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Expression of let-7i is associated with Toll-like receptor 4 signal in coronary artery disease: effect of statins on let-7i and Toll-like receptor 4 signal.
Satoh, M, Tabuchi, T, Minami, Y, Takahashi, Y, Itoh, T, Nakamura, M
Immunobiology. 2012;(5):533-9
Abstract
Toll-like receptor (TLR) 4 signal plays an important role in immunity in coronary artery disease (CAD). A recent report has demonstrated that one of the let-7 family microRNAs, let-7i, directly regulates Toll-like receptor 4 (TLR4) expression and contributes to immune response. The aim of this study was to determine whether let-7i is expressed with TLR4 in patients with CAD, and whether statins (atorvastatin or rosuvastatin) might affect these levels. To determine the effects of let-7i on TLR4 expression, human THP-1 cells transfected with let-7i were analyzed for TLR4 levels. This study included 98 patients with CAD and 48 subjects without CAD (non-CAD). Patients with CAD were randomized to 12 months of treatment with atorvastatin or rosuvastatin. Monocytes were obtained from peripheral blood at baseline and after 12 months of each type of therapy. Levels of let-7i and TLR4 were measured by real-time RT-PCR and FACS. Functional approaches to let-7i showed that transfection of let-7i into human THP-1 cells resulted in regulation of TLR4 expression. Levels of let-7i were lower in the CAD group than in the non-CAD group (0.98±0.42 vs. 4.65±1.21, P<0.01). There was a negative correlation between let-7i and TLR4 levels in patients with CAD (let-7i vs. TLR4 mRNA: r=-0.60, P<0.01; let-7i vs. TLR4 MFI: r=-0.32, P<0.01). The atorvastatin group had markedly increased let-7i levels and diminished TLR4 levels (all P<0.01), whereas the rosuvastatin group showed no change in these levels. This study suggests that atorvastatin down-regulates TLR4 signal via let-7i expression in CAD patients, possibly contributing to the beneficial effects of atorvastatin on let-7i-mediated TLR4 signal in this disorder.
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Improved preservation of residual beta cell function by atorvastatin in patients with recent onset type 1 diabetes and high CRP levels (DIATOR trial).
Strom, A, Kolb, H, Martin, S, Herder, C, Simon, MC, Koenig, W, Heise, T, Heinemann, L, Roden, M, Schloot, NC, et al
PloS one. 2012;(3):e33108
Abstract
BACKGROUND A recent randomized placebo-controlled trial of the effect of atorvastatin treatment on the progression of newly diagnosed type 1 diabetes suggested a slower decline of residual beta cell function with statin treatment. Aim of this secondary analysis was to identify patient subgroups which differ in the decline of beta cell function during treatment with atorvastatin. METHODOLOGY/PRINCIPAL FINDINGS The randomized placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and detectable islet autoantibodies (mean age 30 years, 40% females), in 12 centers in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. For this secondary analysis patients were stratified by single baseline characteristics which were considered to possibly be modified by atorvastatin treatment. Subgroups defined by age, sex or by baseline metabolic parameters like body mass index (BMI), total serum cholesterol or fasting C-peptide did not differ in C-peptide outcome after atorvastatin treatment. However, the subgroup defined by high (above median) baseline C-reactive protein (CRP) concentrations exhibited higher stimulated C-peptide secretion after statin treatment (p = 0.044). Individual baseline CRP levels correlated with C-peptide outcome in the statin group (r(2) = 0.3079, p<0.004). The subgroup with baseline CRP concentrations above median differed from the corresponding subgroup with lower CRP levels by higher median values of BMI, IL-6, IL-1RA, sICAM-1 and E-selectin. CONCLUSIONS/SIGNIFICANCE Atorvastatin treatment may be effective in slowing the decline of beta cell function in a patient subgroup defined by above median levels of CRP and other inflammation associated immune mediators. TRIAL REGISTRATION ClinicalTrials.gov NCT00974740.
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Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination.
Mulder, SF, Jacobs, JF, Olde Nordkamp, MA, Galama, JM, Desar, IM, Torensma, R, Teerenstra, S, Mulders, PF, Vissers, KC, Punt, CJ, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;(13):4541-9
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Abstract
PURPOSE The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib. PATIENTS AND METHODS Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines. RESULTS Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls. CONCLUSION We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib.
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Relationship of oxidized phospholipids and biomarkers of oxidized low-density lipoprotein with cardiovascular risk factors, inflammatory biomarkers, and effect of statin therapy in patients with acute coronary syndromes: Results from the MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering) trial.
Fraley, AE, Schwartz, GG, Olsson, AG, Kinlay, S, Szarek, M, Rifai, N, Libby, P, Ganz, P, Witztum, JL, Tsimikas, S, et al
Journal of the American College of Cardiology. 2009;(23):2186-96
Abstract
OBJECTIVES This study sought to define the relationship between oxidative biomarkers, cardiovascular disease (CVD) risk factors, and inflammatory and thrombosis biomarkers. BACKGROUND Elevated levels of oxidized phospholipids (OxPL) on apolipoprotein B particles (apoB) represent a novel biomarker of CVD. Previous studies suggest that an increase in OxPL/apoB reflects a positive response to statins and a low-fat diet. METHODS This study measured OxPL/apoB, lipoprotein (a) [Lp(a)], and oxidized low-density lipoprotein (OxLDL) biomarkers, consisting of immunoglobulin (Ig)G and IgM autoantibodies to malondialdehyde (MDA)-low-density lipoprotein (LDL) and IgG and IgM apoB-100 immune complexes (IC/apoB), at baseline and after 16 weeks of treatment with atorvastatin 80 mg/day or placebo in 2,342 patients with acute coronary syndromes (ACS) enrolled in the MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering) trial. RESULTS At baseline, potentially atheroprotective IgM autoantibodies and IgM IC/apoB were lower in male patients, diabetic patients, and patients >65 years of age. Patients with an LDL level greater than the median (122 mg/dl) had higher levels of OxPL/apoB, Lp(a), and OxLDL biomarkers compared with those who had an LDL level less than the median. Atorvastatin resulted in significantly larger changes in all biomarkers in female patients, patients age <65 years, patients with LDL cholesterol <122 mg/dl, nonsmokers, and nondiabetic patients (p < 0.0001 for all). In particular, a significant increase in OxPL/apoB in response to atorvastatin was noted in all 20 subgroups evaluated. Weak or no significant correlations were noted between all OxLDL biomarkers and C-reactive protein, serum amyloid A, tissue plasminogen activator, interleukin-6, intercellular adhesion molecule, vascular cell adhesion molecule, P-selectin, and E-selectin at randomization and 16 weeks. CONCLUSIONS In patients with ACS, baseline levels of oxidative biomarkers varied according to specific CVD risk factors and were largely independent of inflammatory biomarkers. Atorvastatin uniformly increased OxPL/apoB levels in all subgroups studied. Future studies are warranted to assess whether the increase in OxPL/apoB levels reflects the benefit of effective therapeutic interventions and prediction of new CVD events.
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Short- and long-term elevation of autoantibody titers against oxidized LDL in patients with acute coronary syndromes. Role of the lipoprotein-associated phospholipase A2 and the effect of atorvastatin treatment.
Papathanasiou, AI, Lourida, ES, Tsironis, LD, Goudevenos, JA, Tselepis, AD
Atherosclerosis. 2008;(1):289-297
Abstract
Oxidized low-density lipoprotein (oxLDL) is immunogenic while oxidized phospholipids (oxPL) formed on oxLDL and lysophosphatidylcholine (lyso-PC) generated during LDL oxidation through the hydrolysis of oxPL by the lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), significantly contribute to oxLDL immunogenicity. We determined the autoantibody titers against various forms of mildly oxLDL in patients with acute coronary syndromes without persistent elevation of the ST segment (NSTE-ACS) and with undetectable serum levels of lipoprotein (a). Moreover, the effect of early atorvastatin administration on these autoantibody titers was evaluated. From the 133 consecutive NSTE-ACS patients, 55 were eligible for the study. Thirty-four received atorvastatin (group A), whereas 21 did not received any hypolipidemic therapy (group B). Two forms of copper-oxidized LDL were prepared at the end of propagation or decomposition phase (oxLDL(P) or oxLDL(D), respectively). Similar types of oxLDL were prepared after previous inactivation of the endogenous Lp-PLA(2) [oxLDL(-)]. In group B, autoantibody titers of IgG class against oxLDL(P) and oxLDL(D) were elevated at 1 month of follow-up to reach the baseline values 3 months afterwards. By contrast the titers against oxLDL(-)(P) and oxLDL(-)(D) increased at 1 month of follow-up and remained elevated for up to 6 months of follow-up. Atorvastatin treatment prevented the elevation of autoantibody titers against all forms of oxidized LDL. We conclude that a short-term immune response against oxLDL(P) and oxLDL(D) (enriched in lyso-PC) and a chronic immune response against oxLDL(-)(P) and oxLDL(-)(D) (enriched in oxPL) are observed after an NSTE-ACS, suggesting an important role of the LDL-associated Lp-PLA(2) in modulating these immune responses. Early atorvastatin treatment prevents both immune responses; however, the clinical significance of this effect remains to be established.
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Short-term atorvastatin treatment enhances specific antibody production following tetanus toxoid vaccination in healthy volunteers.
Lee, PY, Scumpia, PO, Byars, JA, Kelly, KM, Zhuang, H, Shuster, JS, Theriaque, DW, Segal, MS, Reeves, WH, Brantly, ML
Vaccine. 2006;(19):4035-40
Abstract
Statins possess anti-inflammatory and immunomodulatory properties beyond their cholesterol-lowering effects. To determine whether short-term atorvastatin treatment affects the acute phase and humoral immune responses to tetanus toxoid (TT) in normal healthy volunteers, we conducted a randomized, double blind, placebo-controlled trial. Twenty healthy volunteers were assigned a 10-day treatment with atorvastatin (40 mg) or placebo. All volunteers received a TT booster on the fifth day. Subjects in the atorvastatin group had a significant reduction in total and low-density lipoprotein cholesterol (both p<0.001). Unexpectedly, the production of anti-TT antibodies (predominately IgG1) was three-fold higher in the atorvastatin group 15 days post-vaccination (2306 +/- 468 versus 713+/-21 units, p = 0.008). Atorvastatin also suppressed the post-vaccination rise in platelet and lymphocyte counts (both p<0.05). Acute phase parameters did not change significantly in either group. This study illustrates a novel immunomodulatory effect of atorvastatin raising the possibility of using HMG-CoA reductase inhibitors to enhance humoral responses to vaccination.
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The effects of atorvastatin on gluten-induced intestinal T cell responses in coeliac disease.
Ráki, M, Molberg, O, Tollefsen, S, Lundin, KE, Sollid, LM
Clinical and experimental immunology. 2005;(2):333-40
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Abstract
Various experimental models suggest that the cholesterol-lowering drugs statins may also modulate immune responses. Cellular level studies on human disorders are needed, however, to provide a rational basis for clinical testing of statins as immune therapy. Coeliac disease, a chronic small intestinal inflammation driven by HLA-DQ2 restricted mucosal T cells that are specific for ingested wheat gluten peptides, is in many ways ideal for this purpose. In addition, there is a need for alternative treatment to the gluten-free diet in this disorder. Here we have assessed the effects of atorvastatin on gluten-reactive T cells, dendritic cells and the coeliac mucosa by in vitro culture of biopsies. Atorvastatin inhibited gluten-induced proliferation and specific cytokine production of human intestinal gluten-reactive T cell clones and lines. Dendritic cells exposed to atorvastatin displayed a reduced expression of the costimulatory molecule CD83 upon maturation with lipopolysaccharide. Incubation of intestinal biopsy specimens with atorvastatin in vitro, however, did not influence gluten-induced cytokine release. In conclusion, atorvastatin has specific effects on isolated gluten-reactive T cells and dendritic cells, but does not shut down the gluten-induced production of proinflammatory cytokines in intestinal biopsies.
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Atorvastatin and simvastatin in patients on hemodialysis: effects on lipoproteins, C-reactive protein and in vivo oxidized LDL.
van den Akker, JM, Bredie, SJ, Diepenveen, SH, van Tits, LJ, Stalenhoef, AF, van Leusen, R
Journal of nephrology. 2003;(2):238-44
Abstract
BACKGROUND Cardiovascular disease as a result of accelerated atherogenesis is common in patients with end-stage renal disease (ESRD). Dyslipidemia may be a major contributor in this process and can be influenced by lipid-lowering drugs (statins). Moreover, statins may exhibit additional inhibitory effects on the atherogenesis, such as a modulation of the immune system as triggered by oxidatively modified LDL and a reduction of the inflammatory marker C-reactive protein (CRP). METHODS We evaluated in a single-blind randomized trial of 28 ESRD patients on hemodialysis, the dose-depending effects of both atorvastatin and simvastatin on lipids, lipoproteins, LDL particle heterogeneity, high sensitive-CRP, and markers of in vivo LDL oxidation. RESULTS Both statin therapies significantly lowered total plasma cholesterol and LDL-cholesterol concentrations to the same extent, whereas reduction in the concentrations of triglyceride-rich particles was less pronounced. Furthermore, statin therapy reduced LDL cholesterol in all LDL subfractions, without altering the overall LDL particle density. After both statins plasma hs-CRP concentrations were not significantly reduced; parameters of in vivo LDL oxidation (plasma ox-LDL concentration and the oxidation level of isolated LDL), were significantly decreased. Autoantibodies against ox-LDL, however, did not change during this trial period. CONCLUSIONS These results show that atorvastatin and simvastatin exhibit comparable favourable effects on lipid profiles in ESRD. Moreover, the reduction of in vivo oxidatively modified LDL as shown in this ESRD population, may indicate that these statins exhibit favourable effects on oxidative stress in vivo.
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Are early clinical effects of cholesterol lowering mediated through effects on inflammation?
Olsson, AG, Schwartz, GG, Jonasson, L, Linderfalk, C
Acta physiologica Scandinavica. 2002;(2):147-50
Abstract
In a randomized, double-blind trial in 3086 patients with unstable angina pectoris or non-Q wave myocardial infarction we investigated if 80 mg of atorvastatin daily could improve outcome of cardiovascular events during a short period of time (16 weeks) compared with placebo. Baseline LDL cholesterol was 3.2 mmol L-1 (124 mg dL-1) and decreased by 40% to 1.9 mmol L-1 (72 mg dL-1) during atorvastatin treatment. The primary endpoint, which was a composite of death, non-fatal acute myocardial infarction, cardiac arrest with resuscitation or recurrent symptomatic myocardial ischaemia with objective evidence and requiring emergency rehospitalization occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group. The relative risk was 0.84 and 95% confidence interval was 0.70-1.00 (P = 0.048). Thus for patients with acute coronary syndromes, lipid-lowering therapy with high dose atorvastatin reduces recurrent ischaemic events in the short-term. A possible mechanism behind this rapid clinical effect induced by statin treatment is on inflammatory processes. Recent studies strongly suggest that acute T-cell activation is involved in the pathogenesis of unstable angina. In another study we investigated whether circulating T cells showed signs of activation in patients with stable angina pectoris (SA). Systemic venous blood samples were taken from 38 men with SA and 42 healthy controls. The T-cell receptor expression was assessed by three-colour flow cytometry using monoclonal antibodies against CD3,CD4, CD8, CD25 and human leucocyte antigen (HLA)-DR. Soluble interleukin-2 receptor (sIL-2R) was measured as the circulating form in serum. Levels of circulating CD3+ and CD4+ T cells tended to be higher in patients compared with controls. Patients were also shown to have a significant increase in CD4+ T cells expressing the activation markers CD25 (P < 0.05) and HLA-DR (P < 0.01). Furthermore, serum levels of sIL-2R were significantly higher (P < 0.001) in patients than in controls. We also observed that the T-cell response was more pronounced in patients without simvastatin treatment (n = 18) compared with simvastatin-treated patients (n = 20). In conclusion, our findings indicate that a continuous immune system activation takes place in patients with chronic angina pectoris, predominantly involving proliferation of CD4+ T cells. Statin treatment seems to be able to decrease this inflammatory response.