(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Inflammation

Previously, we have shown that slightly to moderately aged arteries in middle-aged males can be rejuvenated functionally by sub-therapeutic, low-dose fluvastatin and valsartan treatment. Here, we explore whether this treatment could also increase telomerase activity. We hypothesized that telomerase activity might be associated with (1) an improvement of arterial wall properties and (2) a reduction of inflammatory/oxidative stress parameters (both observed in our previous studies).. The stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin and valsartan combination (10 and 20 mg), respectively, and placebo (control), were analyzed. The samples were taken before and after treatment lasting 30 days, and 5 months after treatment discontinuation. Telomerase activity was measured in blood leukocytes by a TaqMan Gene Expression Assay.. Low-dose fluvastatin or valsartan increased telomerase activity (106.9% and 59.5% respectively; both p < 0.05, vs. control), whereas their combination was even more effective (an increase of 228.0%; p < 0.001, vs. control). No change was noted in the control group. Importantly, increased telomerase activity obtained in the combination group significantly correlated with arterial function, measured by flow-mediated dilation (FMD) (r = 0.79; p < 0.001) and C-reactive protein concentration (r = -0.54; p = 0.02) and total anti-oxidative status (r = 0.50; p = 0.03).. We found that a low-dose combination of fluvastatin and valsartan substantially increased telomerase activity, which significantly correlated with an improvement of endothelial function and a decrease of inflammation/oxidative stress. These findings could lead to a new innovative approach to arterial rejuvenation.

Topics: Arteries; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Indoles; Inflammation; Leukocytes; Linear Models; Male; Middle Aged; Oxidative Stress; Rejuvenation; Telomerase; Valsartan

Although short-term graft survival has improved substantially in renal transplant recipients, long-term graft survival has not improved over the last decades. The lack of knowledge of specific causes and risk factors has hampered improvements in long-term allograft survival. There is an uncertainty if inflammation is associated with late graft loss.. We examined, in a large prospective trial, the inflammation markers high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) and their association with chronic graft dysfunction. We collected data from the Assessment of Lescol in Renal Transplant trial, which recruited 2102 maintenance renal transplant recipients.. Baseline values were hsCRP 3.8 ± 6.7 mg/L and IL-6 2.9 ± 1.9 pg/mL. Adjusted for traditional risk factors, hsCRP and IL-6 were independently associated with death-censored graft loss, the composite end points graft loss or death and doubling of serum creatinine, graft loss or death.. The inflammation markers hsCRP and IL-6 are associated with long-term graft outcomes in renal transplant recipients.

Topics: Adult; Anticholesteremic Agents; C-Reactive Protein; Creatinine; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Indoles; Inflammation; Interleukin-6; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Survival Rate; Transplantation, Homologous

P-selectin is an adhesion molecule that plays a role in the pathogenesis of atherosclerosis. The aim of this study was to assess whether or not the treatment with fluvastatin for 3 weeks preoperatively would reduce the levels of circulating P-selectin in patients with coronary heart disease undergoing coronary artery bypass grafting surgery (CABG).. Forty-six patients referred to CABG operation were included in the study. The patients were randomized into two groups (1:1): one treated with fluvastatin (80 mg/day, fluvastatin group, n = 23), and the other one treated with placebo (placebo group, n = 23) for three weeks before surgery. All patients underwent CABG using CPB. Blood samples were collected at baseline (the day before surgery), before and after aortic cross-clamping (ACC), at postoperative 0 h (the end of surgical intervention), and at 4, 12, and 24 hours postoperatively. Concentrations of soluble P-selectin (sP-selectin) were analyzed.. The sP-selectin values measured in the fluvastatin group were significantly lower than the values measured in the placebo group. There was less use of intraoperative inotropic agents in the fluvastatin group ( P < 0.015) and the difference in the length of ICU and hospital stay showed a significantly shorter stay for the fluvastatin group.. Pretreatment with fluvastatin seemed to reduce P-selectin levels compared to patients given placebo, and hence, we think that pretreatment with a statin, fluvastatin in our study, might reduce the perioperative cardiac injury caused by cardiopulmonary bypass-induced inflammatory changes. We believe that routine preoperative use of fluvastatin should be carefully considered.

Topics: Aged; Anti-Inflammatory Agents; Cardiopulmonary Bypass; Cardiotonic Agents; Coronary Artery Bypass; Coronary Disease; Critical Care; Down-Regulation; Drug Administration Schedule; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammation; Length of Stay; Male; Middle Aged; Myocardium; P-Selectin; Preoperative Care; Time Factors; Treatment Outcome

To investigate the effects of different doses of fluvastatin on serum levels of high-sensitive C-reactive protein (hs-CRP) and tumour necrosis factor-alpha (TNFalpha) in the early phase of acute coronary syndrome (ACS).. Fifty eight patients with ACS were randomly separated into three groups. 20 patients in group A were given routine therapy, 20 patients in group B were given routine therapy with oral fluvastatin 40 mg once daily for 1 week and 18 patients in group C received routine therapy with oral fluvastatin 80 mg once daily for 1 week. 20 patients with stable coronary heart disease served controls. The serum levels of hs-CRP and TNFalpha before and after therapy were measured with immunoturbidimetric assay and ELISA method.. (1) The serum levels of hs-CRP and TNFalpha in the patients with ACS were significantly higher than those in the control group (P < 0.05). (2) The serum levels of hs-CRP and TNFalpha significantly lowered after one week of therapy in the two fluvastatin treated groups (P < 0.01 in all), especially in the 80 mg fluvastatin group, while no significant difference was observed before and after treatment in the routine therapy group. (3) The serum levels of hs-CRP and TNFalpha had a significant positive correlation in the patients with ACS (r = 0.70, P < 0.01), but no relationship were observed between TC, TG, LDL-C, or HDL-C and hs-CRP or TNFalpha by Pearson correlation analysis.. The serum levels of inflammatory factors including CRP and TNFalpha are increased in patients with ACS and early fluvastatin intervention may decease dose-dependently the serum levels of hs-CRP and TNFalpha. The anti-inflammatory effect of fluvastatin may be beyond that of lipid lowering. Early intensive fluvastatin treatment may yield more significant benefits in the patients with ACS.

Topics: Adult; Aged; Aged, 80 and over; Anticholesteremic Agents; C-Reactive Protein; Coronary Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Indoles; Inflammation; Lipids; Male; Middle Aged; Tumor Necrosis Factor-alpha

Both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as well as peroxisome proliferator-activated receptor (PPAR)alpha activators (fibrates) proved to be effective in the primary and secondary prevention of cardiovascular diseases. The benefits of hypolipemic therapy in cardiovascular diseases cannot be explained only by the lipid-lowering potential of these agents. The aim of this study was to clarify the effect of hypolipemic agents on proinflammatory cytokine release from human monocytes in relationship with their action on plasma levels of sensitive systemic marker of low-grade vascular inflammation. Plasma lipid and high-sensitivity C-reactive protein (hsCRP) levels, and the release of tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta from monocytes were assessed at baseline and 30 and 90 days following randomization of IIa dyslipidemic patients into fluvastatin or simvastatin groups and randomization of type IIb dyslipidemic patients to the micronized form of either ciprofibrate or fenofibrate. Lipopolysaccharide-stimulated monocytes from dyslipidemic patients released significantly more TNFalpha (types IIa and IIb dyslipidemias) and interleukin-1beta (type IIa dyslipidemia) in comparison with monocytes in 59 age-, sex-, and weight-matched control subjects. Their baseline hsCRP levels were also higher. Both statins and fibrates reduced the release of TNFalpha and interleukin-1beta, and lowered plasma hsCRP levels. The effects of hypolipemic agents on cytokine release and plasma hsCRP were unrelated to their lipid-lowering action. Our results have demonstrated that type IIa and IIb dyslipidemic patients exhibit the abnormal pattern of TNFalpha and interleukin-1beta production by activated monocytes. Both HMG-CoA reductase inhibitors and PPARalpha activators normalize monocytic secretion of these cytokines, and this action may partially contribute to the systemic antiinflammatory effect of hypolipemic agents. The statin- and fibrate-induced suppression of proinflammatory cytokine release from monocytes seems to play a role in their beneficial effect on the incidence of cardiovascular events.

Topics: Adult; Anticholesteremic Agents; C-Reactive Protein; Clofibric Acid; Cytokines; Diabetes Mellitus, Type 2; Dyslipidemias; Fatty Acids, Monounsaturated; Female; Fibric Acids; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Inflammation; Interleukin-1; Male; Middle Aged; Monocytes; PPAR alpha; Tumor Necrosis Factor-alpha

Inflammation plays a key role in susceptibility to coronary atherosclerosis and response to therapy. A diverse array of factors modulates inflammation, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and CD14 receptors on the surface of macrophages. Genes encoding for inflammatory markers have variants that regulate their expression and are potential risk factors for atherosclerosis. We prospectively analyzed the possible association of CD14 -260C/T, TNF-alpha -308G/A, and IL-6 -174G/C variants, located in the promoter regions, with the severity, progression, and response to therapy of coronary atherosclerosis in a well-characterized cohort. We studied 375 subjects enrolled in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping. Fasting plasma lipids and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. Distributions of genotypes were--for CD14: 100 CC, 184 CT, and 86 TT; IL-6: 152 GG, 153 GC, and 62 CC; and TNF-alpha: 244 GG, 110 GA, and 17 AA. The CD14 CC genotype was associated with incidence of new coronary occlusion (P=0.026); TNF-alpha AA genotype with history of myocardial infarction (MI, P=0.04), and A allele with total occlusions at baseline (P=0.027), and systolic blood pressure (P=0.046); and IL-6-174 CC genotype with baseline minimum lumen diameter (P=0.043) and reduction in lipoprotein(a) with fluvastatin (P=0.03). Otherwise, no association between the genotypes and the biochemical, angiographic, and clinical phenotypes was detected, and neither were genotype-treatment interactions. Functional variants of CD14 -260C/T, TNF-alpha -308G/A, and IL-6 -174G/C, implicated in the susceptibility to infection, are unlikely to confer major risk for susceptibility to coronary atherosclerosis and its progression or response to therapy in the LCAS population.

Topics: Adult; Aged; Anticholesteremic Agents; Coronary Artery Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Genetic Predisposition to Disease; Humans; Indoles; Infections; Inflammation; Interleukin-6; Lipids; Lipopolysaccharide Receptors; Male; Middle Aged; Prospective Studies; Treatment Outcome; Tumor Necrosis Factor-alpha

Doxorubicin (DOXO) is a cytostatic agent used in the chemotherapy protocol of several cancers for more than 40 years, but usage of this drug in cancer treatment has been limited due to severe renal and cardiac tissue toxicities that may result in death in patients. Fluvastatin (FV) is a fully synthetic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor used as a cholesterol-lowering agent in patients with hypercholesterolemia. Previous studies revealed that FV also exhibits antioxidant, anti-inflammatory, and antitumor activity. Additionally, our previous study indicated that FV exerts a prophylactic effect on DOXO-induced testicular toxicity by preventing lipid peroxidation, supporting the antioxidant system, and regulating the blood-testis barrier-associated genes expression. Herein, we purposed to evaluate the possible therapeutic and the protective effects of FV on the DOXO-induced cardiac and renal toxicitiy model by histochemical, immunohistochemical, biochemical, and real-time polymerase chain reaction (real-time PCR) analyses. Results point out protective use of FV exerts a beneficial effect by repressing lipid peroxidation and by regulating the inducible nitric oxide synthase (iNOS), nitric oxide synthase endothelial (eNOS), nuclear factor kappa-B (NF-κB), and Caspase-3 (Casp3) protein and mRNA expressions, which play an important role in mediating DOXO-induced renal and cardiac toxicity mechanisms. In conclusion, FV may be a candidate agent for the prevention of renal and cardiac toxicities in cancer patients receiving DOXO chemotherapy.

Topics: Animals; Antioxidants; Apoptosis; Cardiotoxicity; Doxorubicin; Fluvastatin; Inflammation; Male; Oxidative Stress; Rats

Atherosclerosis is driven by a diverse range of cellular and molecular processes. In the present study, we sought to better understand how statins mitigate proatherogenic inflammation. 48 male New Zealand rabbits were divided into eight groups, each including 6 animals. The control groups received normal chow for 90 and 120 days. Three groups underwent a hypercholesterolemic diet (HCD) for 30, 60, and 90 days. Another three groups underwent HCD for 3 months, followed by normal chow for one month, with or without rosuvastatin or fluvastatin. The cytokine and chemokine expressions were assessed in the samples of thoracic and abdominal aorta. Rosuvastatin significantly reduced MYD88, CCL4, CCL20, CCR2, TNF-α, IFN-β, IL-1b, IL-2, IL-4, IL-8, and IL-10, both in the thoracic and abdominal aorta. Fluvastatin also downregulated MYD88, CCR2, IFN-β, IFN-γ, IL-1b, IL-2, IL-4, and IL-10 in both aortic segments. Rosuvastatin curtailed the expression of CCL4, IFN-β, IL-2, IL-4, and IL-10 more effectively than fluvastatin in both types of tissue. MYD88, TNF-α, IL-1b, and IL-8 showed a stronger downregulation with rosuvastatin compared to fluvastatin only in the thoracic aorta. The CCL20 and CCR2 levels reduced more extensively with rosuvastatin treatment only in abdominal aortic tissue. In conclusion, statin therapy can halt proatherogenic inflammation in hyperlipidemic animals. Rosuvastatin may be more effective in downregulating MYD88 in atherosclerotic thoracic aortas.

Topics: Animals; Aorta, Abdominal; Aortic Diseases; Atherosclerosis; Chemokines; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interleukin-10; Interleukin-2; Interleukin-4; Interleukin-8; Male; Myeloid Differentiation Factor 88; Rabbits; Rosuvastatin Calcium; Tumor Necrosis Factor-alpha

Statins are HMG-CoA reductase inhibitors prescribed for lowering cholesterol. They can also inhibit inflammatory responses by suppressing isoprenylation of small G proteins. Consistent with this, we previously found that fluvastatin suppresses IgE-mediated mast cell function. However, some studies have found that statins induced pro-inflammatory cytokines in macrophages and NK cells. In contrast to IgE signaling, we show that fluvastatin augments IL-33-induced TNF and IL-6 production by mast cells. This effect required the key mast cell growth factor, stem cell factor (SCF). Treatment of IL-33-activated mast cells with mevalonic acid or isoprenoids reduced fluvastatin effects, suggesting fluvastatin acts at least partly by reducing isoprenoid production. Fluvastatin also enhanced IL-33-induced NF-κB transcriptional activity and promoted neutrophilic peritonitis in vivo, a response requiring mast cell activation. Other statins tested did not enhance IL-33 responsiveness. Therefore, this work supports observations of unexpected pro-inflammatory effects of some statins and suggests mechanisms by which this may occur. Because statins are candidates for repurposing in inflammatory disorders, our work emphasizes the importance of understanding the pleiotropic and possible unexpected effects of these drugs.

Topics: Animals; Cells, Cultured; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunoglobulin E; Inflammation; Interleukin-33; Interleukin-6; Killer Cells, Natural; Macrophages; Mast Cells; Mevalonic Acid; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Peritonitis; Prenylation; Stem Cell Factor; Terpenes; Transcription Factor RelA; Transcription, Genetic; Tumor Necrosis Factor-alpha

A high-cholesterol diet (HCD) induces vascular atherosclerosis through vascular inflammatory and immunological processes via TLRs. The aim of this study is to investigate the mRNA expression of TLRs and other noxious biomarkers expressing inflammation, fibrosis, apoptosis, and cardiac dysfunction in the rabbit myocardium during (a) high-cholesterol diet (HCD), (b) normal diet resumption and (c) fluvastatin or rosuvastatin treatment.. mRNA of TLRs 2, 3, 4 and 8; interleukin-6; TNF-a; metalloproteinase-2; tissue inhibitor of metalloproteinase-1; tumor protein 53; cysteinyl aspartate specific proteinase-3; and brain natriuretic peptide (BNP) increased in HCD. Statins but not resumption of a normal diet decreased levels of these biomarkers and increased levels of antifibrotic factors.. HCD increases the levels of TLRs; inflammatory, fibrotic and apoptotic factors; and BNP in the rabbit myocardium. Atherogenic diets adversely affect the myocardium at a molecular level and are reversed by statins.

Topics: Animals; Cholesterol, Dietary; Disease Models, Animal; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Inflammation; Interleukin-6; Male; Myocardium; Rabbits; Rosuvastatin Calcium; Toll-Like Receptors; Tumor Necrosis Factor-alpha

The pleiotropic effects of statins, including an antiarthritic potential, have been noted. This study aimed to determine the efficacy of statins on rheumatoid arthritis (RA) and clarify how statins affect its pathogenesis. Fluvastatin (500 μg/kg/day) or vehicle was given per os to env-pX rats, which carry the human T-cell leukemia virus type I env-pX gene and spontaneously develop destructive arthritis mimicking RA, for 30 days. Blood sampling and ultrasonography (US) of the ankle joints were conducted on days 0, 10, 20, and 30. On day 30, all rats were euthanized, and the ankle joints were subjected to histological analysis. To clarify how fluvastatin affects the pathogenesis of RA, comprehensive serum exosomal microRNA (miRNA) analysis was performed. Gene expression in the primary culture of synovial fibroblasts derived from arthritic rat and human and non-arthritic rat periarticular tissues was determined quantitatively by real-time reverse transcription-polymerase chain reaction (RT-PCR). As a result, the development of arthritis in env-pX rats was significantly suppressed by fluvastatin, which was evident from the viewpoints of serology, US imaging, and histology. Comprehensive serum exosomal miRNA analysis suggested that the expression of Rho GTPase-activating protein 12 (Arhgap12) was decreased in arthritic env-pX rats but increased with the administration of fluvastatin. Corresponding results were obtained by quantitative RT- PCR using primary culture of synovial fibroblasts. The collective findings suggest that fluvastatin prevents the development of arthritis in env-pX rats via the up-regulation of ARHGAP12. This study suggests that ARHGAP12 can be a possible therapeutic target of RA.

Topics: Animals; Arthritis, Experimental; Exosomes; Fibroblasts; Fluvastatin; GTPase-Activating Proteins; Humans; Inflammation; Joints; Male; MicroRNAs; Rats; RNA, Messenger; Synovial Membrane; Up-Regulation

Previously we revealed the effectiveness of a new therapeutic approach with a short-term, very-low dose fluvastatin-valsartan combination on the improvement of arterial function in type 1 diabetes mellitus patients (T1DM). In this study we explored whether this approach influences inflammation and oxidative stress and explored any association of these effects with arterial function improvement.. This was a supplementary analysis of the two previous double blind randomized studies (included 44 T1DM patients). Treatment group received very-low dose fluvastatin-valsartan, the control group received placebo. Blood samples were collected and inflammation parameters: high-sensitivity CRP (hsCRP), interleukin 6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1) and oxidative stress parameter total antioxidant status (TAS) were measured.. Treatment decreased hsCRP values (by 56.5%, P<0.05) and IL-6 values (by 33.6%, P<0.05) and increased TAS values (by 21.1%; P<0.05) after 30days of treatment. High sensitivity CRP and TAS remained decreased 3months after treatment discontinuation. Importantly, the anti-inflammatory and anti-oxidative action significantly correlated with arterial function improvement.. The approach consisting of short-term (30days) treatment with a very low-dose fluvastatin-valsartan combination acts anti-inflammatory and anti-oxidative in T1DM patients. These observations along with the improvement of arterial function support the assumption that this approach could have an important clinical benefit in T1DM patients.

Topics: Adult; Diabetes Mellitus, Type 1; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammation; Male; Oxidative Stress; Valsartan

Topics: Anti-Inflammatory Agents; Antioxidants; Atorvastatin; Cell Proliferation; Chronic Disease; Dinoprostone; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammation; Interleukin-1beta; Lipids; Lipopolysaccharides; Microglia; Monocytes; Nitric Oxide; Pravastatin; Quinolines; Reactive Oxygen Species; Rosuvastatin Calcium; Simvastatin; THP-1 Cells; Tumor Necrosis Factor-alpha

Cardiovascular disease (CVD) is a major problem during rheumatoid arthritis which leads to morbidity and mortality in arthritic patients. So the present study emphasizes combinatorial effect of Betulinic acid, a triterpenoid and fluvastatin, an HMG CoA reductase inhibitor on atherogenesis during arthritis. Arthritis was induced by bovine type II collagen dissolved in 0.01M acetic acid at a concentration of 4mg/mL and emulsified in equal volume of incomplete Freund's adjuvant. Betulinic acid (2mg/kg) and fluvastatin (5mg/kg) alone and in combination was administered orally from day 14 to 60. At the end of 60days, tissues and blood were isolated for evaluation of biochemical parameters. Treatment with betulinic acid and fluvastatin showed significant (p<0.05) reduction in Arthritic index, Rheumatoid factor, C-reactive protein (CRP), total lipids and anti-CCP (cyclic citrullinated peptide) antibody. Anti-inflammatory enzyme activities and oxidative stress were significantly decreased in the peripheral blood mononuclear cells by the administration of both betulinic acid and fluvastatin than alone treatments. Combination therapy was found to be a potential enhancer of the expression of anti-inflammatory cytokine interleukin-10 whereas it significantly blocked the expression of Toll-like receptors-2 and 4, inflammatory markers such as interleukin-1β, tumor necrosis factor-α, Interferon-γ, cell adhesion molecules and nuclear translocation of NF-kappa B in aorta than drug alone treated groups. So the present study summarizes a combination therapy of betulinic acid and fluvastatin that reduces the risk of both rheumatoid arthritis and CVD by modulating the expression of various inflammatory mediators through Toll-like receptors-4-NF-κB downstream signaling pathway, atherogenic index and oxidative stress in collagen induced arthritis.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Atherosclerosis; Betulinic Acid; C-Reactive Protein; Collagen Type II; Fatty Acids, Monounsaturated; Female; Fluvastatin; Indoles; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-1beta; Leukocytes, Mononuclear; NF-kappa B; Pentacyclic Triterpenes; Rats; Rats, Sprague-Dawley; Toll-Like Receptor 4; Triterpenes; Tumor Necrosis Factor-alpha

Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been shown to ameliorate a number of vascular diseases. We evaluated the inflammatory and angiogenic components of the fibrovascular tissue induced by subcutaneous implants in mice and their modulation by fluvastatin. Our results showed that the statin (0.6 and 6 mg/kg/day) inhibited hemoglobin (Hb) content (51%) and vascular endothelial growth factor (VEGF) levels (71%) in the treated group compared with the control group. The inflammatory component, as assessed by N-acetyl-β-D-glucosaminidase activity and tumor necrosis factor-α (TNF-α) level was also decreased by the compound. In the treated group; the inhibition of the enzyme activity was 33% and the cytokine was 67% relative to the control. In these implants the statin was also able to decrease nitric oxide (NO) production, detected with an NO-sensitive electrode. To our knowledge this is the first study demonstrating an inhibitory role of fluvastatin on the production of NO in inflammatory angiogenesis of newly formed fibrovascular tissue.

Topics: Acetylglucosaminidase; Animals; Chemokine CCL2; Cholesterol; Fatty Acids, Monounsaturated; Fluvastatin; Hemoglobins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammation; Leukocytes; Lipase; Male; Mice; Neovascularization, Pathologic; Nitric Oxide; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

To investigate whether the combination of fluvastatin and losartan synergistically relieve atherosclerosis and plaque inflammation induced by a high-cholesterol diet in rabbits.. Atherosclerosis was induced with a high-cholesterol diet for 3 months in 36 New Zealand white rabbits. The animals were randomly divided into model group, fluvastatin (10 mg·kg(-1)·d(-1)) group, losartan (25 mg·kg(-1)·d(-1)) group, and fluvastatin plus losartan group. After the 16-week treatments, the blood samples the animals were collected, and the thoracic aortas were examined immunohistochemically. The mRNA and protein expression levels of monocyte chemotactic protein-1 (MCP-1) were measured using RT-PCR and Western blot.. Compared to the treatment with losartan or fluvastatin alone, the combined treatment did not produce higher efficacy in reduction of blood cholesterol level. However, the combination did synergistically decrease the intimal and media thickness of thoracic aortas with significantly reduced macrophage infiltration and MCP-1 expression in the plaques.. The combined treatment with losartan and fluvastatin significantly inhibited atherosclerotic progress and reduced inflammation associated with atherosclerotic plaques.

Topics: Animals; Atherosclerosis; Chemokine CCL2; Cholesterol; Drug Synergism; Fatty Acids, Monounsaturated; Fluvastatin; Gene Expression Regulation; Indoles; Inflammation; Losartan; Macrophages; p38 Mitogen-Activated Protein Kinases; Plaque, Atherosclerotic; Rabbits

Inflammation plays an important role in the pathogenesis of metabolic syndrome (MS). We investigated the effect of fluvastatin treatment on inflammatory markers in patients with MS.. The study included 47 patients (36 females; 11 males; mean age 55+/-8 years) with MS. The diagnosis of MS was based on the presence of at least three criteria of the NCEP ATP III guidelines. All the patients received 80 mg fluvastatin treatment for six weeks. Laboratory parameters were measured before and after treatment, and flow cytometric analysis of peripheral blood leukocytes was performed. The results were compared with those of 47 age- and sex-matched healthy controls (33 females, 14 males; mean age 52+/-8 years).. Fluvastatin treatment resulted in significant decreases in levels of total cholesterol, LDL cholesterol, triglyceride (p<0.005), and C-reactive protein (p<0.05). Thirty-three patients (70.2%) had insulin resistance, which remained unchanged following treatment. Flow cytometric analysis after treatment showed significant decreases in total lymphocytes, and in surface antigens of CD16+56 and CD8+(CD28+) on leukocytes, CD11c on granulocytes, and a significant increase in the CD4/CD8 ratio (p<0.05). Compared to the control group, the mean baseline values of fluorescence density (FD) of CD14, CD11b, CD11c, and CD63 on monocytes, and CD11b and CD11c on granulocytes were significantly higher in patients with MS (p<0.05). Following fluvastatin treatment, there were significant decreases in the mean FD of CD3 on lymphocytes, and of CD11b and CD11c on both monocytes and granulocytes (p<0.05); of these, all FD values were similar to those in the control group (p>0.05).. Our data demonstrate that inflammation may have a significant role in the pathogenesis of MS and that this effect can be controlled with statin treatment.

Topics: Antigens, CD; Biomarkers; C-Reactive Protein; Cholesterol; Cholesterol, LDL; Fatty Acids, Monounsaturated; Female; Flow Cytometry; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammation; Insulin Resistance; Lymphocyte Count; Male; Metabolic Syndrome; Middle Aged; Triglycerides

Although it has been demonstrated that statins stabilize atherosclerotic lesions in animal models of advanced atherosclerosis, there is little evidence to suggest that statins have a preventive effect on plaque rupture itself. In the present study, we examined the effect of fluvastatin on plaque disruption using a simple and quick method of plaque disruption in carotid artery lesions in apolipoprotein E-deficient mice. Male apolipoprotein E-deficient mice received normal chow and underwent ligation of the left common carotid artery just proximal to its bifurcation. Four weeks later, a polyethylene cuff was placed around the artery immediately proximal to the ligation site. Fluvastatin (10mg/kg per day) was given by oral gavage every day starting at 3 days before cuff placement. The administration of fluvastatin suppressed atherosclerotic plaque disruption accompanied by luminal thrombi by 31.5% compared with controls at 4 days after the cuff was placed at the ligated carotid artery. Fluvastatin administration decreased matrix metalloproteinase-9 expression, gelatinolytic activity, endothelial adhesion molecules expression and neutrophil infiltration, and increased type I collagen content in the cuffed region. In summary, fluvastatin was found to prevent plaque disruption through pleiotropic effect on acute inflammation in an animal model using apolipoprotein E-deficient mice.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Carotid Stenosis; Disease Models, Animal; Fatty Acids, Monounsaturated; Fluvastatin; Gene Expression; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammation; Male; Matrix Metalloproteinase 9; Mice; Mice, Knockout

Topics: Animals; Atherosclerosis; Fatty Acids, Monounsaturated; Fibrinolysis; Fluvastatin; Hemorrhage; Indoles; Inflammation; Matrix Metalloproteinase 9; Mice

The presence of antiphospholipid antibodies (APLA) is associated with an increased risk of recurrent thrombosis and pregnancy loss. APLA are able to activate endothelial cells (EC) and induce an increase in the expression of inflammatory marker proteins, such as leukocyte adhesion molecules, tissue factor or the monocyte chemoattractant protein-1 (MCP-1). Our objective was to investigate the effect of statins on EC activation induced by APLA in vitro. IgG was purified from the plasma of six patients with APLA and from healthy controls. EC were incubated with patient IgG or with control IgG, in the presence or absence of 5microM of fluvastatin, and expression of the leukocyte adhesion molecules, VCAM-1 and E-selectin, analyzed by flow cytometry and by quantitative reverse transcriptase-PCR (QRT-PCR). The expression of tissue factor and the chemokine MCP-1 was analyzed by QRT-PCR alone. Incubation of EC with patient IgG increased the expression of VCAM-1, E-selectin, tissue factor and MCP-1. Prior treatment of the cells with fluvastatin further increased the expression of these proteins. The fluvastatin effect was reversed by co-incubation with mevalonate or geranylgeranylpyrophosphate and mimicked by the geranylgeranyl transferase inhibitor GGTI-286. Our results show that in cultured human EC, statins increase the extent of inflammatory activation induced by APLA. This effect appears to be mediated by an inhibitory effect of statins on one or more geranylgeranylated protein(s).

Topics: Adolescent; Adult; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Cell Adhesion Molecules; Cells, Cultured; Chemokine CCL2; Endothelium, Vascular; Fatty Acids, Monounsaturated; Female; Fluvastatin; Gene Expression Regulation; Humans; Immunoglobulin G; Indoles; Inflammation; Male; Middle Aged; Thromboplastin; Umbilical Cord

Hemodialysis (HD) patients are frequently in an elevated inflammatory state which is correlated to the atherosclerosis-related and overall morbidity and mortality in this population. Statins, beyond their antilipidemic effects, are also considered to have anti-inflammatory, immunomodulating and antioxidant properties. The individual response of HD patients to a short course of fluvastatin, the mechanisms involved in the immunomodulating and anti-inflammatory effects of this drug and the time interval to the appearance of these effects are investigated in this longitudinal study.. In a group of 51 HD patients, fluvastatin 40 mg/day was administered for 4 weeks. Serial measurements of the lipid profile, C-reactive protein (CRP), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), interleukin-10 (IL-10), and serum oxidized LDL (ox-LDL), were performed before, during, and after the treatment period.. Total cholesterol was significantly reduced after 14 days of treatment with fluvastatin (from mean +/- SD 216.7 +/- 34.3 to 179.2 +/- 42.3 mg/dl, p < 0.001). IL-6 and ox-LDL were reduced on day 28 (p < 0.001 and p < 0.01, respectively) and IL-10 was increased on day 14 (p = 0.05); CRP did not change significantly during the treatment period while sIL-6R was increased on day 28 of fluvastatin administration (p < 0.05). In a subgroup of patients with CRP, IL-6, sIL-6R, and ox-LDL baseline serum values > or = the median and IL-10 < or = the median, CRP was reduced on day 28 of fluvastatin treatment (p < 0.01), IL-6 and ox-LDL were reduced earlier, on day 14 (p = 0.05 and p < 0.05, respectively) while sIL-6R did not change significantly during the treatment period.. Treatment with fluvastatin rapidly modulates inflammation in HD patients. Enhancement of anti-inflammatory mechanisms and attenuation of the inflammatory and oxidative state contribute to this modulation. Patients in an elevated baseline inflammatory state respond more rapidly and effectively to the treatment. This immediate and multi-potent action of the statins could be clinically useful in acute atherosclerosis complications or in the treatment of chronic inflammation in HD patients.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; C-Reactive Protein; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Indoles; Inflammation; Interleukin-10; Interleukin-6; Kidney Failure, Chronic; Lipids; Lipoproteins, LDL; Longitudinal Studies; Male; Middle Aged; Oxidation-Reduction; Receptors, Interleukin-6; Renal Dialysis; Time Factors