Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:Q8NEX9 (reductase)
26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) reduce mortality after myocardial infarction (MI). Although this may be predominantly due to their known anti-ischaemic actions, these drugs are known to have other beneficial effects. 2. Because pathological deposition of extracellular matrix (ECM) material is a key component of remodelling after MI, we sought to determine whether atorvastatin could inhibit ECM production in vitro. 3. The addition of atorvastatin to rat cardiac fibroblasts stimulated with either transforming growth factor (TGF)-beta1 (TGF-beta1) or angiotensin (Ang) II reduced collagen synthesis in a dose-dependent manner (3.7-fold reduction (95% confidence interval (CI) 1.8-15; P < 0.01) and 5.3-fold reduction (95% CI 1.8-7.7; P < 0.01), respectively, compared with stimulant alone). Similar observations were made in human cardiac fibroblast cell culture. Atorvastatin also dose-dependently reduced TGF-beta1 and AngII-induced increases in alpha(I)-procollagen mRNA (P < 0.01 for both), as well as gene expression of the profibrotic peptide connective tissue growth factor. 4. Atorvastatin appears to directly inhibit collagen production by cardiac fibroblasts. This antifibrotic action may contribute to the antiremodelling effect of statins.
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PMID:In vitro inhibitory effects of atorvastatin on cardiac fibroblasts: implications for ventricular remodelling. 1617 24

Elevated blood levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk for atherosclerotic coronary heart disease (CHD). Atorvastatin is a statin drug that inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (the rate-limiting step of cholesterol production) and primarily lowers LDL-C levels. Atorvastatin has also been shown to significantly reduce CHD events. However, as with all statins (and all other monotherapy lipid-altering drugs), atorvastatin alone reduces the risk of CHD in only a minority of patients relative to placebo. Conversely, it is low levels of high-density lipoprotein cholesterol that are associated with increased CHD risk. Torcetrapib is a cholesteryl ester transfer protein inhibitor that primarily raises high-density lipoprotein cholesterol levels, and cholesteryl ester transfer protein inhibition has generally been shown to reduce atherosclerosis in rabbits. Taken together, atorvastatin and torcetrapib provide striking improvements in lipid levels, and complementary actions upon important lipid parameters. This review examines the chemistry, mechanism of action, pharmacokinetics, metabolism, safety/tolerability and efficacy of the combination torcetrapib/atorvastatin agent that is currently in development and that provides complementary lipid benefits towards the goal of reducing CHD risk beyond that of atorvastatin alone.
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PMID:Torcetrapib/atorvastatin combination therapy. 1618 Oct 26

The incidence of type 2 diabetes mellitus is expected to increase dramatically over the next decade. Patients with type 2 diabetes are at a much greater risk for cardiovascular disease (CVD) than are nondiabetic individuals. Consequently, the treatment of CVD risk factors is a healthcare priority in this patient population. Dyslipidemia is a major cardiovascular (CV) risk factor in patients with type 2 diabetes, and it is characterized by elevated triglyceride levels, low high-density lipoprotein (HDL) cholesterol levels, and a preponderance of small, dense low-density lipoprotein (LDL) particles. Subgroup analyses of clinical trial data suggest that treatment of the entire range of lipid abnormalities may reduce CV risk in this patient population. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the best therapy for LDL cholesterol reduction. A number of statin trials have shown significant CV risk reduction through LDL cholesterol lowering in subgroups of patients with diabetes. The recently published Collaborative Atorvastatin Diabetes Study (CARDS), a placebo-controlled trial conducted solely in patients with type 2 diabetes, terminated 2 years earlier than its anticipated length owing to the significant reduction in number of CV events observed in patients randomized to receive low-dose atorvastatin versus placebo. These results suggest that low-dose statin therapy with atorvastatin results in significant reduction of CV events in patients with type 2 diabetes without prior CVD or high LDL cholesterol levels. Based on this evidence, patients with type 2 diabetes may be candidates for statin therapy regardless of LDL cholesterol level and in the absence of a previous CV event.
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PMID:Benefits of lipid-lowering therapy in patients with type 2 diabetes mellitus. 1635 2

The aim of the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial was to determine whether intensive low-density lipoprotein (LDL)-cholesterol lowering to a level of approximately 70 mg/dL (1.8 mmol/L) with atorvastatin 80 mg/day was more efficacious than standard LDL cholesterol lowering to 100 mg/dL (2.6 mmol/L) with pravastatin 40 mg/day in reducing the incidence of cardiovascular events in patients with acute coronary syndrome (ACS). In total, 4,162 men and women aged >18 years, who had been hospitalized for an ACS within the preceding 10 days, were randomized to receive either pravastatin 40 mg/day or atorvastatin 80 mg/day. The median LDL cholesterol levels achieved during follow-up were 95 mg/dL (2.5 mmol/L) in the pravastatin group and 62 mg/dL (1.6 mmol/L) in the atorvastatin group (P <0.001). Standard treatment (statin) with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (pravastatin 40 mg/day) resulted in a 22% reduction in LDL cholesterol levels at 30 days compared with a 51% reduction with intensive therapy (atorvastatin 80 mg/day). At 2 years, a relative risk reduction of 16% (95% confidence interval, 5%-26%; P = 0.005) in the primary end point rate (death, myocardial infarction, documented unstable angina requiring hospitalization, coronary revascularization, or stroke) was seen in patients receiving intensive statin treatment compared with standard statin therapy. The benefit of intensive treatment was apparent as early as 30 days and was consistent over time. The PROVE IT-TIMI 22 data indicate that patients recently hospitalized for an ACS benefit from early and continued lowering of LDL cholesterol to levels substantially below current guideline recommendations.
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PMID:Improved outcome after acute coronary syndromes with an intensive versus standard lipid-lowering regimen: results from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. 1635 5

The pleiotropic effects of statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, have been recently extended to the modulation of angiogenesis. Here, to get more insight into the statins action, the authors have investigated the effect of atorvastatin on the expression of several angiogenic and inflammatory genes in human umbilical endothelial cells (HUVECs). Atorvastatin was proangiogenic at the dose of 10 nM, and antiangiogenic at the concentrations of 1 to 10 micro M. Moreover, these higher concentrations inhibited also the proliferation of HUVECs induced by vascular endothelial growth factor (VEGF). Lower doses of atorvastatin did not influence endothelial cell proliferation. Importantly, atorvastatin at the micromolar concentrations diminished the production of interleukin (IL)-8, a proinflammatory and proangiogenic chemokine, and inhibited the synthesis of urokinase plasminogen activator (uPA), a potent proinflammatory mediator. However, it decreased also the expression of plasminogen activator inhibitor-1 (PAI-1) and thrombospondin-1 (TSP-1), the inhibitors of angiogenesis. Atorvastatin stimulated the expression of angiopoietin (Ang)-2 and moderately enhanced the expression of endothelial nitric oxide synthase (eNOS), whereas heme oxygenase-1 (HO-1) was not significantly affected. In conclusion, the present findings points to other angiogenesis-related effects of atorvastatin, which may be of relevance to the beneficial influence of statins in cardiovascular system.
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PMID:Atorvastatin affects several angiogenic mediators in human endothelial cells. 1641 Feb 22

We investigated the pleiotropic effects of a calcium antagonist (amlodipine) on early atherosclerosis development in the presence and absence of an HMG-CoA-reductase inhibitor (atorvastatin) in apolipoprotein E*3-Leiden/human C-reactive protein (E3L/CRP) transgenic mice. Male E3L/CRP transgenic mice were fed a cholesterol-containing diet either with or without amlodipine and/or atorvastatin. After 31 weeks, atherosclerosis in the aortic root area was quantified. Treatment with amlodipine did not significantly lower blood pressure, but resulted in a 43% reduction (P < 0.03) of lesion area as compared with the untreated group. Treatment with atorvastatin resulted in an 80% reduction of lesion area as compared with the untreated group (P < 0.001). Combined treatment with amlodipine and atorvastatin decreased the lesion area by 93%, significantly more than either treatment alone (P < 0.008). Plasma C-reactive protein levels were mildly elevated, on average 10 +/- 6 mg/L, and did not differ between groups, neither on baseline nor during treatment. Treatment with amlodipine, independently of blood pressure lowering, reduced atherosclerosis development in E3L/CRP mice. Atorvastatin had a strong anti-atherosclerotic effect, whereas co-treatment with amlodipine enhanced this effect significantly. Plasma C-reactive protein levels were not affected by any of the three treatments.
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PMID:Anti-atherosclerotic effect of amlodipine, alone and in combination with atorvastatin, in APOE*3-Leiden/hCRP transgenic mice. 1642 91

Experimental autoimmune myocarditis (EAM) in rats is a T-cell-mediated disorder and has been shown to involve immune imbalance. The aim of this study was to examine the immunomodulatory effects of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, atorvastatin, on the expression of MHC class II molecules in the myocardium of rats with EAM, and to examine its therapeutic potential for EAM. EAM was induced in Lewis rats by injection of porcine cardiac myosin. High-dosage (10 mg/kg per day) or low-dosage (1 mg/kg per day) atorvastatin or vehicle was given orally for 3 weeks. On day 21 after immunization, echocardiography was carried out and the severity of myocarditis was evaluated by histopathological investigations. Immunohistochemistry techniques were used to examine the expression of MHC class II molecules in the myocardium. Type I, III and IV class II transactivator (CIITA) promoter transcription was evaluated by reverse transcription-PCR. Cardiomyocytes were isolated and the expression of MHC class II molecules by them was detected using cytometry. Serum Th1/Th2 cytokines were examined on day 21 by ELISA. Cardiac function was improved in the two atorvastatin-treated groups compared with the untreated one. In atorvastatin groups, the histopathological severity of myocarditis was attenuated and the expression of MHC class II molecules on the 'nonprofessional' APC, the cardiomyocytes, was reduced. mRNA level of type IV CIITA promoter was downregulated in the statin-treated groups in a dosage-dependent manner, but levels of type I and III CIITA mRNA did not differ between the groups statistically. Levels of IFN-gamma and IL-2 increased, whereas levels of IL-4 and IL-10 decreased, in immunized rats from day three through day 21. Atorvastatin reversed these trends in the treated groups. Atorvastatin improves cardiac function and histopathology of the myocardium in EAM by inducing Th2-biased immune responses, and thus 3-hydroxy-3-methyl-glutaryl coenzyme A reductase blockade may be a promising new strategy for the treatment of cardiac autoimmune impairments. The underlying mechanisms may be related to downregulation of MHC class II Ag expression due to silencing of the CIITA mRNA transcription.
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PMID:Immunoregulatory effects of atorvastatin on experimental autoimmune myocarditis in Lewis rats. 1650 27

Immortalized cell lines offer significant logistical advantages over primary cells when used for in-vitro studies. Immortalized cells may, however, exhibit important differences relative to their primary cell counterparts. In this study, microarrays were used to make a genome-wide comparison between primary human umbilical vein endothelial cells (HUVECs) and EA.hy926, an immortalized HUVEC cell line, in their baseline properties and in their response to inhibition of the mevalonate pathway with an inhibitor of hydroxy methylglutaryl-coenzyme A reductase (statin). HUVECs and EA.hy926 were incubated with control medium, atorvastatin, mevalonate, or a combination of atorvastatin and mevalonate for 24 h. Gene expression profiles were obtained in duplicates using Affymetrix Human Genome U133A 2.0 arrays (Santa Clara, California, USA). Probe-sets were selected according to the following criteria: a twofold or greater increase/decrease in atorvastatin-treated cells compared with untreated cells; a twofold or greater reversal of the effect of atorvastatin by combined treatment with atorvastatin and mevalonate; no significant change in gene expression in cells treated with mevalonate alone compared with untreated cells. Most genes that were expressed by untreated HUVECs, were also expressed by untreated EA.hy926 cells. EA.hy926 cells, however, constitutively expressed a large number of additional genes, many of which were related to cell cycle control and apoptosis. Atorvastatin induced differential expression (> or = twofold) of 103 genes in HUVECs (10 up, 93 down) and 466 genes in EA.hy926 cells (198 up, 268 down). Applying the above selection criteria, thrombomodulin and tissue plasminogen activator were up-regulated in both cell types, whereas, connective tissue growth factor, thrombospondin-1, and cysteine-rich angiogenic inducer 61 were down-regulated. In conclusion, EA.hy926 cells retain most of the characteristics of endothelial cells under baseline conditions as well as after treatment with atorvastatin. It is necessary, however, to carefully select and validate changes in genes that are the focus of studies when using EA.hy926 cells. While this cell line is highly useful in studies on some genes, including genes encoding molecules involved in regulating thrombohemorrhagic homeostasis, they appear to be less suited for studies focused on other genes, particularly those involved in the regulation of cell proliferation and apoptosis.
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PMID:Comparative expression profiling in primary and immortalized endothelial cells: changes in gene expression in response to hydroxy methylglutaryl-coenzyme A reductase inhibition. 1657 54

The risks of muscle adverse events related to use of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, increase significantly with the addition of interacting drugs to a patient's therapy. The mechanism for most statin drug interactions involves the cytochrome P-450 system, which provides an indication of which drugs may interact. However, it is difficult to predict the probability of a drug interaction in a given patient because there are individual differences in sensitivity to increased statin drug levels. Drug metabolism studies show simvastatin and lovastatin to be especially sensitive to the inhibiting effects of other drugs on the cytochrome P-450 3A4 (CYP3A4) isoenzyme. Atorvastatin metabolism is less affected by inhibitors of this isoenzyme. Case reports, postmarketing surveillance, and clinical trial data demonstrate the clinical effect of CYP3A4 inhibitors on statins. Also, through possible inhibition of statin biliary excretion and glucuronidation, gemfibrozil given concomitantly with rosuvastatin, lovastatin, and simvastatin significantly increases the risk of myopathy and rhabdomyolysis, a potentially life-threatening consequence of statin drug interactions.
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PMID:Statin safety and drug interactions: clinical implications. 1658 25

1. Adrenocorticotropic hormone (ACTH)-induced hypertension is associated with nitric oxide (NO) deficiency and increased oxidative stress. Atorvastatin (Ato), an HMG-Co-enzyme-A reductase inhibitor has been reported to enhance availability of NO. The aim of the study was to assess whether pretreatment with Ato would prevent the development of ACTH-induced hypertension and whether established ACTH-induced hypertension could be reversed with subsequent administration of Ato in rats. 2. Male Sprague-Dawley rats (n = 60) were treated with Ato (30 mg/kg per day in drinking water) or tap water for 15 days. ACTH (0.2 mg/kg per day s.c) or saline was started 4 days after Ato treatment or non-treated rats and continued for 11-13 days (prevention study). In the reversal study, Ato was given on day 8 of ACTH/Saline treatment for 5 days. Systolic blood pressure (SBP) was measured on alternate days using the tail cuff method. 3. Adrenocorticotropic hormone treatment increased SBP (110 +/- 2-136 +/- 2 mmHg, P < 0.001) and aortic superoxide production (P < 0.001). Ato alone did not alter SBP, but Ato pretreatment prevented ACTH-induced hypertension compared with that in rats treated with ACTH alone (118 +/- 2 and 136 +/- 2 mmHg, respectively, P cent < 0.01). Ato partially reversed ACTH-induced hypertension (124 +/- 3 and 136 +/- 2 mmHg, respectively, P cent < 0.05). Plasma nitrate/nitrite (NOx) was decreased in ACTH-treated rats compared with saline treated rats (6.6 +/- 0.4 saline and 4.5 +/- 0.5 micromol/L ACTH, P < 0.001). Atorvastatin affected neither plasma NOx nor aortic superoxide production. 4. Atorvastatin prevented and partially reversed ACTH-induced hypertension in the rat.
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PMID:Atorvastatin prevented and partially reversed adrenocorticotropic hormone-induced hypertension in the rat. 1662 Mar 3


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