Lipophilic statins suppress cytotoxicity by freshly isolated natural killer cells through modulation of granule exocytosis

NK cells, a component of the innate immune system, provide a first line of defense against viral infections and malignancies, interact with the adaptive immune system and have a role in rejection of allogeneic bone marrow transplants and solid allo- and xenotransplants. Immunoregulatory activity by the anti-hypercholesterolemia agents, 3-hydroxy-3-methyl-glutaryl Coenzyme A (HMG-CoA) reductase inhibitors, known as statins, has recently been reported. We analyzed the effects of three statins on human NK cell cytotoxicity. Two lipophilic statins (simvastatin and fluvastatin) suppressed the cytotoxic activity of fresh and IL-2-stimulated NK cells, while pravastatin, a hydrophilic statin, did not. Suppression was not associated with changes in intracellular perforin, granzyme A or granzyme B levels, or with changes in expression of leukocyte function-associated antigen-1, an integrin known to regulate NK activity and reported to be altered by statin treatment. Decreased cytotoxicity was associated with decreased CD107a surface expression, indicating that the exocytosis pathway was compromised by simvastatin and fluvastatin but not by pravastatin. Mevalonate, the immediate downstream product of HMG-CoA reductase, partially reversed the effect of lipophilic statins on cytotoxicity and CD107a expression. Lipophilic statins also suppressed the release of the granule component, granzyme B, by IL-2-activated NK cells following stimulation with K562. That lipophilic statins suppress NK cell activity through inhibition of the exocytosis pathway suggest an additional potential role for statins in inhibition of transplantation responses.     

Rosuvastatin: characterization of induced myopathy in the rat

Rosuvastatin is a relatively new member of the statin family (HMG-CoA reductase inhibitors), with superior lipid-lowering effects and a pattern of clinical side effects, including a low incidence of myopathy, similar to other widely prescribed statins. This article describes investigations of myopathy in the rat following administration of very high doses of rosuvastatin. The nature of the changes were found to be entirely consistent with those seen with other statins, including a differential sensitivity of muscle fibers (with glycolytic fibers [type IIB] the most sensitive and oxidative fibers [type I] the least), a delay of approximately 10 days after the start of oral dosing before necrosis was apparent, and ultrastructural alterations appearing first in mitochondria. In addition, the development of myopathy was prevented by coadministration of mevalonate, the product of HMG-CoA reductase. The findings illustrate a pattern of induced myopathy in the rat directly attributable to inhibition of HMG-CoA reductase that is entirely consistent between the various statins, with the oral dose required to produce the changes being a differentiating feature (based on these new data and a previously reported study from the same laboratory): cerivastatin dose less than simvastatin, and simvastatin dose less than rosuvastatin.     

Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on ageing: Molecular mechanisms

Human ageing is determined by degenerative alterations and processes with different manifestations such as gradual organ dysfunction, tissue function loss, increased population of aged (senescent) cells, incapability of maintaining homeostasis and reduced repair capacity, which collectively lead to an increased risk of diseases and death. The inhibitors of HMG-CoA reductase (statins) are the most widely used lipid-lowering agents, which can reduce cardiovascular morbidity and mortality. Accumulating evidence has documented several pleiotropic effects of statins in addition to their lipid-lowering properties. Recently, several studies have highlighted that statins may have the potential to delay the ageing process and inhibit the onset of senescence. In this review, we focused on the anti-ageing mechanisms of statin drugs and their effects on cardiovascular and non-cardiovascular diseases.     

Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death

Statins are inhibitors of HMG-CoA reductase that have been recently recognized as anti-inflammatory and neuroprotective drugs. Herein, we investigated anti-excitotoxic and anti-seizure effects of statins by using kainic acid (KA)-rat seizure model, an animal model for temporal lobe epilepsy and excitotoxic neurodegeneration. We observed that pre-treatment with Lipitor (atorvastatin) efficiently reduced KA-induced seizure activities, hippocampal neuron death, monocyte infiltration and proinflammatory gene expression. In addition, we also observed that lovastatin treatment attenuated KA- or glutamate-induced excitotoxicity of cultured hippocampal neurons. These observations suggest a potential for use of statin treatment in modulation of seizures and other neurological diseases associated with excitotoxicity.     

Antiinflammatory and immunomodulatory properties of statins

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase or statins constitute the most powerful class of lipid lowering drugs, widely used in medical practice. During the past several years additional actions of statins unrelated to cholesterol reduction have been identified which includes antiinflammatory and immunomodulatory properties. Since atherosclerosis is a form of inflammation and the immune system play an important role in its pathogenesis, pleiotropic effect of statins may provide complementary explanation to their clinical benefit. This article reviews the data regarding the antiinflammatory and immunomodulatory properties of the statins that are available in the treatment of atherosclerosis and possibly may be applicable in other inflammatory diseases or conditions with the involvement of the immune system.     

Statin therapy reduces serum levels of glycosylphosphatidylinositol-specific phospholipase D

Statin therapy is associated with changes in low-density, very low-density, and high- density lipoprotein metabolism. The effect of statin therapy on a minor high-density lipoprotein particle containing glycosylphosphatidylinositol-specific phospholipase D has not been examined. Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) has been implicated in triglyceride metabolism. A double-blind, crossover design comparing the effect of simvastatin (80 mg) and atorvastatin (80 mg) on serum lipid and glycosylphosphatidylinositol-specific phospholipase D levels was conducted in 13 patients with low high-density lipoproteins. Both statins reduced cholesterol, triglycerides, and apolipoprotein B and significantly lowered serum glycosylphosphatidylinositol-specific phospholipase D levels (16%). This statin effect seems to occur in the plasma compartment as neither statin altered GPI-PLD mRNA levels in HepG2 cells. Serum glycosylphosphatidylinositol-specific phospholipase D levels are regulated by statins and may represent an additional biochemical mechanism for affecting serum triglyceride levels.     

Statins and autoimmune diseases

Inhibitors of 3-hydroxy-3methylglytaryl coenzyme A (HMG-CoA) reductase or statins are effective lipid lowering drugs widely used in cardiovascular disease. In the recent years, pleotropic effects of statins have been reported, which include anti-inflammatory and immunomodulatory properties. This review discusses the anti-inflammatory and immunomodulatory roles of statins and their possible use for the treatment of other inflammatory diseases or conditions with the involvement of the immune system.     

Simvastatin inhibits interferon-γ-induced MHC class II up-regulation in cultured astrocytes

Based on their potent anti-inflammatory properties and a preliminary clinical trial, statins (HMG-CoA reductase inhibitors) are being studied as possible candidates for multiple sclerosis (MS) therapy. The pathogenesis of MS is unclear. One theory suggests that the development of autoimmune lesions in the central nervous system may be due to a failure of endogenous inhibitory control of MHC class II expression on astrocytes, allowing these cells to adapt an interferon (IFN)-γ-induced antigen presenting phenotype. By using immunocytochemistry in cultured astrocytes derived from newborn Wistar rats we found that simvastatin at nanomolar concentrations inhibited, in a dose-response fashion, up to 70% of IFN-γ-induced MHC class II expression. This effect was reversed by the HMG-CoA reductase product mevalonate. Suppression of the antigen presenting function of astrocytes might contribute to the beneficial effects of statins in MS.     

Statins may enhance the proteolytic cleavage of proBDNF: implications for the treatment of depression

The family of hydroxymethylglutaryl coenzyme A reductase inhibitors, collectively known as statins, are used clinically to reduce plasma cholesterol levels. Recent reports indicate that statin therapy is associated with a reduced risk of depression, although the mechanism underlying this antidepressant effect is unknown. Evidence suggests that increasing central BDNF activity plays an important role in the treatment of major depression. In the nervous system, the proteolytic cleavage of pro-BDNF, a BDNF precursor, to BDNF through the tissue-type plasminogen activator (tPA)-plasmin pathway represents one mechanism that can regulate the action of BDNF. In vitro studies have demonstrated that statins can induce tPA and inhibit plasminogen activator inhibitor-1, the major inhibitor of tPA. It is therefore possible that statins could act through the tPA-plasminogen pathway to increase BDNF and achieve an antidepressant effect. It is suggested that statins could be of therapeutic potential for patients with major depression: especially those that have an abnormality in the tPA-plasminogen pathway or comorbidities relating to cardiovascular disease. Furthermore, BDNF dysfunction has also been implicated in several other neuropsychiatric diseases, such as Alzheimer's disease, attention-deficit hyperactivity disorder and Rett syndrome. The potential use of statins in these diseases may warrant further exploration.     

Action profiles of statins and calcineurin inhibitors during human mixed lymphocyte reaction

The cell-to-cell interaction through binding intercellular adhesion molecule (ICAM)-1 and CD40 on monocytes and their ligands such as lymphocyte function-associated antigen (LFA)-1 and CD40 ligand (CD40L) on T-cells plays roles in cytokine production and T-cell proliferation. Interleukin (IL)-18, which is elevated in the plasma during acute rejection after organ transplantation, induces the expression of ICAM-1 and CD40 on monocytes, the production of interferon (IFN)-gamma and IL-12 and the proliferation of T-cells during the human mixed lymphocyte reaction (MLR). In addition to the cholesterol lowering effect, statins improve patient survival and decrease rejection episodes in transplant recipients. In the present study, we investigated the difference of effect of statins and calcineurin inhibitors during MLR. 3-Hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, fluvastatin and pravastatin and statin-derived LFA-1 inhibitors, LFA703 and LFA878, which did not inhibit HMG-CoA reductase, suppressed the production of IFN-gamma and IL-12 and the lymphocyte proliferation as well as the expression of ICAM-1 and CD40 on monocytes regardless of the presence of IL-18. However, the calcineurin inhibitors, tacrolimus and cyclosporine A (CsA), inhibited the IL-18-enhanced cytokine production and lymphocyte proliferation without any effect on the adhesion molecule expression. Thus, the action mechanism of stain is different from that of calcineurin inhibitors.     

Atorvastatin suppresses interferon-gamma -induced neopterin formation and tryptophan degradation in human peripheral blood mononuclear cells and in monocytic cell lines

Inhibitors of 3-hydroxy-3methylglutaryl-co-enzyme A (HMG-CoA) reductase, so-called statins, are used in medical practice because of their lipid-lowering effect and to reduce the risk of coronary heart disease. Recent findings indicate that statins also have anti-inflammatory properties and can modulate the immune response. In vitro, we investigated the effect of atorvastatin on the T cell/macrophage system in peripheral blood mononuclear cells (PBMC) and in the human monocytic cell lines THP-1 and MonoMac6. We monitored neopterin production and tryptophan degradation in PBMC after treatment with 10 micro m and 100 micro m atorvastatin in the presence or absence of 100 U/ml IFN-gamma, 10 micro g/ml phytohaemagglutinin (PHA) or 10 micro g/ml concanavalin A (ConA) and in monocytic cell lines THP-1 and MonoMac6 with or without stimulation with 100 U/ml IFN-gamma or 10 ng/ml to 1 micro g/ml lipopolysaccharide (LPS). In stimulated PBMC 100 micro m atorvastatin inhibited neopterin formation and tryptophan degradation completely, whereas 10 micro m atorvastatin was only partially effective. Also in monocytic cell lines THP-1 and MonoMac6, atorvastatin was able to suppress IFN-gamma- and LPS-induced formation of neopterin and degradation of tryptophan. Our data from PBMC agree well with previous investigations that statins inhibit T cell activation within the cellular immune response. In addition we demonstrate that atorvastatin directly inhibits IFN-gamma-mediated pathways in monocytic cells, suggesting that both immunoreactivity of T cells and of monocyte-derived macrophages are down-regulated by this statin.     

Comparison of hydrophobic surfactant and cholestyramine on lipid and sterol balance in the rat

The effects of dietary supplement with hydrophobic surfactant, Pluronic L-81, on sterol and lipid metabolism in rats consuming a high-fat high-cholesterol diet was determined. Results were compared both to rats on the high-fat high-cholesterol diet alone and to other rats on a similar diet supplemented with cholestyramine. All treatment programs were well tolerated. Pluronic L-81 therapy produced reductions of plasma and hepatic cholesterol levels compared to rats on the diet alone. Additionally, plasma triglycerides were reduced. These changes were associated with relatively high fecal outputs of neutral steroids but acidic steroid excretion was less than observed for rats on diet alone. No malabsorption of neutral lipid was observed for detergent-treated rats. Cholestyramine was also effective in limiting hepatic cholesterol accumulation. Fecal losses of both neutral and acidic steroids were greater in this group compared to rats on diet alone. This was associated with a marked increase of hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity in the cholestyramine-treated group. Both types of treatment limit cholesterol accumulation in rats on a high cholesterol diet. Pluronic L-81 treatment, however, does not significantly increase endogenous cholesterol synthesis while it is greatly increased in response to cholestyramine as reflected by hepatic activities of HMG-CoA reductase.     

Attenuated T-Lymphocyte Response to HIV Therapy in Individuals Receiving HMG-CoA Reductase Inhibitors

Abstract

Purpose: The protease inhibitor class of antiretroviral agents is associated with the unwanted side effect of hypertriglyceridemia, which is usually treated with either HMG-CoA reductase inhibitors (statins) or fibrates. However, since statin therapy is intrinsically immunomodulatory, we questioned whether the T-cell response of patients who received PI-based therapy plus statin differed from the response of patients on PI therapy alone or on PI therapy with a fibrate. Method: Retrospective cohort study. Results: Thirty-five patients who had received ritonavir/saquinavir (R/S)-based antiretroviral therapy for 5 or more years were evaluated and stratified into four treatment groups: patients on R/S alone (n = 9), patients on R/S and stavudine/lamivudine (d4T/3TC) (n = 10), patients on R/S with or without d4T/3TC and statin (n = 11), or patients on R/S with or without d4T/3TC and fibrate (n = 5). All patients had suppressed levels of viral replication at all time points. T-cell responses were similar in all four groups before they were exposed to lipid-lowering agents. After the addition of lipid-lowering agents, absolute CD4 T-cell responses were lower in the statin group than in all other groups (p < .05), when measured after 6, 12, and 18 months of treatment. Conclusion: These data suggest that T-cell responses are influenced by the choice of anti-lipid agent and suggest that a prospective comparison is needed to determine the clinical relevance of these findings.     

Stimulatory effects of statins on bone marrow-derived mesenchymal stem cells. Study of a new therapeutic agent for fracture

Recent studies have reported that statins, inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, increase bone formation in osteoblasts in vitro, suggesting that statins may have a new therapeutic application in the treatment of osteoporosis. During the reparative phase of healing of bone fractures, bone marrow-derived mesenchymal stem cells differentiate into osteoblasts or chondrocytes to form callus. If statins also stimulate bone formation in bone marrow-derived mesenchymal stem cells they may have beneficial effects in the treatment of bone fractures. In this study, we assessed the effect of statins on bone formation in rat bone marrow-derived mesenchymal stem cells in vitro. The statins fluvastatin, simvastatin and pravastatin did not significantly enhance mineralization, alkaline phosphatase (ALP) activity and bone gra protein (BGP, osteocalcin). These findings suggest that statins do not increase bone formation in bone marrow-derived mesenchymal stem cells.     

Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study

Efavirenz (EFV) is associated with hyperlipidemia when used in combination with other antiretroviral drugs. EFV is a mixed inducer/inhibitor of cytochrome P450 (CYP) 3A4 isozyme and may interact with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are primarily metabolized via CYP3A4. To assess the drug-drug interaction of EFV used in combination with simvastatin (SIM), atorvastatin (ATR), or pravastatin (PRA), an open-label trial was conducted in 52 healthy adult HIV-seronegative subjects across AIDS Clinical Trials Group sites in the United States. Subjects received 40 mg of SIM, 10 mg of ATR, or 40 mg of PRA daily on days 0 through 3 and days 15 through 18. EFV was administered daily at a dose of 600 mg on days 4 through 18. SIM, ATR, and PRA concentrations were determined before and after EFV, and EFV concentrations were determined before and after statins. EFV reduced SIM acid exposure (area under the curve at 0 to 24 hours [AUC0-24 h]) by 58% (Wilcoxon signed rank test, P=0.003) and active HMG-CoA reductase inhibitory activity by 60% (P<0.001). EFV reduced ATR exposure by 43% (P<0.001) and the total active ATR exposure by 34% (P=0.005). EFV administration resulted in a 40% decrease in PRA exposure (P=0.005). SIM, ATR, and PRA had no effect on non-steady-state EFV concentrations. In conclusion, EFV, when administered with SIM, ATR, or PRA, can result in significant induction of statin metabolism. The reduced inhibition of HMG-CoA reductase activity during coadministration of EFV may result in diminished antilipid efficacy at usual doses of SIM, ATR, and PRA.     

Combined statin/coenzyme Q10 as adjunctive treatment of chronic heart failure

Statins and coenzyme Q10 are both used as adjuncts in the treatment of chronic heart failure (CHF) due to their anti-inflammatory and antioxidant effects, respectively. And both have been variously shown to improve cardiac function in patients with CHF. The two agents interact in two ways; statins inhibit coenzyme Q10 synthesis through inhibition of HMG-CoA reductase, the rate limiting step in cholesterol synthesis, also shared by coenzyme Q10. Secondly, they both exhibit their antioxidant effects through activation of the enzyme superoxide dismutase, the rate limiting step in nitric oxide metabolism and main antioxidant mechanism of coenzyme Q10. We hypothesize that the interaction between statins and coenzyme Q10 is more than just a replacement, but a synergistic interaction on superoxide dismutase that could result in better cardiac function, improvement in patient symptoms, shortening of duration of hospital stay and improvement in patient quality of life.     

Statins inhibit NK‐cell cytotoxicity by interfering with LFA‐1‐mediated conjugate formation

Inhibitors of the 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase, commonly referred to as statins, are inhibitors of cholesterol biosynthesis. They are broadly used for treating hypercholesterolemia and for prevention of cardio‐ and cerebrovascular diseases. Recent publications show that statins also act as immunomodulatory drugs. Here, we show that lipophilic statins inhibit NK‐cell degranulation and cytotoxicity. This effect was reversible by addition of substrates of isoprenylation, but not by addition of cholesterol. In NK‐target cell conjugates intracellular Ca²⁺ flux was unaffected by statin treatment. However, statins strongly reduced the amount of conjugate formation between NK and target cells. This inhibition was paralleled by a statin‐dependent inhibition of LFA‐1‐mediated adhesion and a reduction of NK‐cell polarization. This demonstrates that statins impair the formation of effector–target cell conjugates resulting in the disruption of early signaling and the loss of NK‐cell cytotoxicity.