Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Decreased insulin sensitivity plays a major role in various human diseases. particularly type 2 diabetes mellitus, and is associated with a higher risk of atherosclerosis and cardiovascular complications. Thiazolidinediones, more commonly termed glitazones, are the first drugs to specifically target muscular insulin resistance. They have proven efficacy for reducing plasma glucose levels in patients with type 2 diabetes mellitus treated with diet alone, sulphonylureas, metformin or insulin. In addition, they are associated with some improvement of the cardiovascular risk profile. However, troglitazone, the first compound approved by the Food and Drug Administration in the US, proved to be hepatotoxic and was withdrawn from the market after the report of several dozen deaths or cases of severe hepatic failure requiring liver transplantation. It remains unclear whether or not hepatotoxicity is a class effect or is related to unique properties of troglitazone. Rosiglitazone and pioglitazone, two other glitazones, appear to have similar efficacy with regard to blood glucose control in patients with type 2 diabetes mellitus as compared with troglitazone. In controlled clinical trials, the incidence of significant (> or =3 x upper limit of normal) increases in liver enzyme levels (ALT in particular) was similar with rosiglitazone or pioglitazone as compared with placebo, whereas troglitazone was associated with a 3-fold greater incidence. In contrast to the numerous case reports of acute liver failure in patients receiving troglitzone, only a few case reports of hepatotoxicity have been reported in patients treated with rosiglitazone until now, with a causal relationship remaining uncertain. Furthermore, no single case of severe hepatotoxicity has been reported yet with pioglitazone. It should be mentioned that troglitazone, unlike pioglitazone and rosiglitazone, induces the cytochrome P450 isoform 3A4, which is partly responsible for its metabolism, and may be prone to drug interactions. Importantly enough, obesity, insulin resistance and type 2 diabetes mellitus are associated with liver abnormalities, especially non-alcoholic steatohepatitis, independent of any pharmacological treatment. This association obviously complicates the selection of patients who are good candidates for a treatment with glitazones as well as the monitoring of liver tests after initiation of therapy with any thiazolidinedione compound. While regular monitoring of liver enzymes is still recommended and more long term data are desirable, current evidence from clinical trials and postmarketing experience in the US supports the conclusion that rosiglitazone and pioglitazone do not share the hepatotoxic profile of troglitazone.
 ...
PMID:Hepatotoxicity with thiazolidinediones: is it a class effect? 1173 45

Atherosclerosis, in its myriad incarnations the foremost killer disease in the industrialized world, is characterized by aberrant proliferation of vascular smooth muscle (VSM) cells in part as a result of the recruitment of inflammatory cells to the blood vessel wall. The epoxyeicosatrienoic acids are synthesized from arachidonic acid in a reaction catalyzed by the cytochrome P450 system and are vasoactive substances. Metabolism of these compounds by epoxide hydrolases results in the formation of compounds that affect the vasculature in a pleiotropic manner. As an outgrowth of our observations that urea inhibitors of the soluble epoxide hydrolase (sEH) reduce blood pressure in spontaneously hypertensive rats as well as the findings of other investigators that these compounds possess antiinflammatory actions, we have examined the effect of sEH inhibitors on VSM cell proliferation. We now show that the sEH inhibitor 1-cyclohexyl-3-dodecyl urea (CDU) inhibits human VSM cell proliferation in a dose-dependent manner and is associated with a decrease in the level of cyclin D1. In addition, cis-epoxyeicosatrienoic acid mimics the growth-suppressive activity of CDU; there is no evidence of cellular toxicity or apoptosis in CDU-treated cells when incubated with 20 microM CDU for up to 48 h. These results, in light of the antiinflammatory and antihypertensive properties of these compounds that have been demonstrated already, suggest that the urea class of sEH inhibitors may be useful for therapy for diseases such as hypertension and atherosclerosis characterized by exuberant VSM cell proliferation and vascular inflammation.
 ...
PMID:Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation. 1184 28

Resveratrol (3,5,4'-trihydroxystilbene) is a naturally occurring compound shown to modulate the risk of cardiovascular degenerative diseases (atherosclerosis) and inhibit chemical carcinogenesis in rodents. Various studies have demonstrated the effect of this phytoalexin on biological mechanisms involved in cardioprotection. These include modulation of lipid turnover, inhibition of eicosanoid production, prevention of the low-density lipoprotein oxidation and inhibition of platelet aggregation. Carcinogenesis in animal models can be divided at least into three stages: initiation, promotion and progression. Initiation occurs as result of interaction of a reactive form of carcinogen with DNA. Chemical carcinogens like polycyclic aromatic hydrocarbons are metabolized to reactive species by cytochrome P450 dependent enzymes activated through aryl hydrocarbon (Ah) receptor. The inhibition of tumor initiation by resveratrol most probably occurs through preventing the activation of Ah receptor. Resveratrol affects also several factors involved in tumor promotion and progression. Since tumor promoting agents alter the expression of genes whose products are associated with inflammation, chemoprevention of cardiovascular diseases and cancer may share the same common mechanisms. This includes principally modulation of the expression of growth factors and cytokines. Recently, chemopreventive properties of resveratrol have been associated with the inhibition of NF-kappaB. This transcription factor is strongly linked to inflammatory and immune responses, regulation of cell proliferation and apoptosis, thus it is important for tumor development and many other diseases including atherosclerosis. Although the mechanisms by which resveratrol interferes with the activation of NF-KB are not clear, it seems that inhibition of its degradation which is necessary for its cellular activation is the principal target. Based on the quantity and diversity of data available on the biological activity of resveratrol, it has to be considered a very promising chemoprotector and chemotherapeutic. Urgent investigations on its bioavailability and effects on in vivo systems, especially in humans, are necessary.
 ...
PMID:Resveratrol, a natural chemopreventive agent against degenerative diseases. 1198 29

Initiation of lipid peroxidation and the formation of bioactive eicosanoids are pivotal processes in inflammation and atherosclerosis. Currently, lipoxygenases, cyclooxygenases, and cytochrome P450 monooxygenases are considered the primary enzymatic participants in these events. Myeloperoxidase (MPO), a heme protein secreted by activated leukocytes, generates reactive intermediates that promote lipid peroxidation in vitro. For example, MPO catalyzes oxidation of tyrosine and nitrite to form tyrosyl radical and nitrogen dioxide ((.)NO(2)), respectively, reactive intermediates capable of initiating oxidation of lipids in plasma. Neither the ability of MPO to initiate lipid peroxidation in vivo nor its role in generating bioactive eicosanoids during inflammation has been reported. Using a model of inflammation (peritonitis) with MPO knockout mice (MPO(-/-)), we examined the role for MPO in the formation of bioactive lipid oxidation products and promoting oxidant stress in vivo. Electrospray ionization tandem mass spectrometry was used to simultaneously quantify individual molecular species of hydroxy- and hydroperoxy-eicosatetraenoic acids (H(P)ETEs), F(2)-isoprostanes, hydroxy- and hydroperoxy-octadecadienoic acids (H(P)ODEs), and their precursors, arachidonic acid and linoleic acid. Peritonitis-triggered formation of F(2)-isoprostanes, a marker of oxidant stress in vivo, was reduced by 85% in the MPO(-/-) mice. Similarly, formation of all molecular species of H(P)ETEs and H(P)ODEs monitored were significantly reduced (by at least 50%) in the MPO(-/-) group during inflammation. Parallel analyses of peritoneal lavage proteins for protein dityrosine and nitrotyrosine, molecular markers for oxidative modification by tyrosyl radical and (.)NO(2), respectively, revealed marked reductions in the content of nitrotyrosine, but not dityrosine, in MPO(-/-) samples. Thus, MPO serves as a major enzymatic catalyst of lipid peroxidation at sites of inflammation. Moreover, MPO-dependent formation of (.)NO-derived oxidants, and not tyrosyl radical, appears to serve as a preferred pathway for initiating lipid peroxidation and promoting oxidant stress in vivo.
 ...
PMID:Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. 1235 14

Newer, more effective statins are powerful agents for reducing elevated levels of low-density lipoprotein (LDL) cholesterol and thereby lowering the risk of coronary heart disease (CHD) and related adverse events. Although LDL remains the primary target of therapy for reducing CHD risk, increased interest is focusing on apolipoprotein B (apoB)-containing lipoprotein subfractions--particularly very-low-density lipoprotein (VLDL). VLDL remnants, and intermediate-density lipoproteins (IDL)--as secondary targets of therapy. Elevated apoB is known to be an important risk factor for CHD, and dysregulation of the metabolism of apoB-containing lipoproteins is involved in the progression of atherosclerosis. Statins reduce circulating concentrations of atherogenic apoB-containing lipoproteins by decreasing the production of VLDL in the liver and, thus, the production of VLDL remnants and LDL. Statins also increase the clearance of these particles through upregulation of LDL receptors in the liver. Efforts to develop statins with enhanced lipid-modifying properties are ongoing. The optimal statin would offer a high degree of inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a prolonged duration of action, hepatic selectivity for maximal upregulation of LDL receptors, and a low potential for drug-drug interactions. Recent studies have shown that rosuvastatin, a new agent in this class, demonstrates these qualities. Rosuvastatin is a highly effective inhibitor of HMG-CoA reductase, is relatively nonlipophilic, has a half-life of approximately 20 h, exhibits hepatic selectivity, has little systemic availability, and has a low potential for drug-drug interactions because of its limited degree of metabolism by the cytochrome P450 system. A recent double-blind, crossover study revealed that treatment with rosuvastatin resulted in marked reductions in apoB-containing lipoproteins in patients with type IIa or IIb dyslipidemia. By reducing the number of atherogenic lipoprotein particles, rosuvastatin decreases the atherosclerotic burden in hyperlipidemic patients at high risk for CHD and related adverse outcomes.
 ...
PMID:New dimension of statin action on ApoB atherogenicity. 1253 16

Cigarette smoking as an addictive habit has accompanied human beings for more than 4 centuries. It is also one of the most potent and prevalent environmental health risks human beings are exposed to, and it is responsible for more than 1000 deaths each day in the United States. With recent research progress, it becomes clear that cigarette smoking can cause almost all major diseases prevalent today, such as cancer or heart disease. These detrimental effects are not only present in active smokers who choose the risk, but also to innocent bystanders, as passive smokers, who are exposed to cigarettes not-by-choice. While the cigarette-induced harm to human health is indiscriminate and severe, the degree of damage also varies from individual to individual. This intersubject variability in cigarette-induced pathologies is partly mediated by genetic variants of genes that may participate in detoxification process, eg, cytochrome P450 (CYP), cellular susceptibility to toxins, such as p53, or disease development. Through population studies, we have learned that certain CYP1A1 variants, such as Mspl polymorphism, may render the carriers more susceptible to cigarette-induced lung cancer or severe coronary atherosclerosis. The endothelial nitric oxide synthase intron 4 rare allele homozygotes are more likely to have myocardial infarction if they also smoke. In vitro experimental approach has further demonstrated that cigarettes may specifically regulate these genes in genotype-dependent fashion. While we still know little about genetic basis and molecular pathways for cigarette-induced pathological changes, understanding these mechanisms will be of great value in designing strategies to further reduce smoking in targeted populations, and to implement more effective measures in prevention and treatment of cigarette-induced diseases.
 ...
PMID:Genetic influence on cigarette-induced cardiovascular disease. 1270 94

Lipid mediators generated by oxidative pathways play essential roles in vascular homeostasis and disease through activating signal transduction pathways that control a variety of cellular functions, including vascular tone, gene expression, and leukocyte and platelet activation. Several enzyme families generate oxidized lipids, and a number of these are either constitutively expressed or inducible in the endothelium, including prostaglandin H synthases, lipoxygenases, and cytochrome P450 isoforms. Mediators generated by these enzymes are predominantly arachidonate-derived and include lipid hydroxides, epoxides, hydroperoxides, and prostanoids. These enzymes may also generate low levels of lipid-derived radicals in the vasculature following escape of substrate radicals from the active site. Lipid oxidation enzymes are often up-regulated in atherosclerosis and hypertension, with several lines of evidence suggesting that they play a central role in the pathogenesis of the disease process itself. This review will describe the isoforms of lipid oxidation enzymes present in endothelial cells focusing on their physiological functions and proposed roles in initiation and progression of vascular disease.
 ...
PMID:Free radicals and lipid signaling in endothelial cells. 1271 79

Oxidized low-density lipoprotein (oxLDL) affects macrophages and plays a critical role in the development of atherosclerosis. In the present paper, we demonstrate that high concentrations of oxLDL provoked apoptosis of human Mono-Mac-6 cells, which was blocked by diphenylene-iodonium (DPI), an inhibitor of flavin-containing enzymes, such as NADPH oxidase, suggesting the involvement of reactive oxygen species (ROS). Importantly, pre-treatment of cells with low concentrations of oxLDL prevented apoptosis in response to high concentrations of oxLDL by up-regulating manganese superoxide dismutase (MnSOD). DPI prevented expression of MnSOD by oxLDL, whereas inhibitors of cytochrome P450 (methoxalen) or xanthine oxidase (allopurinol) did not, thus pointing to a role of NADPH-oxidase-derived ROS in oxLDL-induced MnSOD expression. Transfection of cells with MnSOD antisense, but not scrambled antisense, oligonucleotides significantly attenuated oxLDL-mediated MnSOD expression and hindered cytoprotective effects of non-toxic oxLDL concentrations. Our findings suggest that up-regulation of MnSOD by low concentrations of oxLDL is critical for protection towards oxLDL-mediated cytotoxicity.
 ...
PMID:Induced expression of manganese superoxide dismutase by non-toxic concentrations of oxidized low-density lipoprotein (oxLDL) protects against oxLDL-mediated cytotoxicity. 1282 16

Dioxin is known to cause many toxic effects that vary greatly in different tissues, ages, genders, and species. In this review, an attempt has been made to sort out major signaling pathways involved in the expression of the toxicities of dioxin. The major strategy adopted in analyzing its major signaling pathways is to view the toxic actions of dioxin as the result of the Ah receptor-mediated expression of a major cellular emergency stress response signal. Evidence pointing to the similarities between the symptoms of poisoning by dioxin and those produced by chronic administration of typical stressors, particularly lipopolysaccharides (LPS), bacterial endotoxins, has been assembled and analyzed. The common symptoms are wasting syndrome, atherosclerosis, fatty liver, and thymic atrophy. On the other hand, oxidative stress caused by cytochrome P450 induction is one of the typical stresses of dioxin poisoning, but not LPS poisoning. One of the major means through which dioxin triggers stress responses via "stress-activated kinase pathways" is stimulation of the cellular production of cytokines/autocrines, particularly growth factors. In the case of hepatocytes for instance, transforming growth factor-alpha plays a pivotal role in the dioxin-induced activation of the epidermal growth factor receptor and the extracellular signal-related kinase pathway, which acts as a signal to suppress apoptosis induced by cellular stress. These observations as well as additional experimental data support the idea that one of the major functions of the Ah receptor could be the elicitation of cellular stress response reactions. Another key point in understanding the toxic action of dioxin is that, unlike other cases of stressors, dioxin signaling becomes chronically sustained because of its extreme persistence in the human body, its half-life of 7-10 years, and its selective accumulation in fatty target tissues.
 ...
PMID:On the significance of the role of cellular stress response reactions in the toxic actions of dioxin. 1290 18

Excessive proliferation of vascular smooth muscle cells (VSMCs) is a critical element in the development of several vascular pathologies, particularly in atherosclerosis and in restenosis due to angioplasty. We have shown that butyrate, a powerful antiproliferative agent, a strong promoter of cell differentiation and an inducer of apoptosis inhibits VSMC proliferation at physiological concentrations with no cytotoxicity. In the present study, we have used cDNA array technology to unravel the molecular basis of the antiproliferative effect of butyrate on VSMCs. To assess the involvement of gene expression in butyrate-inhibited VSMC proliferation, proliferating VSMCs were exposed to 5 mmol/l butyrate 1 through 5 days after plating. Expression profiles of 1.176 genes representing different functional classes in untreated control and butyrate treated VSMCs were compared. A total of 111 genes exhibiting moderate (2.0-5.0 fold) to strong (> 5.0 fold) differential expression were identified. Analysis of these genes indicates that butyrate treatment mainly alters the expression of four different functional classes of genes, which include: 43 genes implicated in cell growth and differentiation, 13 genes related to stress response, 11 genes associated with vascular function and 8 genes normally present in neuronal cells. Examination of differentially expressed cell growth and differentiation related genes indicate that butyrate-inhibited VSMC proliferation appears to involve down-regulation of genes that encode several positive regulators of cell growth and up-regulation of some negative regulators of growth or differentiation inducers. Some of the down-regulated genes include proliferating cell nuclear antigen (PCNA), retinoblastoma susceptibility related protein p130 (pRb), cell division control protein 2 homolog (cdc2), cyclin B1, cell division control protein 20 homolog (p55cdc), high mobility group (HMG) 1 and 2 and several others. Whereas the up-regulated genes include cyclin D1, p21WAF1, p141NK4B/p15INK5B, Clusterin, inhibitor of DNA binding 1 (ID1) and others. On the other hand, butyrate-responsive stress-related genes include some of the members of heat shock protein (HSP), glutathione-s-transferase (GST), glutathione peroxidase (GSH-PXs) and cytochrome P450 (CYP) families. Additionally, several genes related to vascular and neuronal function are also responsive to butyrate treatment. Although involvement of genes that encode stress response, vascular and neuronal functional proteins in cell proliferation is not clear, cDNA expression array data appear to suggest that they may play a role in the regulation of cell proliferation. However, cDNA expression profiles indicate that butyrate-inhibited VSMC proliferation involves combined action of a proportionally large number of both positive and negative regulators of growth, which ultimately causes growth arrest of VSMCs. Furthermore, these butyrate-induced differential gene expression changes are not only consistent with the antiproliferative effect of butyrate but are also in agreement with the roles that these gene products play in cell proliferation.
 ...
PMID:Gene expression profile of butyrate-inhibited vascular smooth muscle cell proliferation. 1467 79


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>