptor and enhances cellular cholesterol accumulation. 189 83

Hypertension has two main effects on the heart; it increases afterload, causing left ventricular hypertrophy, and precipitates the risk factor for coronary atherosclerosis. Left ventricular hypertrophy is an independent risk factor, but hypertension is a clustering of cardiovascular risks with many metabolic abnormalities, one of which is the recently described endocrinological Syndrome X (hyperinsulinaemia, resistance to insulin-stimulated glucose uptake, glucose intolerance, high triglyceride levels, low HDL and hypertension, which is apparently unrelated to the cardiological Syndrome X (angina with normal coronary arteries). However, the link between both Syndromes X may be the derangement of microvasculture, particularly endothelial dysfunction of nitric oxide (NO) production.
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PMID:Global and regional ischaemia in left ventricular hypertrophy reactive to hypertension. 828 58

Insulin resistance is associated with a variety of cardiovascular risk factors including hypertension, dyslipidemia, and non-insulin-dependent diabetes. In blacks, the relation between insulin resistance, hypertension, and atherosclerosis has been questioned. Most data collected on the Insulin Resistance Syndrome have been collected in nondiabetic subjects; therefore, no inference can be drawn to exogenous insulin use in diabetic subjects where improved glycemic control is usually associated with improved cardiovascular risk factors (especially dyslipidemia) in the absence of weight gain.
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PMID:Progress in population analyses of the insulin resistance syndrome. 932 38

Two problems in the treatment of hypertension continue to be largely unsolved. The first, and more simple, is our inability to adequately control blood pressure in the majority of hypertensive patients. This not only reflects the difficulty of retaining patients in effective treatment programs, but also of convincing physicians to strive for optimal blood pressure levels. There is a continuing need for new antihypertensive drugs and combinations to help accomplish these goals. The second major problem is that the major clinical endpoints, including coronary events and renal failure, have not been adequately reduced by traditional therapies. Standard regimens, particularly those including diuretics, have protected against strokes and heart failure. Our improved understanding of vascular biology in hypertension has directed interest to the mechanisms in hypertensive patients that might accelerate atherosclerosis and vascular events in these individuals. This involves addressing the concomitant metabolic risk factors that comprise the "Hypertension Syndrome," and, perhaps of equal importance, finding therapies that directly inhibit unwanted types of growth and proliferative activities within the walls of critical arteries. Many substances within the endothelium and the vascular wall may participate as initiators or mediators of pathology, but most information thus far has focused on the renin-angiotensin system. Angiotensin converting enzyme inhibitors (and potentially angiotensin receptor blockers) have provided coronary and renal protection in various cardiovascular conditions, though not yet in formal hypertension trials. Calcium channel blockers have also shown promise, including recent stroke and cardiovascular benefits in patients with isolated systolic hypertension, but, again, definitive coronary data in hypertension are awaited. Unless concomitant conditions mandate the selection of a particular antihypertensive drug class, physicians currently have a dilemma: should they choose drugs from older classes that have not provided full protection? Or, should they prescribe newer agents with exciting potential but with, as yet, unproved endpoint benefits in hypertension? Until currently ongoing prospective trials of antihypertensive therapy are completed, physicians must be guided by their own interpretations of the available data.
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PMID:Translating data on antihypertensive drugs into clinical practice. 965 68

Insulin resistance describes an impaired biological response to insulin, which underpins the development of type 2 (non-insulin-dependent) diabetes mellitus (T2DM). Initially, insulin resistance causes a compensatory hyperinsulinaemia, which gives way to pancreatic beta-cell failure. Insulin resistance and hyperinsulinaemia conspire together in the development of a diverse collection of risk factors for coronary heart disease, namely obesity, T2DM, dyslipidaemia, hypertension, atherosclerosis, and a pro-coagulant state. This collection of factors is commonly found in T2DM patients, and is recognised as the Insulin Resistance Syndrome or Syndrome X. By targeting insulin resistance as a treatment strategy for T2DM, it should be possible to broaden the potential benefits, so that improved glycaemic control is complemented with improvements to other components of Syndrome X. At present, metformin and thiazolidinediones are the only therapies for T2DM that directly address aspects of insulin resistance. Increasing awareness of the clinical implications of insulin resistance, and increasing knowledge of the cellular basis of insulin resistance, provide the rationale and a means for developing an anti-insulin resistance approach to the treatment of T2DM.
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PMID:Insulin resistance and antidiabetic drugs. 1053 41

We sought to assess the impact of coronary angiography results on use of lipid-lowering agents among women enrolled in the Women's Ischemia Syndrome Evaluation [WISE] study. WISE is a multicenter study designed to evaluate new diagnostic modalities among women undergoing angiography for suspected coronary artery disease (CAD). History of atherosclerosis, risk factors for CAD, and low-density lipoprotein (LDL) cholesterol are determined at baseline. The percentage of women at LDL cholesterol goal, use of lipid-lowering agents, and eligibility for lipid-lowering therapy were determined based on National Cholesterol Education Program II guidelines at baseline and 6-week follow-up. Among the 212 women for whom angiographic data were available, 84 had known atherosclerosis, 80 had no history of atherosclerosis but > or =2 risk factors (high risk), and 48 had no history of atherosclerosis and <2 risk factors (low risk). At baseline, LDL cholesterol goals were met in 24% women with atherosclerosis, in 56% high-risk women, and in 88% low-risk women. Angiography revealed previously undiagnosed CAD in 70% of the high-risk and in 42% of the low-risk women. After angiography results were available, 6 women started lipid-lowering therapy and 2 stopped. Based on National Cholesterol Education Program II guidelines, 63 additional women would have been eligible for pharmacologic lipid-lowering therapy. Intensification of lipid-lowering therapy was not apparent 6 weeks after coronary angiography in women with newly diagnosed CAD or among women whose diagnosis was confirmed.
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PMID:Effect of coronary angiography on use of lipid-lowering agents in women: a report from the Women's Ischemia Syndrome Evaluation (WISE) study. For the WISE Investigators. 1078 56

Obesity and Type 2 diabetes are now major public health issues in developed nations and have reached epidemic proportions in many developing nations, as well as disadvantaged groups in developed countries, e.g., Mexican-Americans, African-Americans, and Australian Aborigines. These groups all show hyperinsulinemia and insulin resistance, which have been demonstrated to be future predictors of Type 2 diabetes and have also been suggested as key factors in the etiology of the Metabolic Syndrome. It is now increasingly recognized that Type 2 diabetes is part of a cluster of cardiovascular disease (CVD) risk factors comprising the Metabolic Syndrome. This group is at very high risk of atherosclerosis because each of the risk factors in the Metabolic Syndrome cluster in its own right is an important CVD risk factor. They also contribute cumulatively to atherosclerosis. A key strategy in reducing macrovascular disease lies in the better understanding of the Metabolic Syndrome--glucose intolerance, hypertension, hyperlipidemia, and central obesity. Although it has been suggested that hyperinsulinemia/insulin resistance is the central etiological factor for the Metabolic Syndrome, epidemiological data do not support the idea that this can account for all of the cluster abnormalities. We have animal and human data suggesting that hyperleptinemia rather than, or synergistically with, hyperinsulinemia may play a central role in the genesis of the CVD risk factor cluster that constitutes the syndrome. Studies in Psammomys obesus (the Israeli sand rat) suggest hyperinsulinemia/insulin resistance is an early metabolic lesion in the development of obesity and Type 2 diabetes. This animal also develops other features of the Metabolic Syndrome, making it an excellent model to investigate etiology. Psammomys, when placed on an ad libitum laboratory diet, develops hyperinsulinemia, insulin resistance, impaired glucose tolerance, diabetes, and dyslipidemia. It also develops hyperleptinemia and leptin insensitivity, and hyperleptinemia is correlated with insulin resistance independent of changes in body weight. It is likely that a similar sequence occurs in the transition from the prediabetic state to Type 2 diabetes in humans. More recently, other potential players in the etiology of the Metabolic Syndrome have been suggested including endothelial dysfunction and acetylation-stimulating protein (ASP). It has been suggested that endothelial dysfunction may be an antecedent for both Type 2 diabetes and the Metabolic Syndrome. In addition, ASP is a serious new candidate for an important role in insulin resistance. The ASP pathway plays a critical role in fatty acid metabolism and storage, and it has been suggested that ineffective storage of fatty acids by adipocytes due to a defect in the ASP pathway may lead to insulin resistance and Type 2 diabetes.
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PMID:Etiology of the metabolic syndrome: potential role of insulin resistance, leptin resistance, and other players. 1084 50

Hyperglycemia in Type 2 diabetes represents a steady-state re-regulation of plasma glucose to a higher-than-normal level after an overnight fast. The underlying pathophysiology represents an interaction between impaired beta-cell function and peripheral and hepatic insulin resistance which leads to abnormal hepatic glucose production. Subjects with the Metabolic Syndrome are at an increased risk for Type 2 diabetes and often have one or both of these disorders present even when glucose tolerance is normal. Thus, sophisticated measures of beta-cell function and insulin sensitivity demonstrate a high frequency in populations characterized as having a high prevalence of atherosclerosis, central obesity, hypertension, and dyslipidemia with or without impaired glucose tolerance. Hyperglycemia compensates for the impairment of beta-cell function and therefore, in our view, the beta-cell is the critical factor in its development. Hyperinsulinemia, a curvilinear compensation for insulin resistance that is closely correlated with central adiposity, is another important predictor of hyperglycemia. In a Japanese-American population followed for five years, impaired beta-cell function was present at baseline and preceded the accumulation of intraabdominal fat in those who developed Type 2 diabetes five years later. This interaction between these two pathophysiologic abnormalities in this sequence supports the hypothesis that beta-cell dysfunction contributes to the development of central adiposity by reduced CNS insulin signaling.
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PMID:Mechanisms for hyperglycemia in the metabolic syndrome. The key role of beta-cell dysfunction. 1084 53

Both hepatic lipase (HL) and apolipoprotein C-III (apoC-III) influence lipid metabolism. Common variation in promoters of both genes, LIPC -514C > T and APOC3 -482C > T, respectively, have been shown to affect plasma lipids and lipoproteins and glucose tolerance. We studied the interaction between both variants on parameters of glucose tolerance and lipid metabolism in 714 healthy young males participating in the second European Atherosclerosis Research Study (EARS-II). Approximately 18% of the subjects were carriers of at least one rare LIPC and APOC3 allele. These subjects exhibited, after fasting and oral fat loading, the highest values of triglyceride-rich lipoproteins, but there was no significant interactive effect on any lipid variable. However, interaction occurred on basal diastolic blood pressure (p =0.036) and, during oral glucose tolerance testing, on peak (p = 0.0065) and area under the curve for glucose (p =0.049), and insulin (p = 0.035). This resulted in the highest diastolic blood pressure and lowest glucose tolerance in carriers of at least one rare allele of both genes. Thus gene:gene interaction between LIPC and APOC3, even in these healthy young males, leads to changes in parameters that are typically characteristic of Syndrome-X.
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PMID:Interaction of the common apolipoprotein C-III (APOC3 -482C > T) and hepatic lipase (LIPC -514C > T) promoter variants affects glucose tolerance in young adults. European Atherosclerosis Research Study II (EARS-II). 1142 82

Atherosclerosis is a major vascular complication of diabetes and the primary cause of mortality in persons with this disease. Metabolic abnormalities related to the Insulin Resistance Syndrome or Metabolic Syndrome may importantly contribute to the increased risk of atherosclerosis associated with diabetes. Thiazolidinediones (TZDs) are oral insulin sensitizers in broad clinical use that enhance insulin-stimulated glucose uptake into skeletal muscle. TZDs can also improve cardiovascular risk factors and exert direct effects on vascular cells to potentially retard the atherosclerotic process. Direct vascular effects of TZDs likely result from their activity as ligands for the nuclear receptor, PPARgamma. All of the major cell types in the vasculature express PPARgamma, including intimal macrophages and vascular smooth muscle cells (VSMCs) in human atheroma. TZDs block VSMC growth by inducing cell cycle arrest in G1 through an inhibition of retinoblastoma protein phosphorylation. Migration of monocytes and VSMCs is also inhibited by TZDs, possibly through decreased matrix metalloproteinase production. Activation of PPARgamma by TZDs in macrophages induces ABCA1 transporter expression to promote reverse cholesterol transport. These antiatherogenic activities may also occur in vivo because TZDs have been shown to inhibit lesion formation in several animal models. Thus, TZD activation of PPARgamma may protect against atherosclerosis both by normalizing proatherogenic metabolic abnormalities of the insulin resistance/diabetes milieu and through an inhibition of vascular cell growth and movement.
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PMID:PPARgamma and atherosclerosis: effects on cell growth and movement. 1174 60


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