Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases?

Pleiotropic effects are now described for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (or statins) that might have utility in the context of chronic inflammatory autoimmune disease. Here we discuss the pharmacology and established uses of statins and in this context describe potential anti-inflammatory and immune-modulatory effects. An extensive in vitro data set defines roles for statins in modifying endothelial function, particularly with respect to adhesion molecule expression and apoptosis. Broader effects on leukocyte function have now emerged including altered adhesion molecule expression, cytokine and chemokine release and modulation of development of adaptive immune responses via altered MHC class II upregulation. In vivo data in several inflammatory models, including collagen-induced inflammatory arthritis and experimental autoimmune encephalomyelitis, suggest that such effects might have immune-modulatory potential. Finally, a recent clinical trial has demonstrated immunomodulatory effects for statins in patients with rheumatoid arthritis. Together with their known vasculoprotective effects, this growing body of evidence provides compelling support for longer-term trials of statin therapy in human disease such as rheumatoid arthritis.     

Immunoneutralization of chemokines for the prevention and treatment of central nervous system autoimmune disease

Chemokine-induced lymphocyte migration has long been hypothesized to regulate the appearance and continued presence of lymphocytes and monocytes in tissue-specific autoimmune diseases, including central nervous system autoimmune diseases such as multiple sclerosis. For instance, a large body of evidence points to the temporal association of chemokine expression with the appearance of T lymphocytes and monocytes/macrophages. Furthermore, experiments using mice with targeted mutations for chemokines have shown the importance of those molecules in the development of central nervous system autoimmune disease. We have hypothesized that temporal and spatial expression of chemokines is a key factor in the pathogenesis of experimental autoimmune encephalomyelitis and multiple sclerosis. To test our hypothesis we have employed the strategy of eliminating chemokine function by the passive transfer of chemokine-specific polyclonal antibodies. This approach has allowed us not only to test the function of chemokines in experimental autoimmune encephalomyelitis development, but also to ask questions about the roles of chemokines during disease progression. Moreover, this approach has allowed us to assess the efficacy of targeting chemokines and their receptors for treatment of ongoing disease. In the present report we summarize our experience using anti-chemokine administration for the prevention and treatment of experimental autoimmune encephalomyelitis as well as provide specific examples of how this approach is efficacious for disease treatment.     

TGF-beta1: a novel target for cardiovascular pharmacology

Transforming growth factor beta-1 (TGF-beta1) plays a key role in cardiovascular disease by a process which allows the loss of its protective properties. The first therapeutic attempt to restore its function by selectively designed novel drugs are being made. In addition, it has been recognized that the TGF-beta1 pathway is involved in the vascular mechanism of action of some current clinical drugs, such as acetylsalicylic acid, thiazolidinediones and statins. The aim of this paper is to review the possible value of TGF-beta1 as both a disease marker and a therapeutical target for cardiovascular disease.     

Statins: a revised appraisal for potential additional future treatment indications

Beside statins'' well established positive influence on atherosclerotic vascular disease caused by hypercholesterolemia through selective competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, additional effects on the immune system have been described for them. These observations have raised great hopes for additional future treatment indications, including rheumatoid arthritis and multiple sclerosis. Ten years of searching for such novel treatment indications have not led to breakthroughs and future efforts must be seen with skepticism.In the previous issue of Arthritis Research and Therapy Vandebriel and colleagues [1] report that the statins atorvastatin and pravastatin orally administered before disease induction in collagen-induced arthritis (CIA) in male DBA/lOlaHsd mice led to accelerated onset and higher disease incidence compared to controls. In addition, atorvastatin applied after induction of CIA resulted in earlier disease onset than administration before induction of CIA. Atorvastatin, but not pravastatin, administration also resulted in increased production of anti-collagen autoantibodies. In line with these novel findings in CIA, the same group recently demonstrated in a retrospective analysis of patients with rheumatoid arthritis (RA) that statins increase the risk for development of RA [2].Statins are one of the most prescribed drugs in clinical medicine at present. Their main mechanism of action is selective, competitive inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of sterols, including cholesterol.Statins are indicated in patients with significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia for reduction of mortality from coronary heart disease, non-fatal myocardial infarction and stroke and reduction of coronary and non-coronary revascularization procedures. Furthermore, statins are indicated in patients with various forms of hyperlipidemia. While statins have a clear and well established positive effect in the disease conditions named above, emerging data for additional indications is rather weak and side effects should be taken into consideration.In addition to the inhibition of HMG-CoA reductase, a multitude of additional drug-related and off-target effects with possible therapeutic value have been described. Importantly, it has also been demonstrated that statins have immunomodulatory properties. Most prominently, atorvastatin application in experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, leads to reduced disease severity due to effects on antigen presentation and T-cell activation and phenotype [3]. Unexpectedly, clinical studies in multiple sclerosis patients could not confirm the beneficial effects of statins observed in experimental autoimmune encephalomyelitis [4]. Statins that pass the blood-brain barrier should also be used with caution for other reasons, since some experimental- data indicate that statins inhibit remyelination [5].Statins have been evaluated as a treatment of Alzheimer''s disease. There are positive trends, but the data are conflicting and further studies in patients with mild Alzheimer''s disease will possibly clarify the assumed therapeutic value [6].The findings of Vandebriel and colleagues are in contrast to previously published reports in which atorvastatin, pravastatin, simvastatin and rosuvastatin given by various routes after CIA induction in mice have been reported to reduce disease or to have no effect (summarized in [1]). The reasons for the discrepancy could be differences in disease induction, route of dosing and dose, used substrains of mice and the animal housing environment. On the other hand, there is no previously published study in which statins were given before disease induction of CIA.So far statins have also been considered of potential future therapeutic value in RA. In RA there are data indicating that atorvastatin as an add on therapy to disease-modifying antirheumatic drugs (DMARDs) has beneficial effects in patients with RA: the randomized double blind placebo-controlled Atorvastatin in Rheumatoid Arthritis (TARA) study demonstrated some modest effects on acute phase variables and swollen joints, while other parameters remained unaffected [7]. Another study equally demonstrated beneficial effects in patients with RA treated with atorvastatin and reported an increased number of regulatory T cells as a possible mechanism of action [8]. Others reported effects on inflammatory parameters and Th1/Th2 balance leading to beneficial treatment effects of simvastatin in RA [9].Recently, the US Food and Drug Administration (FDA) changed its safety label for statins and indicated that liver injury associated with statin use is rare but can occur. They also acknowledged that statin use can be associated with memory loss, forgetfulness and confusion. In addition, a small, increased risk of raised blood sugar levels and the development of type 2 diabetes have been reported. Moreover, there is a risk for muscle damage.Vandebriel and colleagues also demonstrate an influence on collagen type II autoantibody titers after treatment with atorvastatin [1]. Since this was only the case for atorvastatin and not pravastatin, the data could indicate varying effects on the immune response of different- types of statins. Possibly the B-cell arm of autoimmune diseases could be affected by statin administration, leading to increased autoantibody titers. In line with the speculation that the B-cell arm of the immune response is affected by statin administration is the increased incidence of lupus-like syndromes in patients receiving statins [10].In summary, the work by Vandebriel and colleagues [1] suggests that broad use of statins could lead to increased incidence of autoimmune disease, especially RA. Further work will be necessary to demonstrate the cell biological and immunological mechanisms explaining these findings. Future studies in rodents and humans should better delineate the differences in the properties of individual statins with regard to their modes of action. The hypothesis that statins will have additional future indications for treatment of autoimmune diseases like RA or multiple sclerosis is more unlikely. Presently, there are no convincing data for the use of statins in these indications outside of controlled clinical trials. Exceptions remain co-morbidities with cardiovascular disease, stroke and hyperlipidemia.     

Toward a role for statins in immunomodulation

The family of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, collectively known as statins, is used clinically to reduce cholesterol levels in patients. Recent reports suggest that not only would statin therapy be beneficial for at-risk (genetically predisposed) people without symptoms of hypercholesterolemia, but that statins may have beneficial, pleiotropic effects in the treatment of autoimmune diseases. Youssef et al. have described how an HMG-CoA inhibitor, atorvastatin, might ameliorate experimental autoimmune encephalomyelitis (EAE), the mouse model for human multiple sclerosis. The possible clinical use of statins as anti-inflammatory drugs has also been demonstrated in other published reports. These provocative results suggest a role for statins in relieving autoimmune diseases such as multiple sclerosis.     

Immunomodulatory activity of mesenchymal stem cells

Mesenchymal stem cells (MSCs) were discovered as a rare population of non-hematopoietic stem cells that reside in the bone marrow and interact closely with hematopoietic stem cells to support their growth and differentiation. MSCs are multipotent cells that have the ability to differentiate into cells of the mesenchymal lineage including adipocytes, osteocytes and chondrocytes and they have been reported to home to areas of tissue injury and participate in tissue repair. More recently, MSCs have also been described to possess anti-inflammatory and immunomodulatory properties that can affect multiple arms of the immune system. MSCs have been shown to inhibit T and B cell proliferation, downregulate the lytic activity of cytotoxic T lymphocytes and NK cells, inhibit the maturation and antigen-presenting function of dendritic cells and modulate macrophage function through both contact-dependent and contact-independent mechanisms. The administration of MSCs in models of autoimmune disease such as collagen-induced arthritis, EAE and autoimmune diabetes has provided additional evidence for an immunoregulatory role of MSCs supporting their use in controlling autoimmunity. The administration of allogeneic MSCs as immunosuppressive agents represents a viable approach as they appear to be largely non-immunogenic and clinical trials with allogeneic MSCs are currently underway in graftversus- host disease, Crohn's disease and type I diabetes indications. The immunomodulatory properties, mechanism of action and potential clinical utility of MSCs are reviewed herein.     

Liposomal nanocarriers for statins: A pharmacokinetic and pharmacodynamics appraisal

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are a well-known class of drug with beneficial therapeutic effects in cardiovascular disease and lipid disorders and have potential use against cancer. However, the bioavailability of statins is hampered due to low aqueous solubility and rapid metabolism. To improve pharmacokinetic profiles of statins, development of drug delivery systems is promising. Hence, the use of liposomes for selective delivery of statins to a selected site or for bioavailability enhancement is an effective strategy to increase statin therapeutic effects. Moreover, liposomal delivery can reduce the required dose of statins especially in terms of antitumor effects. Liposomes, because of their unique properties and biphasic and amphiphilic nature, have attracted much interest and can be considered as a suitable choice for delivery of both hydrophilic and lipophilic statins. In this review article, we focus on liposomes and evaluate the effects of different liposomal delivery systems, based on differences in size, phospholipid composition, circulation half-life, and cholesterol content, on statin function.     

Suppression of autoimmune retinal disease by lovastatin does not require Th2 cytokine induction

Intraocular inflammatory diseases are a common cause of severe visual impairment and blindness. In an acute mouse model of autoimmune retinal disease, we demonstrate that treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, lovastatin, suppresses clinical ocular pathology, retinal vascular leakage, and leukocytic infiltration into the retina. Efficacy was reversed by coadministration of mevalonolactone, the downstream product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, but not by squalene, which is distal to isoprenoid pyrophosphate metabolites within the cholesterol biosynthetic pathway. Lovastatin treatment (20 mg/kg/day i.p.) over 7 days, which resulted in plasma lovastatin hydroxyacid concentrations of 0.098 +/- 0.03 microM, did not induce splenocyte Th2 cytokine production but did cause a small reduction in Ag-induced T cell proliferation and a decrease in the production of IFN-gamma and IL-10. Thus, it is possible to dissociate the therapeutic effect of statins in experimental autoimmune uveitic mice from their activity on the Th1/Th2 balance. Statins inhibit isoprenoid pyrophosphate synthesis, precursors required for the prenylation and posttranslational activation of Rho GTPase, a key molecule in the endothelial ICAM-1-mediated pathway that facilitates lymphocyte migration. Consistent with inhibition of leukocyte infiltration in vivo, lovastatin treatment of retinal endothelial cell monolayers in vitro leads to inhibition of lymphocyte transmigration, which may, in part, account for drug efficacy. Unlike lovastatin, atorvastatin treatment showed little efficacy in retinal inflammatory disease despite showing significant clinical benefit in experimental autoimmune encephalomyelitis. These data highlight the potential differential activity of statins in different inflammatory conditions and their possible therapeutic use for the treatment of human posterior uveitis.     

Statin therapy in heart failure

PURPOSE OF REVIEW: The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors, or statins, have been shown to reduce cardiovascular morbidity and mortality among a wide spectrum of patients with established atherosclerotic vascular disease. Mounting experimental and clinical evidence also suggest a potential benefit as well as theoretical harm of statin therapy in patients with heart failure. RECENT FINDINGS: This article briefly summarizes the therapeutic properties of statins that may be of benefit to patients with heart failure and the theoretical adverse effects of cholesterol reduction in this group of patients. A number of nonrandomized clinical studies over the past several years have shown an association between statin use and reduced overall mortality. Several large-scale randomized studies designed to confirm these findings are currently under way. SUMMARY: Statin therapy appears to improve clinical outcomes in patients with both ischemic and nonischemic cardiomyopathy independently of their cholesterol-lowering properties. The theoretical adverse properties of statins in heart failure patients have not been substantiated in small to medium-sized clinical trials. Although the encouraging results of these preliminary studies suggest a role for statin therapy in heart failure, larger studies are needed to validate these findings. Several ongoing randomized trials are currently under way to evaluate the effect of statin therapy on cardiovascular outcomes in heart failure patients. The results of these studies, expected in the next several years, should provide scientific evidence for the role of statins in the treatment of failure.     

Statins,stem cells,and cancer

The statins (3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors) were proven to be effective antilipid agents against cardiovascular disease. Recent reports demonstrate an anticancer effect induced by the statins through inhibition of cell proliferation, induction of apoptosis, or inhibition of angiogenesis. These effects are due to suppression of the mevalonate pathway leading to depletion of various downstream products that play an essential role in cell cycle progression, cell signaling, and membrane integrity. Recent evidence suggests a shared genomic fingerprint between embryonic stem cells, cancer cells, and cancer stem cells. Activation targets of NANOG, OCT4, SOX2, and c‐MYC are more frequently overexpressed in certain tumors. In the absence of bona fide cancer stem cell lines, human embryonic stem cells, which have similar properties to cancer and cancer stem cells, have been an excellent model throwing light on the anticancer affects of various putative anticancer agents. It was shown that key cellular functions in karyotypically abnormal colorectal and ovarian cancer cells and human embryonic stem cells are inhibited by the statins and this is mediated via a suppression of this stemness pathway. The strategy for treatment of cancers may thus be the targeting of a putative cancer stem cell within the tumor with specific agents such as the statins with or without chemotherapy. The statins may thus play a dual prophylactic role as a lipid‐lowering drug for the prevention of heart disease and as an anticancer agent to prevent certain cancers. This review examines the relationship between the statins, stem cells, and certain cancers. J. Cell. Biochem. 106: 975–983, 2009. © 2009 Wiley‐Liss, Inc.     

Controlling oxidative stress as a novel molecular approach to protecting the vascular wall in diabetes

PURPOSE OF REVIEW: In diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications; therefore an antioxidant therapy would be of great interest in this disease. RECENT FINDINGS: Hyperglycemia directly promotes an endothelial dysfunction--inducing process of overproduction of superoxide at the mitochondrial level. This is the first and key event able to activate all the pathways involved in the development of vascular complications of diabetes. It has recently been shown that statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1 blockers, calcium channel blockers, and thiazolidinediones have a strong intracellular antioxidant activity. SUMMARY: Classic antioxidants, such as vitamin E, failed to show beneficial effects on diabetic complications probably because their action is only "symptomatic". The preventive activity against hyperglycemia-induced oxidative stress shown by statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1 blockers, calcium channel blockers, and thiazolidinediones justifies use of these compounds for preventing complications in patients with diabetes, in whom antioxidant defences have been shown to be defective.     

The dyslipidemia of chronic renal disease: effects of statin therapy

PURPOSE OF REVIEW: Dyslipidemia is a prevalent condition in patients with chronic renal disease, but is often left untreated. Statin treatment constitutes an effective way to improve lipid abnormalities. This review summarizes present studies on dyslipidemia and its treatment in patients with chronic renal disease. RECENT FINDINGS: The specific dyslipidemia in renal disease is associated with the presence of proteinuria and decreased creatinine clearance, and may even adversely affect the progression of chronic renal disease. Statin therapy may have renoprotective effects due to a combination of lipid lowering and pleiotropic effects. Statins exert several anti-inflammatory properties and lead to a decrease of proteinuria. Post-hoc analyses of large-scale lipid lowering trials have shown that the reduction of cardiovascular risk was equivalent to the reduction achieved in patients without chronic renal failure. We feel, however, that if intervention with statins is postponed until patients reach end-stage renal disease, statins have limited benefit. SUMMARY: Present studies suggest that patients with renal disease should be screened early for dyslipidemia and that statins have to be considered as the lipid lowering therapy of choice. These drugs reduce cardiovascular risk. Further studies are needed to firmly establish whether statins preserve renal function.     

Immunotropic Effects and Proposed Mechanism of Action for 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors (Statins)

Inhibitors of HMG-CoA reductase (statins) are the major group of lipid-lowering drugs. Along with hypocholesterolemic activity, statins exhibit anti-inflammatory and immunomodulatory properties that expand their clinical use, particularly, in the treatment of chronic inflammatory and autoimmune disorders. In this review, we critically analyze the data of statin effects on immune cells (e.g., monocytes and T cells) involved in the development of atherosclerosis and other chronic inflammatory diseases. We (i) discuss the properties of statins and routes of cell entry, as well as their major intracellular targets; (ii) evaluate the data on the effects of statins on the subset composition of circulatory monocytes, ability of monocytes to migrate to the site of inflammation (cell motility and expression of adhesion molecules and chemokine receptors), production of cytokines, matrix metalloproteinases, and reactive oxygen species by monocytes/macrophages, and antigen-presenting activity in peripheral blood monocyte-derived dendritic cells; and (iii) summarize the data on the regulation of proliferation and differentiation of various CD4⁺ T cell subsets (type 1/2/17 helper T cells and regulatory T cells) by statins.     

Mechanisms of statin-mediated inhibition of small G-protein function

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been reported to reduce the risk of Alzheimer disease. We have shown previously that statins inhibit a beta-amyloid (Abeta)-mediated inflammatory response through mechanisms independent of cholesterol reduction. Specifically, statins exert anti-inflammatory actions through their ability to prevent the isoprenylation of members of the Rho family of small G-proteins, resulting in the functional inactivation of these G-proteins. We report that statin treatment of microglia results in perturbation of the cytoskeleton and morphological changes due to alteration in Rho family function. Statins also block Abeta-stimulated phagocytosis through inhibition of Rac action. Paradoxically, the statin-mediated inactivation of G-protein function was associated with increased GTP loading of Rac and RhoA, and this effect was observed in myeloid lineage cells and other cell types. Statin treatment disrupted the interaction of Rac with its negative regulator the Rho guanine nucleotide dissociation inhibitor (RhoGDI), an interaction that is dependent on protein isoprenylation. We propose that lack of negative regulation accounts for the increased GTP loading. Isoprenylation of Rac is also required for efficient interaction with the plasma membrane, and we report that statin treatment dramatically reduces the capacity of Rac to interact with membranes. These results suggest a mechanism by which statins inhibit the actions of Rho GTPases and attenuate Abeta-stimulated inflammation.     

Autoimmune Disease Classification by Inverse Association with SNP Alleles

With multiple genome-wide association studies (GWAS) performed across autoimmune diseases, there is a great opportunity to study the homogeneity of genetic architectures across autoimmune disease. Previous approaches have been limited in the scope of their analysis and have failed to properly incorporate the direction of allele-specific disease associations for SNPs. In this work, we refine the notion of a genetic variation profile for a given disease to capture strength of association with multiple SNPs in an allele-specific fashion. We apply this method to compare genetic variation profiles of six autoimmune diseases: multiple sclerosis (MS), ankylosing spondylitis (AS), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), Crohn''s disease (CD), and type 1 diabetes (T1D), as well as five non-autoimmune diseases. We quantify pair-wise relationships between these diseases and find two broad clusters of autoimmune disease where SNPs that make an individual susceptible to one class of autoimmune disease also protect from diseases in the other autoimmune class. We find that RA and AS form one such class, and MS and ATD another. We identify specific SNPs and genes with opposite risk profiles for these two classes. We furthermore explore individual SNPs that play an important role in defining similarities and differences between disease pairs. We present a novel, systematic, cross-platform approach to identify allele-specific relationships between disease pairs based on genetic variation as well as the individual SNPs which drive the relationships. While recognizing similarities between diseases might lead to identifying novel treatment options, detecting differences between diseases previously thought to be similar may point to key novel disease-specific genes and pathways.     

A comprehensive review on the lipid and pleiotropic effects of pitavastatin

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, are administered as first line therapy for hypercholesterolemia, both in primary and secondary prevention. There is a growing body of evidence showing that beyond their lipid-lowering effect, statins have a number of additional beneficial properties. Pitavastatin is a unique lipophilic statin with a strong effect on lowering plasma total cholesterol and triacylglycerol. It has been reported to have pleiotropic effects such as decreasing inflammation and oxidative stress, regulating angiogenesis and osteogenesis, improving endothelial function and arterial stiffness, and reducing tumor progression. Based on the available studies considering the risk of statin-associated muscle symptoms it seems to be also the safest statin. The unique lipid and non-lipid effects of pitavastatin make this molecule a particularly interesting option for the management of different human diseases. In this review, we first summarized the lipid effects of pitavastatin and then strive to unravel the diverse pleiotropic effects of this molecule.     

How statin drugs affect exosomes?

Statins reduce serum cholesterol and isoprenoids by the inhibition of cholesterol synthesis in the mevalonate pathway. Exosomes are extracellular vesicles (30–200 nm) released by all cells that regulate cell-to-cell communication in health and disease by transferring functional proteins, metabolites and nucleic acids to recipient cells. There are many reports that show an effect of statins on exosomes, from their production and release to their content and performance. In this review, we have summarized existing data on the impact of statins on the biosynthesis, secretion, content, uptake and function of exosomes.     

The therapeutic potential of HDAC inhibitors in the treatment of multiple sclerosis

Multiple sclerosis (MS) is a devastating autoimmune disorder of the central nervous system (CNS) for which there is no efficacious cure. Thanks to numerous preclinical and clinical studies, drugs able to mitigate the inexorable course of the disease have been made available recently. Still, there is a terrible need for compounds capable of reducing the severity of the autoimmune attack and of blocking progression of the disorder. Also, besides the classic immunosuppressive strategies, it is now appreciated that compounds directly targeting neuronal death can be of relevance to the treatment of MS patients. Acetylation homeostasis is a key regulator of both immune cell activation and neuronal survival. Of note, potent histone deacetylase inhibitors (HDACi) endowed with antiinflammatory and neuroprotective properties have been identified. Efficacy of HDACi in experimental models of MS has been reported consistently. In this review, we provide an appraisal of the literature on HDACi and MS, also discussing the mechanisms by which HDACi can suppress the autoimmune attack to the CNS.