Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nephrotic-range proteinuria is associated with a several-fold increase risk of cardiovascular infarction. This increased risk is accompanied by endothelial dysfunction, which is not related to increased blood pressure and is not correctable by acute administration of L-arginine. The latter is in direct contrast to what has been found in patients with primary hypercholesterolemia, suggesting that either hypoalbuminemia itself or other aspects of the dyslipidemia characteristic of the nephrotic syndrome impair endothelial function. Lysophosphatidylcholine (lyso-PC) is formed during oxidative modification of cholesterol, and lyso-PC in oxidized low-density lipoprotein (LDL) is responsible for reduced endothelial function in vitro. However, in the circulation, lyso-PC is tightly bound to albumin. Indeed, the addition of albumin can restore endothelial function, which was previously disturbed by lyso-PC. Hypoalbuminemia induces a shift in lyso-PC to lipoproteins, notably LDL, and to erythrocytes. The latter directly induces a reduction in deformability that can also be corrected by the addition of albumin. Hypoalbuminemia may disturb endothelial function, either by directly affecting Gi-protein-dependent signal transduction or indirectly by changing the configuration of the cell membrane. Such a change in cell membrane configuration will disturb binding of ligands to receptors and of endothelial nitric oxide (NO) synthase to caveolin. However, other pathways have been suggested, such as stimulation by lyso-PC of vasoconstriction mediated by protein kinase C. It remains to be shown whether lipid-lowering and antiproteinuric strategies have independent positive effects on endothelial function in nephrotic subjects.
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PMID:Endothelial function in proteinuric renal disease. 1041 39

There have been increasing reports of acute coronary thrombotic events in patients with HIV. Although these clinical events have been attributed primarily to dyslipidemia associated with protease inhibitor therapy, autopsy studies in children with HIV suggest the presence of an underlying arteriopathy. This study demonstrates that the HIV envelope protein, gp120, activates human arterial smooth muscle cells to express tissue factor, the initiator of the coagulation cascade. The induction of tissue factor by gp120 is mediated by two biologically relevant coreceptors for HIV infection, CXCR4 and CCR5, and is also dependent on the presence of functional CD4. Induction of tissue factor by gp120 requires activation of mitogen-activating protein kinases, activation of protein kinase C, and generation of reactive oxygen species, signaling pathways that have protean effects on smooth muscle cell physiology. The activation of smooth muscle cells by gp120 may play an important role in the vascular, thrombotic, and inflammatory responses to HIV infection.
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PMID:HIV envelope gp120 activates human arterial smooth muscle cells. 1150 23

Protease inhibitors decrease the viral load in HIV patients, however the patients develop hypertriglyceridemia, hypercholesterolemia, and atherosclerosis. It has been assumed that protease inhibitor-dependent increases in atherosclerosis are secondary to the dyslipidemia. Incubation of THP-1 cells or human PBMCs with protease inhibitors caused upregulation of CD36 and the accumulation of cholesteryl esters. The use of CD36-blocking antibodies, a CD36 morpholino, and monocytes isolated from CD36 null mice demonstrated that protease inhibitor-induced increases in cholesteryl esters were dependent on CD36 upregulation. These data led to the hypothesis that protease inhibitors induce foam cell formation and consequently atherosclerosis by upregulating CD36 and cholesteryl ester accumulation independent of dyslipidemia. Studies with LDL receptor null mice demonstrated that low doses of protease inhibitors induce an increase in the level of CD36 and cholesteryl ester in peritoneal macrophages and the development of atherosclerosis without altering plasma lipids. Furthermore, the lack of CD36 protected the animals from protease inhibitor-induced atherosclerosis. Finally, ritonavir increased PPAR-gamma and CD36 mRNA levels in a PKC- and PPAR-gamma-dependent manner. We conclude that protease inhibitors contribute to the formation of atherosclerosis by promoting the upregulation of CD36 and the subsequent accumulation of sterol in macrophages.
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PMID:HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages. 1256 55

Thrombogenesis depends on the balance between coagulation and fibrinolysis in vasculature. Vascular endothelial cells (EC) synthesize activators and inhibitors for fibrinolysis, tissue and urokinase plasminogen activators (tPA and uPA) and plasminogen activator inhibitor-1 (PAI-1). Increased levels of PAI-1 with various levels of tPA have been frequently found in plasma of patients with coronary heart disease (CHD) or diabetes mellitus (DM). Dyslipidemia is common feature in patients with CHD or DM, which is characterized by elevated levels of total cholesterol, triglycerides, low or very low density lipoproteins (LDL or VLDL) and decreased levels of high density lipoprotein (HDL). LDL and VLDL stimulated the generation of PAI-1 from cultured EC. LDL and lipoprotein(a) [Lp(a)], another lipoprotein risk factor for CHD, reduced the generation of tPA from EC. HDL did not greatly alter the release of PAI-1 from EC. Oxidative modification by copper, ultraviolet or long exposure to EC enhanced the effect of LDL on the generation of PAI-1 and tPA from EC. Glycation amplified the effect of LDL and Lp(a) on the changes in the generation of the fibrinolytic regulators from EC. Treatment with antioxidants or HDL normalized glycated LDL-induced changes in the generation of fibrinolytic regulators from EC. Activation of protein kinase C is required for oxidized LDL or Lp(a)-induced PAI-1 production in EC. VLDL, but not LDL or its oxidized form, stimulated PAI-1 production through the activation of the VLDL-responsive element in the PAI-1 promoter. Plasma levels of fibrinolytic regulators in CHD or DM patients may be normalized by HMG-CoA reductase inhibitors and angiotensin II converting enzyme inhibitors. This review summarizes the up-to-date information on effects, mechanism and management for disorders in EC-derived fibrinolytic regulators induced by modified lipoproteins.
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PMID:Impact and mechanism for oxidized and glycated lipoproteins on generation of fibrinolytic regulators from vascular endothelial cells. 1284 45

Dietary fat has a dual role in human physiology: a) it functions as a source of energy and structural components for cells; b) it functions as a regulator of gene expression that impacts lipid, carbohydrate, and protein metabolism, as well as cell growth and differentiation. Fatty acid effects on gene expression are cell-specific and influenced by fatty acid structure and metabolism. Fatty acids interact with the genome through several mechanisms. They regulate the activity or nuclear abundance of several transcription factors, including PPAR, LXR, HNF-4, NFkappaB, and SREBP. Fatty acids or their metabolites bind directly to specific transcription factors to regulate gene transcription. Alternatively, fatty acids indirectly act on gene expression through their effects on a) specific enzyme-mediated pathways, such as cyclooxygenase, lipoxygenase, protein kinase C, or sphingomyelinase signal transduction pathways; or b) pathways that involve changes in membrane lipid/lipid raft composition that affect G-protein receptor or tyrosine kinase-linked receptor signaling. Further definition of these fatty acid-regulated pathways will provide insight into the role dietary fat plays in human health and the onset and progression of several chronic diseases, like coronary artery disease and atherosclerosis, dyslipidemia and inflammation, obesity and diabetes, cancer, major depressive disorders, and schizophrenia.
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PMID:Fatty acid regulation of gene transcription. 1507 23

Insulin resistance and type 2 diabetes are associated with elevated circulating levels of nonesterified FA (NEFA) and lipoprotein remnants. The dyslipidemia is an important contributor to the excess arterial disease associated with insulin resistance and type 2 diabetes, but the mechanisms involved are elusive. In the present study we examined the effect of NEFA on macrophages. For this purpose, we utilized human macrophages, prepared by treating THP-1 monocytes with phorbol ester. We found that albumin-bound NEFA at physiological levels increase the secretion of granulocyte macrophage-colony stimulating factor (GM-CSF) by the THP-1 macrophages in a dose-dependent manner. The effect was registered as an increase in mRNA, and the amount of GM-CSF secreted correlated with the accumulation of TAG and DAG in the cell. The NEFA-induced rise in GM-CSF appeared to be mediated by activation of protein kinase C, probably acting on extracellular signal-regulated kinases 1 and 2 and being calcium dependent. We speculate that increased secretion of GM-CSF by resident macrophages in the intima exposed chronically to high levels of NEFA, such as those present in insulin resistance, may contribute to a proatherogenic response of arterial cells.
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PMID:Fatty acids induce increased granulocyte macrophage-colony stimulating factor secretion through protein kinase C-activation in THP-1 macrophages. 1523 3

Hyperglycemia and dyslipidemia are significant and independent risk factors for the vascular complications in patients with diabetes. They have been suggested to cause cardiovascular pathologic changes in diabetic states through the following molecular mechanisms: formation and accumulation of advanced glycation end products; increased oxidative stress; activation of protein kinase C pathway; increased activity of hexosamine pathway; and vascular inflammation and the impairment of insulin action in the vascular tissues.
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PMID:Introduction of hyperglycemia and dyslipidemia in the pathogenesis of diabetic vascular complications. 1579 10

Insulin resistance, the impaired action of insulin, has been linked to many important consequences, including Type 2 diabetes, hypertension, dyslipidemia, acanthosis nigricans and polycystic ovarian syndrome. Although there are some genetic causes for insulin resistance, the most common cause is an excess of nutrition a condition called "Nutrient Toxicity". Both excess glucose and excess fat can cause insulin resistance in muscle and fat tissues and excess fat can cause insulin resistance in the liver. High fat feeding and fat infusion rapidly lead to the development of insulin resistance caused by impairment in glucose transport. Other studies have shown defects in insulin signaling possibly secondary to activation of Protein Kinase C resulting from the accumulation of active fatty acyl CoA's. Glucose toxicity has been studied both in vivo and in vitro. In vivo it has been shown that rats over-expressing the gluconeogenic enzyme Phosphoenol Pyruvate Carboxykinase (PEPCK) develop insulin resistance in fat and muscle tissues and some features of the metabolic syndrome including mild obesity and dyslipidemia. Excess glucose entry in fat cells results in increased flux through the hexosamine biosynthesis pathway leading to activation of protein kinase C and impairment of glucose transport. Obesity resulting from excess nutrient intake can also cause insulin resistance by an increase in the production of agents that impair insulin action such as TNFalpha and resistin and a decrease in the production of an insulin sensitizing compound adiponectin. Both glucose and free fatty acids acutely stimulate insulin secretion but chronic exposure to high levels of either nutrient leads to impairment of beta cell function. The combination of insulin resistance and beta cell failure leads to diabetes. Nutrient toxicity is thus the driving cause of the diabetes epidemic that is being recorded around the world.
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PMID:Mechanisms of insulin resistance caused by nutrient toxicity. 1620 73

Alterations in the microvasculature seen early in type 1 diabetes appear to be related to glycemic control. The later abnormalities occur primarily in patients with incipient or overt nephropathy and are likely to represent a more generalized vascular dysfunction as indicated by the increased cardiovascular risk in these groups. The mechanisms involved may be related to genetic susceptibility in combination with impaired hemorheology, dyslipidemia, hypertension, or the toxic effects of hyperglycemia. Many of these effects may relate to a common final pathway such as activation of PKC or increased oxidative stress. Therapeutic interventions to inhibit either PKC effects or decrease oxidative stress have been effective in reducing microangiopathy in diabetic animals. Vitamin C or E supplementation may improve vascular function in type 1 diabetes. The results of ongoing trials of PKC inhibitors are awaited with interest. Whether such interventions will influence the course of microangiopathy remains to be determined.
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PMID:The microvasculature in type 1 diabetes. 1622 92

Tissue factor (TF), formerly known as thromboplastin, is the key initiator of the coagulation cascade; it binds factor VIIa resulting in activation of factor IX and factor X, ultimately leading to fibrin formation. TF expression and activity can be induced in endothelial cells, vascular smooth muscle cells, and monocytes by various stimuli such as cytokines, growth factors, and biogenic amines. These mediators act through diverse signal transduction mechanisms including MAP kinases, PI3-kinase, and protein kinase C. Cellular TF is present in three pools as surface, encrypted, and intracellular protein. TF can also be detected in the bloodstream, referred to as circulating or blood-borne TF. Elevated levels of TF are observed in patients with cardiovascular risk factors such as hypertension, diabetes, dyslipidemia, and smoking as well as in those with acute coronary syndromes. TF may indeed be involved in the pathogenesis of atherosclerosis by promoting thrombus formation; in addition, it can induce migration and proliferation of vascular smooth muscle cells. As a consequence, therapeutic strategies have been developed to specifically interfere with the action of TF such as antibodies against TF, site-inactivated factor VIIa, or recombinant TF pathway inhibitor. Inhibition of TF action appears to be an attractive target for the treatment of cardiovascular diseases.
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PMID:Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications. 1646 45


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