OBJECTIVETo assess the effect of atorvastatin on lipopolysaccharide (LPS)-induced TNF-α production in RAW264.7 macrophages.

METHODSRAW264.7 macrophages were treated in different LPS concentrations or at different time points with or without atorvastatin. TNF-α level in supernatant was measured. Expressions of TNF-α mRNA and protein and heme oxygenase-1 (HO-1) were detected by ELISA, PCR, and Western blot, respectively. HO activity was assayed.

RESULTSLPS significantly increased the TNF-α expression and secretion in a dose- and time-dependent manner. The HO-1 activity and HO-1 expression level were significantly higher after atorvastatin treatment than before atorvastatin treatment and attenuated by SB203580 and PD98059 but not by SP600125, suggesting that the ERK and p38 mitogen-activated protein kinase (MAPK) pathways participate in regulating the above-mentioned effects of atorvastatin. Moreover, the HO-1 activity suppressed by SnPP or the HO-1 expression inhibited by siRNA significantly attenuated the effect of atorvastatin on TNF-α expression and production in LPS-stimulated macrophages.

CONCLUSIONAtorvastatin can attenuate LPS-induced TNF-α expression and production by activating HO-1 via the ERK and p38 MAPK pathways, suggesting that atorvastatin can be used in treatment of inflammatory diseases such as sepsis, especially in those with atherosclerotic diseases.

Adjuvants, Immunologic ; pharmacology ; Animals ; Atorvastatin Calcium ; Enzyme Activation ; drug effects ; Heme Oxygenase-1 ; genetics ; metabolism ; Heptanoic Acids ; pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacology ; Lipopolysaccharides ; pharmacology ; Macrophages ; drug effects ; Membrane Proteins ; genetics ; metabolism ; Mice ; Pyrroles ; pharmacology ; Tumor Necrosis Factor-alpha ; metabolism

BACKGROUND: Reperfusion in ischemia is believed to generate cytotoxic oxidative stress, which mediates reperfusion injury. These stress conditions can initiate lipid peroxidation and damage to proteins, as well as promote DNA strand breaks. As biliverdin and bilirubin produced by heme oxygenase isoform 1 (HO-1) have antioxidant properties, the production of both antioxidants by HO-1 may help increase the resistance of the ischemic brain to oxidative stress. In the present study, the survival effect of HO-1 was confirmed using hemin. METHODS: To confirm the roles of HO-1, carbon monoxide, and cyclic guanosine monophosphate further in the antioxidant effect of HO-1 and bilirubin, cells were treated with cycloheximide, desferoxamine, and zinc deuteroporphyrin IX 2,4 bis glycol, respectively. RESULTS: HO-1 itself acted as an antioxidant. Furthermore, iron, rather than carbon monoxide, was involved in the HO-1-mediated survival effect. HO-1 activity was also important in providing bilirubin as an antioxidant. CONCLUSION: Our results suggested that HO-1 helped to increase the resistance of the ischemic brain to oxidative stress.
Animals ; Antioxidants ; Bilirubin ; Biliverdine ; Brain* ; Carbon Monoxide ; Cycloheximide ; DNA ; Guanosine Monophosphate ; Heme ; Heme Oxygenase (Decyclizing) ; Hemin ; Iron ; Ischemia ; Lipid Peroxidation ; Microvessels* ; Oxidative Stress ; Oxygen* ; Oxygenases ; Rats* ; Reperfusion ; Reperfusion Injury ; Zinc

No abstract available.
Diabetes Mellitus, Type 2 ; Heptanoic Acids ; Humans ; Hypercholesterolemia ; Pyrroles ; Retrospective Studies ; Atorvastatin Calcium

No abstract available.
Diabetes Mellitus, Type 2 ; Heptanoic Acids ; Humans ; Hypercholesterolemia ; Pyrroles ; Retrospective Studies ; Atorvastatin Calcium

PURPOSE: Statins are known as cholesterol-lowering agents, but have been suggested for the treatment of asthma because of their anti-inflammatory effects. In this study, the potential therapeutic effects of atorvastatin were investigated in asthmatic patients. METHODS: A total of 62 patients with persistent mild to moderate asthma who presented at asthma clinics of Arak University of Medical Sciences were recruited in a double-blind randomized clinical trial. The asthma clinical control score was assessed based on the standardized Asthma Control Test. Lung volume, i.e., percentage of forced expiratory volume in one second (FEV1%) and percentage of forced vital capacity (FVC%), and peripheral blood eosinophils were also measured. The intervention group was treated with atorvastatin 40 mg per day for 8 weeks, while the control group received a placebo. Asthma controller treatments were not changed. At the beginning and end of the study, serum cholesterol and triglyceride levels were measured to evaluate adherence of the patients to the treatment. RESULTS: The asthma control score did not significantly differ between the intervention and control groups (P=0.06). Difference in FEV1%, FVC%, and blood eosinophil count between the intervention and control groups were not statistically significant (P>0.05). The differences in post-treatment cholesterol and low-density lipoprotein cholesterol levels were significant (P<0.05). CONCLUSIONS: Our study shows that atorvastatin is not effective in the treatment of persistent mild to moderate asthma.
Asthma ; Cholesterol ; Eosinophils ; Forced Expiratory Volume ; Heptanoic Acids ; Humans ; Lipoproteins ; Lung ; Pyrroles ; Vital Capacity ; Atorvastatin Calcium

Atorvastatin Calcium ; Eosinophilia ; chemically induced ; Heptanoic Acids ; adverse effects ; Humans ; Male ; Middle Aged ; Pyrroles ; adverse effects

BACKGROUND: To compare the effects of low dose and high dose of statin treatment on endothelial function and carotid intima-media thickness (IMT) in patients with variant angina (VAP). METHODS: A total of 70 patients with VAP were divided into two groups; atorvastatin 10 mg treatment group (group I: n = 35, 54.2 +/- 12.5 years) versus atorvastatin 40 mg treatment group (group II: n = 35, 52.6 +/- 9.8 years). Flow mediated vasodilation (FMD) of the brachial artery and IMT of the carotid artery were compared between the groups after 6 months of statin treatment. RESULTS: The baseline FMD and carotid IMT were not different between the groups. After 6 months of statin therapy, FMD was significantly improved in both groups (7.7 +/- 2.5% to 8.9 +/- 2.2% in group I, p = 0.001, 7.9 +/- 2.7% to 9.5 +/- 2.8% in group II, p < 0.001), but the degree of FMD change and FMD at 6 month were not different between the groups. Carotid IMT were not changed in both groups after 6 months of statin therapy. CONCLUSION: The use of statin for 6 months significantly improved endothelial function in patients with VAP, but carotid IMT was not changed. The use of high dose statin did not show significant additional benefit as compared with the use of low dose statin. The present study suggested that statin therapy would be beneficial in the treatment of VAP.
Atorvastatin Calcium ; Brachial Artery ; Carotid Arteries ; Carotid Intima-Media Thickness ; Heptanoic Acids ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Pyrroles ; Vasodilation

BACKGROUND: There have been few clinical studies on 10 mg atorvastatin as a starting dosage for treatment of hypercholesterolemia in type 2 diabetes mellitus (T2DM) patients. This retrospective study aims to evaluate the efficacy of 10 mg dosage of atorvastatin in clinical setting. METHODS: One hundred five enrolled patients with high levels of low density lipoprotein cholesterol (LDL-C, > 100 mg/dL) took 10 mg atorvastatin. After 6 months, they were divided into 'Responder group' (LDL-C < 100 mg/dL) and 'Non-responder group' (LDL-C > or = 100 mg/dL), and the response rate was calculated. Thereafter, we subdivided the 'Responder group' into Maintenance (10 mg), Reduced dosage (5 mg), and Discontinuance group (0 mg). The 'Non-Responder group' was subdivided into Maintenance (10 mg) and Double dosage group (20 mg). After consecutive 6 months, the response rates of each 10 mg Maintenance groups were compared to those of the other groups, respectively. RESULTS: Following the first 6 months, the response rate of 10 mg fixed dosage was 74.3%. In the 'Responder group', response rates of 10 mg, 5 mg and Discontinuance groups following 6 months were 52.6%, 53.1%, and 12.5%, respectively. In the 'Non-responder group', response rates of 10 mg and 20 mg groups were 28.6% and 50.0%. Baseline LDL-C levels and body mass index (BMI) of 'Responder group' were significantly lower than those of 'Non-responder group' (P = 0.004, respectively). CONCLUSION: Hypercholesterolemia treatment with 10 mg, fixed dosage of atorvastatin was effective in three quarters of the subjects during the first 6-month treatment; however, a significant number of patients with high LDL-C levels and/or BMI require higher starting and maintenance dosage.
Body Mass Index ; Cholesterol ; Cholesterol, LDL ; Diabetes Mellitus, Type 2 ; Heptanoic Acids ; Humans ; Hypercholesterolemia ; Lipoproteins ; Pyrroles ; Retrospective Studies ; Atorvastatin Calcium

BACKGROUND AND OBJECTIVES: Existing data on the spatiotemporal expression patterns of a variety of galectins in murine atherosclerosis are limited. We investigated the expression levels of galectins, and their in vivo spatiotemporal expression patterns and statin responsiveness in the inflamed atherosclerotic plaques of apolipoprotein E (apoE)-/- mice. MATERIALS AND METHODS: Galectins expression patterns in aortic atherosclerotic plaques and serum galectin-3 levels were investigated in 26-week-old apoE-/- (n=6) and C57BL/6 mice (n=9). To investigate the spatial and temporal patterns of galectin-1 and galectin-3 in plaques, high-cholesterol diet-fed 26-week-old (n=12) and 36-week-old apoE-/- mice (n=6) were sacrificed and their aortas were examined for galectins' expression using immunoblot analysis and immunohistochemical stain. 36-week-old apoE-/- mice were treated with atorvastatin (n=3, 0.57 mg/kg/day) for the evaluation of its effect on aortic galectins' expression. RESULTS: Immunoblot analyses showed that galectin-1 and galectin-3 were the predominant galectins expressed in murine atherosclerosis. The serum galectin-3 level was significantly higher in apoE-/- mice (p<0.001). While galectin-1 was weakly expressed in both intimal plaques and the media of atherosclerotic aortas, galectin-3 was heavily and exclusively accumulated in intimal plaques. Galectin-3 distribution was colocalized with plaque macrophages' distribution (r=0.66). As the degree of plaque extent and inflammation increased, the intraplaque galectin-3 expression levels proportionally elevated (p<0.01 vs. baseline), whereas galectin-1 expression had not elevated (p=0.14 vs. baseline). Atorvastatin treatment markedly reduced intraplaque galectin-3 and macrophage signals (p<0.001 vs. baseline), whereas it failed to reduce galectin-1 expression in the aortas. CONCLUSION: Galectin-3 is the predominant gal and is colocalized with macrophages within atherosclerotic plaques. Intraplaque galectin-3 expression reflects the degree of plaque inflammation.
Animals ; Aorta ; Apolipoproteins ; Atherosclerosis ; Galectin 1 ; Galectin 3 ; Galectins ; Heptanoic Acids ; Inflammation ; Macrophages ; Mice ; Plaque, Atherosclerotic ; Pyrroles ; Atorvastatin Calcium

BACKGROUND AND OBJECTIVES: Although recent lipid-lowering therapies are effective in reducing low density lipoprotein-cholesterol (LDL-C) levels, many patients treated with lipid-lowering agents do not achieve target LDL-C levels, especially in very high risk patients. The aim of this study is to compare the effect of ezetimibe/simvastatin 10/20 mg and atorvastatin 20 mg on achieving a target LDL-C goal in very high risk patients. SUBJECTS AND METHODS: A total of 74 patients with very high risk were enrolled in the study. Very high risk patients were defined as patients that displayed established cardiovascular disease with multiple major risk factors, poorly controlled risk factors, multiple risk factors of the metabolic syndrome and acute coronary syndromes. Patients were randomized into two groups: ezetimibe/simvastatin 10/20 mg (n=36) and atorvastatin 20 mg (n=38). Follow-up lipid profile was obtained 6 weeks later. A target goal of LDL-C was defined as less than 70 mg/dL at follow-up. RESULTS: Baseline clinical and laboratory data were similar between the two groups. Achieving a target LDL-C goal was observed in 41.7% of Group 1 and 44.7% of Group 2 at 6 weeks (p=0.82). Changes in other lipid profiles were not significantly different but the tolerability of the two groups was similar. CONCLUSION: Ezetimibe/simvastatin 10/20 mg and atorvastatin 20 mg showed similar effects in achieving target LDL-C levels in patients with very high risk.
Acute Coronary Syndrome ; Azetidines ; Cardiovascular Diseases ; Follow-Up Studies ; Heptanoic Acids ; Humans ; Pyrroles ; Risk Factors ; Simvastatin ; Atorvastatin Calcium ; Ezetimibe