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)

Allograft coronary artery disease represents a major limitation to long-term survival after cardiac transplantation. Hyperlipidemias have been linked to the development of native coronary atherosclerosis, and hyperlipidemic states have correlated with the severity of allograft coronary artery disease. Heart transplant recipients typically manifest increases in plasma levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and triglycerides within the first 3-12 months following transplantation. Factors known to promote post-transplant hyperlipidemia include the use of corticosteroids, cyclosporine (interference with clearance and increased oxidizability of LDL), sirolimus (hypertriglyceridemia), and patient-specific causes of hyperlipidemia which contributed to their underlying heart disease. Hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors are the foundation of antilipid therapy following cardiac transplantation. Pravastatin is effective in lowering plasma cholesterol levels and is associated with a decreased incidence and progression of allograft coronary artery disease. All HMG-CoA reductase inhibitors except pravastatin are metabolized by the hepatic cytochrome P450 system which metabolizes cyclosporine, increasing the risk of myostitis when they are used in large dosages with cyclosporine. Simvastatin, atorvastatin and fluvastatin have been studied in heart transplant recipients. Gemfibrozil has proved effective in transplant recipients when there is isolated marked elevation of plasma triglyceride levels. When hyperlipidemia persists despite therapy, some benefit may result with conversion from cyclosporine to tacrolimus. Although a definitive link between hyperlipidemia and allograft coronary disease has yet to be proven, available evidence points to abnormal lipid metabolism as part of the complex etiologic machinery driving the process of 'chronic rejection'. Consensus exists within the transplant community that a HMG-CoA reductase inhibitor such as pravastatin, should be part of the routine post-transplant drug regimen, and persistent hyperlipidemia should be aggressively treated.
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PMID:Strategies for minimizing hyperlipidemia after cardiac transplantation. 1472 53

Dyslipidemia, characterized by elevated serum levels of triglycerides and reduced levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol, has been recognized in patients with human immunodeficiency virus (HIV) infection. It is thought that elevated levels of circulating cytokines, such as tumor necrosis factor-alpha and interferon-alpha, may alter lipid metabolism in patients with HIV infection. Protease inhibitors, such as saquinavir, indinavir and ritonavir, have been found to decrease mortality and improve quality of life in patients with HIV infection. However, these drugs have been associated with a syndrome of fat redistribution, insulin resistance, and hyperlipidemia. Elevations in serum total cholesterol and triglyceride levels, along with dyslipidemia that typically occurs in patients with HIV infection, may predispose patients to complications such as premature atherosclerosis and pancreatitis. It has been estimated that hypercholesterolemia and hypertriglyceridemia occur in greater than 50% of protease inhibitor recipients after 2 years of therapy, and that the risk of developing hyperlipidemia increases with the duration of treatment with protease inhibitors. In general, treatment of hyperlipidemia should follow National Cholesterol Education Program guidelines; efforts should be made to modify/control coronary heart disease risk factors (i.e. smoking; hypertension; diabetes mellitus) and maximize lifestyle modifications, primarily dietary intervention and exercise, in these patients. Where indicated, treatment usually consists of either pravastatin or atorvastatin for patients with elevated serum levels of LDL-C and/or total cholesterol. Atorvastatin is more potent in lowering serum total cholesterol and triglycerides compared with other hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, but it is also associated with more drug interactions compared with pravastatin. Simvastatin and lovastatin are significantly metabolized by cytochrome P450 enzymes (CYP3A4) and are therefore not recommended for coadministration with protease inhibitors. A fibric acid derivative (gemfibrozil or fenofibrate) should be used in patients with primary hypertriglyceridemia. However, it must be kept in mind that protease inhibitors, such as nelfinavir and ritonavir, induce enzymes involved in the metabolism of the fibric acid derivatives and may, therefore, reduce the lipid-lowering activity of coadministered gemfibrozil or fenofibrate. In certain patients HMG-CoA reductase inhibitors may be used in combination with fibric acid derivatives but patients should be carefully monitored for liver and skeletal muscle toxicity. Select patients may experience improvements in serum lipid levels when their offending protease inhibitor(s) is/are exchanged for efavirenz, nevirapine, or abacavir; however each patient's virologic and immunologic status must be taken closely into consideration.
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PMID:Management of protease inhibitor-associated hyperlipidemia. 1472 85

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors mediating ligand-dependent transactivation. Among the 3 isoforms, PPAR- alpha is involved in lipid metabolism in the liver, while PPAR-gamma(-gamma1 and -gamma2) is involved in adipocyte differentiation. Recently, PPARs have been suggested to be involved in renal electrolyte metabolism as well as atherosclerosis. PPAR-alpha is known to regulate cytochrome P450 gene expression, and may possibly affect sodium retention in the kidney. Moreover, PPAR-gamma is involved in the transcription regulation of blood pressure regulatory genes, including thromboxane and angiotensin II type 1 receptors. In the kidney, although expression of PPARs has been reported, detailed immunohistochemical analyses have not been performed. We here generated isoform-specific anti-PPAR antibodies to localize their proteins in the kidney. Anti-PPAR antibodies were raised against synthetic peptides. Their isoform specificity was confirmed by immunoblot analyses, immunoprecipitations, and antibody supershift experiments by electrophoretic mobility shift assay. We therefore studied the protein expression of PPARs in the kidney of adult Sprague-Dawley rats using these antibodies. Immunoblot analyses demonstrated protein expression of PPAR-alpha and -gamma1, but not of -gamma2, in the kidney nuclear extracts. Immunohistochemical analyses demonstrated that both PPAR-alpha and -gamma1 proteins were widely expressed in the nuclei of mesangial and epithelial cells in glomeruli, proximal and distal tubules, the loop of Henle, medullary collecting ducts, and intima/media of renal vasculatures. PPAR-alpha and -gamma1 proteins are thus widely expressed along the nephron segments, and may affect gene expression at these segments. Further studies will be needed to identify additional target genes for PPARs along the nephron segments.
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PMID:Expression of peroxisome proliferator-activated receptor isoform proteins in the rat kidney. 1525 7

This review provides an overview of gender-specific differences in the incidence and development of cardiovascular diseases, including hypertension, atherosclerosis, heart failure and the corresponding myocardial remodeling. The review discusses the possible mechanisms by which estrogen affords a beneficial effect on cardiovascular function via genomic vs non genomic regulation; estrogen receptor-dependent vs estrogen receptor-independent pathways, specific signal transduction cascades, especially those involving protein kinase B (Akt) and mitogen activated protein kinase (MAPK), as well as their downstream targets, such as nitric oxide synthase, cyclooxygenase, cytochrome P450 (CYP), NADPH oxidase and superoxide dismutase. Having considered the essential role of the microcirculation in the control of vascular resistance in vivo, estrogen-related regulation of microvascular function and blood pressure is highlighted. Attention is focused on the effects of estrogen on pressure (myogenic)-dependent and flow/shear stress-dependent mechanisms of arterioles, which contribute significantly to the control of local blood flow and peripheral resistance via alterations in the release of endothelial mediators, such as nitric oxide, prostaglandins and endothelium-derived hyperpolarizing factor.
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PMID:Gender-specific regulation of cardiovascular function: estrogen as key player. 1528 95

Several genes are regulated by tocopherols which can be categorized, based on their function, into five groups: genes that are involved in the uptake and degradation of tocopherols (Group 1) include alpha-tocopherol transfer protein (alpha-TTP) and cytochrome P450 (CYP3A); genes that are associated with lipid uptake and atherosclerosis (Group 2) include CD36, SR-BI and SR-AI/II. Genes that modulate the expression of extracellular proteins (Group 3) include tropomyosin, collagen(alpha1), MMP-1, MMP-19 and connective tissue growth factor (CTGF). Genes that are related to inflammation, cell adhesion and platelet aggregation (Group 4) include E-selectin, ICAM-1, integrins, glycoprotein IIb, II-2, IL-4 and IL-beta. Group 5 comprises genes coding for proteins involved in cell signaling and cell cycle regulation and consists of PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27 and CD95 (Apo-1/Fas ligand). The expression of P27, Bcl2, alpha-TTP, CYP3A, tropomyosin, II-2, PPAR-gamma, and CTGF appears to be up-regulated by one or more tocopherols whereas all other listed genes are down-regulated. Several mechanisms may underlie tocopherol-dependent gene regulation. In some cases protein kinase C has been implicated due to its deactivation by alpha-tocopherol and its participation in the regulation of a number of transcription factors (NF-kappaB, AP-1). In other cases a direct involvement of PXR/RXR has been documented. The antioxidant responsive element (ARE) appears in some cases to be involved as well as the transforming growth factor beta responsive element (TGF-beta-RE). This heterogeneity of mediators of tocopherol action suggests the need of a common element that could be a receptor or a co-receptor, able to interact with tocopherol and with transcription factors directed toward specific regions of promoter sequences of sensitive genes. Here we review recent results of the search for molecular mechanisms underpinning the central signaling mechanism.
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PMID:Regulation of gene expression by alpha-tocopherol. 1531 6

Cardiovascular diseases due to atherosclerosis are the leading causes of mortality in the Western world. Cholesterol-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme Areductase inhibitors (statins) has demonstrated a reduction in cardiovascular morbidity and mortality in diverse populations. Fluvastatin (Lescol, Novartis Pharmaceuticals) was the first totally synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor on the market and has recently become available in an extended-release formulation (Lescol XL, Novartis Pharmaceuticals). Data from several clinical outcome trials have shown substantial benefits from fluvastatin treatment in diverse populations. Fluvastatin exists primarily in its acid form and as inactive metabolites in vivo, while active metabolites as well as the lactone form are only present in small amounts. The demonstration of the safe use of fluvastatin in a wide range of patients may be associated with the predominant acid form of the drug in vivo, as well as its predominant metabolism via the cytochrome P450 2C9 pathway.
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PMID:Fluvastatin and fluvastatin extended release: a clinical and safety profile. 1535 Jan 66

There is accumulating evidence that supports a role of infection in atherosclerosis, with possible mechanism by injuring to the endothelium and inducing an autoimmune response to heat shock proteins (HSPs). In this study, a cDNA array, containing 588 human cardiovascular genes, was utilized to analyze the gene expression profile of Chlamydia pneumoniae (C. pneumoniae) infected human umbilical vein endothelial cells (HUVECs). After 48h of C. pneumoniae infection, the HUVECs were harvested and subjected to immunofluorescent staining, electron microscopy, cDNA array hybridization, RT-PCR, and immunoblotting. This study found a panel of human host genes that were upregulated by C. pneumoniae. The majority of these genes were related to complex lipid metabolism, adhesion receptors, hormones, hormone receptors, and a metalloproteinase that may contribute to atherosclerosis in vivo. Representatives of upregulated gene products, i.e., heat shock protein 60 (HSP60), macrophage scavenger receptor, cytochrome P450, and VEGF165R were immunofluorescently detected in HUVECs, with their greater expression induced by C. pneumoniae infection. These findings supported the opinion that C. pneumoniae might contribute to atherosclerotic development in vivo.
Atherosclerosis 2004 Dec
PMID:Chlamydia pneumoniae (C. pneumoniae) infection upregulates atherosclerosis-related gene expression in human umbilical vein endothelial cells (HUVECs). 1553 Aug 96

alpha-Tocopherol modulates two major signal transduction pathways centered on protein kinase C and phosphatidylinositol 3-kinase. Changes in the activity of these key kinases are associated with changes in cell proliferation, platelet aggregation, and NADPH-oxidase activation. Several genes are also regulated by tocopherols partly because of the effects of tocopherol on these two kinases, but also independently of them. These genes can be divided in five groups: Group 1. Genes that are involved in the uptake and degradation of tocopherols: alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine synthetase heavy subunit, and glutathione-S-transferase. Group 2. Genes that are implicated with lipid uptake and atherosclerosis: CD36, SR-BI, and SR-AI/II. Group 3. Genes that are involved in the modulation of extracellular proteins: tropomyosin, collagen-alpha-1, MMP-1, MMP-19, and connective tissue growth factor. Group 4. Genes that are connected to adhesion and inflammation: E-selectin, ICAM-1 integrins, glycoprotein IIb, IL-2, IL-4, IL-1b, and transforming growth factor-beta (TGF-beta). Group 5. Genes implicated in cell signaling and cell cycle regulation: PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27, CD95 (APO-1/Fas ligand), and 5a-steroid reductase type 1. The transcription of p27, Bcl2, alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine sythetase heavy subunit, tropomyosin, IL-2, and CTGF appears to be upregulated by one or more tocopherols. All the other listed genes are downregulated. Gene regulation by tocopherols has been associated with protein kinase C because of its deactivation by alpha-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, AP1). A direct participation of the pregnane X receptor (PXR) / retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element (TGF-beta-RE) appear in some cases to be implicated as well.
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PMID:Vitamin E mediates cell signaling and regulation of gene expression. 1575 36

Previous data have indicated that modification of proteins/lipids by glucoxidation and/or lipid oxidation may initiate/propagate the formation of atherosclerotic plaques. Although the biomarker carboxymethyllysine (CML) has been detected in these lesions, the origin of the reactive oxygen species (ROS) leading to its formation and the source of its carbon backbone are unknown. As presented here, the stimulation of cultured monocytes by phorbol-12-myristate-13-acetate (TPA), an activator of protein kinase C that can mimic the effects of high glucose, angiotensin II, and other physiological stimuli, leads to cellular ROS generation and concomitant formation of intracellular CML. Inhibitors of ROS-generating cellular systems such as NO synthase, xanthine oxidase, or cytochrome P450 oxidase had no effect on CML formation. Likewise, in cells with inactive NAD(P)H oxidase no reduced CML formation was found. In cells exhibiting a high glycolysis rate, CML formation was unaffected. Because we found rapid CML formation in the presence of unsaturated fatty acids, it appears that lipid oxidation is quantitatively more important. In vivo studies revealed strong intracellular CML staining in areas of histiocytic/monocytic infiltration or proliferation, mostly associated with atheroma formation. Corresponding CML staining patterns were found in healing wounds of different ages, indicating that formation of atherosclerosis is a chronic wound repair associated with a low-grade inflammatory reaction. In summary, CML is formed concomitantly with oxidative stress in activated monocytes and can be regarded as a biomarker for a low-grade inflammatory tissue reaction in the atherosclerotic plaque. Its formation via lipid oxidation may be involved in the development of atherosclerosis.
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PMID:Role of glucoxidation and lipid oxidation in the development of atherosclerosis. 1603 56

Polycyclic aromatic hydrocarbons (PAHs) have been known to induce atherosclerosis. It has been reported that the metabolic activation of PAHs by cytochrome P450 (CYP) is an important step for PAH-induced atherosclerosis. We recently reported that PAHs down-regulated the liver X receptor (LXR) alpha-regulated genes via aryl hydrocarbon receptor (AHR) as one of the causes responsible for atherosclerosis induced by PAHs. Thus, the aim of this study was to clarify the role of CYP1A1 in the suppression of LXR-mediated signal transductions by 3-methlychoranthrene (MC), one of the PAHs. We found that LXR-mediated transactivation was inhibited by the PAH, but not by halogenated aromatic hydrocarbon, which is scarcely metabolized by CYP1A1. The repression of LXR-mediated signal transductions by MC was restored by co-treatment of HepG2 cells with a CYP1A1 inhibitor, alpha-naphthoflavone, and by the transfection of short interference RNA for CYP1A1. Based on these lines of evidence, we propose that the metabolic activation of PAHs by CYP1A1, but not the activation of AHR by PAHs, is a direct mechanism for atherosclerosis via the suppression of LXR-mediated signal transductions.
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PMID:CYP1A1-mediated mechanism for atherosclerosis induced by polycyclic aromatic hydrocarbons. 1620 79


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