Cardiovascular & Hematological Agents in Medicinal Chemistry, 2009, 7, 279-294 279

1871-5257/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

Immunomodulator Activity of 3-Hydroxy-3-Methilglutaryl-CoA Inhibitors

Costantino Smaldone, Salvatore Brugaletta, Vincenzo Pazzano and Giovanna Liuzzo*

Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy

Abstract: Statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA are best known for their lipid-lowering effects but they

also possess immunomodulatory properties that are, at least in part, independent of changes in serum cholesterol. Some

recent clinical trials (eg. PROVE-IT) have shown that statins exert beneficial cardiovascular effects independently of the

resultant level of LDL cholesterol.

These “pleiotropic” effects seem to be due to inhibition of prenylation of several proteins such as the small GTP-binding

proteins Ras and Rho, and to the disruption, or depletion, of cholesterol rich membrane micro-domains (membrane rafts).

Through these pathways statins are able to modulate immune responses by modulating cytokine levels and by affecting

the function of cells involved in both innate and adaptive responses. Over the past decade, a large number of studies re-

ported a prominent role of inflammation and immune response in atherosclerosis, thus, the ability of statins to modulate

immune-inflammatory processes could explain their cardiovascular beneficial effects beyond lipid-lowering effects.

Moreover, various studies demonstrated beneficial effects of statins in inflammatory and auto-immune diseases, such as

rheumatoid arthritis, multiple sclerosis, and others.

The purpose of this review is to summarize clinical and experimental evidence of immunomodulatory properties of these

drugs, highlighting their clinical and, thus, therapeutic implications.

INTRODUCTION

Statins, inhibitors of 3-Hydroxy-3-Methilglutaryl-CoA (HMG-CoA) reductase, are potent inhibitors of cholesterol biosynthesis and have revolutionized the treatment of hyper-cholesterolemia. Indeed, statins are very efficient drugs to reduce serum cholesterol levels and are well known to improve prognosis in patients with high cholesterol and/ or atherosclerotic disease. Clinical trials have demonstrated that statins greatly reduce coronary and cerebrovascular morbidity and mortality in both primary and secondary prevention [1-4].

Initially, statins showed beneficial effects in patients with substantially elevated cholesterol serum levels, and their benefits have also been demonstrated in patients with average cholesterol levels [5-8]. Accordingly, the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction 22 (PROVE IT – TIMI 22) trial showed that in acute coronary syndrome (ACS) setting intensive statin therapy was able to reduce mortality and major cardiovascular events in patients with baseline average and low cholesterol levels. In patients whose C-reactive protein (CRP) serum level did not achieve the goal of CRP levels < 2.0 mg/L, clinical outcomes were worse than in patients that achieved the “dual goal” of LDL-cholesterol below 70 mg/dL and CRP inferior to 2.0 mg/dL [9-11]. Moreover, although there is no association between blood cholesterol levels and stroke events, statins reduce the risk of

*Address correspondence to this author at the Institute of Cardiology,

Catholic University of the Sacred Heart, Rome, Italy;

E-mail: giovannaliuzzo@gmail.com

cerebrovascular ischemic events in patients with coronary artery disease [4, 12-14].

According to current literature no drug is able to modify

plaque volume except statins: statin therapy can reduce athe-

rosclerotic burden in both peripheral, namely carotid arteries, and coronary arteries. Initially, observational studies and

little randomized trials demonstrated that statins may stop

the progression or induce regression of coronary artery ateromatous plaques as assessed by quantitative angiogra-

phy. Statins may also reduce volume of atherosclerotic

plaques in carotid arteries as assessed by eco-color Doppler imaging. Recently, two trials assessed the effect of statin

therapy on coronary plaque dimension by using intravascular

ultrasound (IVUS): the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial demon-

strated that high dose therapy with atorvastatin may stop

progression of atherosclerotic plaque [15], while A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultra-

sound-Derived Coronary Atheroma Burden (ASTEROID)

trial showed that rosuvastatin, at high dosage, may determine a mean reduction of total plaque volume of -14.7 mm

3

(25.7%) [16].

Various studies on inflammatory diseases demonstrated beneficial effects of statins which are thought to be completely independent of cholesterol levels. Recent evidence suggests that statin therapy may have anti-fibrotic and vasodilator effects in patients with systemic sclerosis [17]. A recent clinical trial showed that atorvastatin markedly reduces the number and volume of brain lesions in patients with multiple sclerosis [18]. Data from the TARA trial demonstrated that statins can mediate modest but clinically apparent anti-

280 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2009, Vol. 7, No. 4 Smaldone et al.

inflammatory effects with modification of vascular risk factors in the context of high-grade autoimmune inflamma-tion [19]. Moreover, statin therapy is associated with a 47% relative risk reduction of colorectal cancer in an observa-tional study [20].

Taken together, these data support the hypothesis that the therapeutic effect of statins goes beyond their lipid-lowering effects. Actually, these drugs also exert immune-modulatory effects that are known as “pleiotropic effects”.

BEYOND LIPID-LOWERING EFFECTS OF STATINS IN CARDIOVASCULAR DISEASES

Inflammation and activation of immune system play a pivotal role in the pathogenesis of atherosclerosis and its complications. Increased serum level of acute phase proteins and cytokines is linked to the pathogenesis and the worsen-ing of prognosis in atherosclerotic disease, moreover, many studies show that the increase of inflammatory cell content in atherosclerotic plaques and the presence of an increased number of activated T-cells are directly involved in destabi-lization of the plaque [21-23].

LDL cholesterol (C) is intrinsically linked to atherothrombosis and is oxidized by free radicals to oxLDL-C, which in turn has a number of deleterious effects. Hence, reductions in the circulating LDL-C pool will likely reduce the amount of the LDL-C substrate available for oxidation and, therefore, potentially have beneficial early effects. Non-statin therapies that lower LDL-C, such as ileal bypass or use of bile acid sequestrants, require five to seven years to show a clinical effect, in contrast to the earlier benefit observed in statin trials. Although statins reduce LDL-C and markers of inflammation, such as CRP, the correlation coefficient be-tween LDL-C and CRP is weak (approximately 0.13), sug-gesting that the CRP reduction cannot be explained by the reduction of LDL-C levels alone. In the Aggrastat to Zocor (A to Z) trial, an intensive vs standard statin regimen was associated with a 60-mg/dl LDL-C reduction at four months, but clinical benefit was observable only later, and no CRP difference was shown earlier than four months after the ran-domization [24]. In contrast, in the PROVE-IT trial, patients treated with an intensive statin therapy had less LDL-C re-duction (32 mg/dl), but a greater and earlier CRP reduction and earlier benefit [9]. In this trial atorvastatin 80 mg/day, compared to pravastatin 40 mg, lowered more efficaciously CRP levels at 30 days, and this was associated with clinically significant benefit at four months. In contrast, in patients with stable coronary artery disease (CAD) benefit was de-layed. Inspection of the Kaplan-Meier curves shows little detectable separation in the first year (Scandanavian Simvas-tatin Survial Study - 4S - and Longterm Intervention with Pravastatin in Ischemic Disease - LIPID - studies [5, 25]) or in two years (Cholesterol And Recurrent Events - CARE – trial [26]). These differences suggest that the clinical benefits of intensive statin therapy observed in ACS patients occurred very early, and perhaps earlier than the reduction of LDL-C levels, making difficult to consider this change in lipid pro-file as the direct cause of the beneficial effect on disease progression. Two recent publications have intensified the debate about choice and dose of statins in ACS. The Pravas-tatin in Acute Coronary Treatment (PACT) study tested the

effects at 30 days of administering pravastatin 20 or 40 mg/day versus placebo, starting within 24 hours after the onset of ACS. There seemed to be no difference between the pravastatin 20 mg group and placebo, but benefit tended to occur only in the pravastatin 40 mg group, in an overall negative trial [27]. In the recent Z phase of the A to Z study, simvastatin 40 mg failed to lower CRP at one month com-pared with placebo, and in turn no significant clinical benefit was observed in the first four months after randomization [28].

The Atorvastatin for Reduction of Myocardial Damage during Angioplasty (ARMYDA) trial showed significant clinical benefit of pre-treatment with statins (one week pre-treatment with atorvastatin) in patients undergoing percuta-neous coronary interventions (PCI). This study enrolled only patients with stable angina [29]. Then, the same study group designed the ARMYDA-ACS trial, in which it was demon-strated that an acute high dose pre-treatment with statins (80 mg 12h before PCI and 40 mg 2h before PCI) in patients with high-risk non ST elevation ACS improves clinical out-comes at 30 days. Multivariable analysis of the data showed an 88% risk reduction of major adverse cardiovascular events (MACE) at one month in the treated arm, principally due to reduction in peri-procedural infarctions [30]. This early protection effects of atorvastatin are unlikely attribut-able to its lipid-lowering effects. They may also be depend-ent on a protective effect of atorvastatin on the myocardium. Indeed, Bell and coll. demonstrated that in a murine model of cardiac ischemia and reperfusion, increasing doses of atorvastatin reduced the infarct area with a dose-dependent effect [31].

A prospective sub-study of the Effects of Atorvastatin vs

Simvastatin on Atherosclerosis Progression (ASAP) trial

examined the effects of statins on CRP. It showed that the

greater reductions in CRP levels (34% vs 9%) obtained after

2 years of treatment with atorvastatin 80 mg/d vs simvastatin

40 mg/d were associated with significantly greater decreases

in carotid intima-media thickness, respectively, –40.1% with

atorvastatin and -19.7% with simvastatin [32]. Interestingly,

in the recent Ezetimibe and Simvastatin in Hypercholes-

terolemia Enhances Atherosclerosis Regression (ENHANCE)

trial, in a population of 720 patients with familial hypercholes-

terolemia, there was no significant difference between

patients treated with 80 mg simvastatin and others treated

with 80 mg simvatatin plus 10 mg ezetimibe in carotid

intima-media thickness, despite significant reductions in

LDL-C, triglyicerides, and CRP levels in the co-therapy

arm [33]. In a little study 56 patients with clinically stable

CAD were randomized to receive 40 mg atorvastatin or 10

mg atorvastatin plus 10 mg ezetimibe daily, and it was

demonstrated that platelet reactivity and chemokines levels

were lower in the mono-therapy arm [34].

In the ORION trial, 43 patients with moderate hypercho-lesterolemia were randomized to low- (5 mg) or high-dose (40 mg) rosuvastatin. Results at 2 years follow-up showed a greater reduction of carotid plaques’ lipid-rich necrotic core at MRI in the high-dose arm [35].

The evidence from clinical trials suggesting beneficial effects of statins in coronary artery disease is also supported

Immunomodulator Activity of 3-Hydroxy-3-Methilglutaryl-CoA Cardiovascular & Hematological Agents in Medicinal Chemistry, 2009, Vol. 7, No. 4 281

by results of histopathological and biological studies. In a recent report, it has been shown that short-term atorvastatin treatment tended to reduce the T-cell content of atheroscle-rotic plaques, thus, indicating modulation of cell-mediated immunity in atherosclerotic disease [36]. However, although atorvastatin may reduce the T-cell content of atherosclerotic lesions, it seems not to change lipid, collagen, smooth muscle cell, or macrophage content [37]. These effects seem not to be dependent on lipid-lowering effects of HMG-CoA reductase inhibitors.

Moreover, we recently demonstrated a potentially useful effect of statins in ACS, modulating circulating levels and activity of CD4

+CD28

null T cells. CD4

+CD28

null T-

lymphocytes are a unique population of T cells characterized by a prominent Th1 phenotype and result from long-term antigenic stimulation, as they are typically oligoclonal. This T cell subset, known to be expanded in the elderly and in chronic inflammatory diseases, like rheumatoid arthritis and systemic sclerosis, has been found in unstable angina and in unstable coronary plaques and may directly contribute to plaque instability through the release, in the plaque micro-environment, of a large amount of pro-inflammatory cytoki-nes. Moreover, its expansion is linked to a worse prognosis, only in part dependent on cardiovascular morbidity, in RA, and other autoimmune diseases [38, 39].

Levels of these lymphocytes can predict the recurrence of unstable coronary events: patients with a high blood fre-quency (>4%) or very high frequency (>10%) of these pecu-liar subtypes of T-cell experiment a higher number of acute coronary events than patients with low CD4

+CD28

null T-cells

blood frequency. Notably, in the subgroup of patients that was taking statins, this difference was absent [40], and in another study, carried out on a population of 111 patients with unstable angina, we also demonstrated that statin ther-apy could lower the frequency of these particular T-cells [41].

Naturally occurring CD4+CD25

+Foxp3

+ regulatory T

cells (Tregs) also have a key role in the prevention of various inflammatory and autoimmune disorders by suppressing immune responses, and recently it has been reported that blood Tregs frequency is reduced in patients with ACS [42]. In a recent study, statins appeared to significantly influence the peripheral pool of Tregs in humans, in particular treat-ment with pravastatin or simvastatin significantly increased Tregs frequency in patients with a hyperlipemic status [43].

Link and coll. randomized 35 patients with troponin-positive ACS to 20 mg/day rosuvastatin therapy or to

pla-

cebo treatment. Anti-inflammatory effects of rosuvastatin

measured by lymphocyte intracellular cytokine production were

taken before initiation of treatment and on days 1, 3,

and 42. Compared with placebo, rosuvastatin treatment sig-

nificantly

reduced plasma concentrations of pro-inflammatory cytokines

TNF- and IFN- at 72 h. Rosuvas-

tatin also induced a rapid and significant reduction of TNF-

and IFN- production in stimulated T-lymphocytes at 72 h.

When compared with placebo, rosuvastatin inhibited the Th-

1-immune response measured at 72 h [44]. In an observa-

tional study, a significant increase was also observed in the number of IFN- CD4

+ cells after PCI only in patients not

treated with statins before the intervention [45].

In the Atorvastatin and Thrombogenicity of the Carotid

Atherosclerotic Plaque (ATROCAP) study, it was assessed

that the thrombogenicity of atherosclerotic carotid plaque

specimens was obtained from 59 patients scheduled for two-

step bilateral endo-atherectomy and randomly assigned to

placebo or atorvastatin before surgery. Atorvastatin treat-

ment before and between subsequent bilateral carotid endo-

atherectomy reduced tissue factor plaque activity, when

specimens obtained at the first and second operation were

compared [46]. In a retrospective study, patients with symp-

tomatic carotid stenoses on statin treatment before endo-

atherectomy showed a reduced in-hospital

mortality and

ischemic stroke rate compared to patients that did not take

statins. Importantly, this benefit was not seen in asympto-

matic patients, indicating that statins contributed to plaque

stabilization in patients with vulnerable plaques. Accord-

ingly, endo-atherectomy specimens of symptomatic internal

carotid artery plaques from statin-pretreated patients showed

less macrophage and T-cell inflammation, reduced MMP-2

immunoreactivity,

increased expression of MMP tissue

inhibitor (TIMP) and a higher collagen content [47].

Statins additionally exert profound down-regulatory

effects on systemic markers of inflammation in patients with

atherosclerosis, such as CRP and serum amyloid A levels.

Oxidative processes may be involved in the development of

plaque instability. Indeed, oxLDL-C levels are associated

with markers of plaque instability (increased number of

macrophages) in human carotid endo-atherectomy specimens

[48]. Similarly, the severity of ACS has been shown to corre-

late with plasma oxLDL-C [49]. Statins have well known

antioxidant properties, which are being evaluated in ongoing

trials. Recently, it was evidenced that in humans statins can

lower markers of oxidation. Simvastatin, for instance, lowers

urinary 8-Iso-PGF2 in hypercholesterolemic individuals, an

effect that is not enhanced by vitamin E supplementation

[50].

The immunomodulatory effects of statins raised the sus-

picion of a possible increased risk of cancer, particularly

using high dosages. Indeed, the presence of tumor-

infiltrating T cells has been correlated to a better clinical

outcome in various kind of cancer. This suspicion was rein-

forced by a meta-analysis on the safety of high dosage statin

therapy recently published [51]. In this study, high dosage

therapy with atorvastatin and simvastatin was associated

with an increased risk of cancer directly proportional to the

magnitude of LDL-C reduction. However, a recent meta-

analysis of 42 studies showed that statins had no effect on

the overall incidence of cancer or on the incidence of lung,

breast or prostate cancer. Moreover, they seemed to protect

from stomach and liver cancer, and from lymphoma [52]. So

far, high-dose statin treatment is safe and effective in athero-

sclerosis and its acute complications.

However, although statin therapy represents a corner-

stone in the treatment of atherosclerosis, mainly in its acute

complications, data on heart failure (HF) are not so encour-

aging. Anti-inflammatory activity and improvement of endo-

thelial function should be beneficial in patients with HF, and

statins also seem to have protective effects on cardiomyo-

282 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2009, Vol. 7, No. 4 Smaldone et al.

cytes. Nonetheless, the Controlled Rosuvastatin Multina-

tional Trial in Heart Failure (CORONA) trial tested the

effects of an intermediate dose of rosuvastatin (10 mg) in

patients with ischemic and non-ischemic dilated cardio-

myopathy, and the primary composite outcome of death,

non-fatal stroke and myocardial infarction was not signifi-

cantly different between the two arms, while statin therapy

reduced hospitalizations for worsening HF and improved

NYHA functional class. The failure of statins in reducing

mortality might be related to arrhythmic events that can not

be prevented with these drugs [53]. We should also remem-

ber that statins have a little epato- and myotoxic effect that

could be of great relevance in individuals with hepatic

dysfunction and muscular abnormalities, such as patients

with severe HF.

CORONARY ALLOGRAFT VASCULOPATHY AND STATINS

Cardiac allograft vasculopathy (CAV) represents one of the major causes of mortality and morbidity after heart trans-plantation, and is characterized by typical histopathological features reviewed elsewhere. The mechanisms underlying CAV development are not completely known despite exten-sive basic and clinical studies. However, inflammation and immunity are well known to be associated with the patho-genesis of this condition. Immunological features that have been shown to lead to CAV include HLA mismatching, in-creased T helper activity and increased cytokine production. Moreover, even non immunological factors such as diabetes, smoking, hyperlipemia, endothelial dysfunction and viral infection are associated with the development of graft atherosclerosis. Notably, local inflammation seems to play a pivotal role in the pathogenesis of CAV, as this pattern of arteriopathy is not seen in other vessels in the recipient organism. Due to these peculiar characteristics, CAV is con-sidered by many authors like a sort of immunity-induced atherosclerosis. Some immunosuppressive drugs, such as everolimus, are able to reduce long-term morbidity and mortality in patients undergoing heart transplantation by reducing CAV incidence [54].

In this context, it is important to underline that statins exert beneficial effects in patients with cardiac allograft vasculopathy. Indeed, in some observational studies, it was demonstrated that statin treatment can prevent development of vasculopathy and improve prognosis of these patients [55, 56]. Hyperlipidemia is very common after cardiac trans-plantation, and there is increasing evidence to suggest that lipid-lowering therapy is a very important intervention in this population. The cause of hyperlipidemia is multifactorial: immunosuppressive therapy is certainly an important factor, as well as the dose of prednisone. Kobashigawa et al. dem-onstrated in a randomized trial that patients taking pravas-tatin, starting within 2 weeks after the transplantation, had less rejection, less mortality, and lower incidence of allograft vasculopathy at 1 year. Simvastatin and pravastatin are associated with similar beneficial effects on cardiac allograft rejection and 1-year survival. For this reason, HMG-CoA reductase inhibitors (simvastatin or pravastatin) should be used routinely following heart transplantation. [57].

MOLECULAR AND CELLULAR BASIS OF IMMU-

NOMODULATORY EFFECTS OF STATINS

Statins share structural similarity to HMG-CoA, a pre-

cursor of cholesterol, and are competitive inhibitors of HMG-CoA reductase. This enzyme regulates an important

step in the cholesterol synthesis: the biosynthesis of

mevalonate. The resulting decrease in the intracellular cholesterol level leads to transcriptional up-regulation of

LDL-receptor synthesis, increases LDL entry into the hepatic

cells and, thus, reduces LDL circulating levels.

The inhibition of mevalonate biosynthesis also reduces

the levels of intermediate products of the mevalonate path-

way [58]. This leads to inhibition of various cellular proc-

esses that depend on the synthesis of these molecules. Me-

valonate is the precursor of isoprenoids, molecules contain-

ing isoprenic groups serving as attachments for the post-

translational modification of several proteins, such as small

GTPases, which play an important regulatory role in many

cellular processes (Fig. 1) [58-60]. GTPases are small

monomeric guanin nucleotide-binding proteins. They cycle

between GDP-bound (inactive) and GTP-bound (active)

states, and mediate crucial signals for the regulation of many

cell processes, such as cell growth and migration, cytoskele-

tal organization, and molecular trafficking, which are fun-

damental during the activation of immune cells. Their activ-

ity is regulated by isoprenylation as the attachment of a lipo-

philic isoprenyl group (generally farnesyl or geranylgeranyl)

enables them to anchor to cell membranes, which are essen-

tial to exert their biological functions. Eight subfamilies of

GTPases have been identified, and among these the most

important and investigated are the Ras and Rho families.

Mutations in the Ras family of proto-oncogenes are found in

20-30% of human tumors, and the inappropriate activation of

the Ras has a key role in signal transduction, proliferation,

and malignant transformation. Among Rho proteins, Rho,

Rac and Cdc42 are the best characterized. They regulate ac-

tin cytoskeletal change, microtubule dynamics, vesicle traf-

ficking, cell polarity, and cell-cycle progression. Other small

GTPases include Rab, Rap, Ran, Rheb, Rad, Rit and Arf.

They are important for many cellular processes, such as

membrane trafficking, nucleocytoplasmic transport, and the

regulation of cell proliferation (Fig. 2) [61-63].

An alternative or complementary mechanism underlying the pleiotropic effects of statins is the disruption, or deple-tion, of cholesterol-rich membrane micro-domains also known as membrane rafts. Lipid rafts are highly enriched in cholesterol and glycosphingolipids and range in size from 50 to 70 nm. Proteins present within these domains are severely limited in their capacity to diffuse freely over the plasma membrane. The principal role of lipid rafts seems to be the recruitment and concentration of cell signaling molecules in the plasma membrane and the regulation of their diffusion [64-66]. Membrane rafts have been shown to be very impor-tant in both B and T cells functioning, and, probably, also for other immune cell types, such as NK [67-71]. Statin treat-ment in vivo and in vitro results in disruption of membrane rafts that impairs Fc- receptor signaling and T-cell cytotox-icity, and recently, it has also been demonstrated that statin-

Immunomodulator Activity of 3-Hydroxy-3-Methilglutaryl-CoA Cardiovascular & Hematological Agents in Medicinal Chemistry, 2009, Vol. 7, No. 4 283

induced reduction of NK cells citotoxicity is at least in part dependent on depletion of lipid rafts [70, 72-75]. Moreover, oral simvastatin treatment in healthy subjects at standard therapeutic dosage leads to a reduction of lymphocytes membrane raft levels [76].

The immunomodulatory properties of statins were origi-nally recognized by the fact that they were able to reduce MHC II expression in several cell types. MHC II molecules, expressed on the surface of specialized cells, are directly involved in the activation of T-lymphocytes and in the con-trol of immune responses [77]. Although constitutive expres-sion of MHC II molecules is restricted to professional anti-gen presenting cells (APCs), several cell types express MHC II molecules upon cytokines stimulation, in particular by INF- [78]. In a recent study, Kwak and coll. reported that

statins effectively repress the MHC II protein and gene expression induced by INF- in endothelial cells and monocyte/macrophages and, thus, act as direct repressors of MHC II mediated T-cell activation, whereas do not affect constitutive expression of MHC II by professional APCs. These effects seem to be due to reduction of the activation of inducible promoter IV of CIITA [79, 80]. However, other studies found that statins are also able to inhibit constitutive MHC II expression on B-lymphocytes, dendritic cells, and microglia. Notably, statin treatment of immature dendritic cells (DCs) inhibits enhancement of MHC II surface expres-sion during DCs maturation process. All these effects have been observed with statins currently used in clinical practice, such as atorvastatin, simvastatin, pravastatin, and lovastatin [72, 81-84].

Fig. (1). Biochemical effects of statins on cholesterol synthesis.

Fig. (2). Inhibition of mevalonate by statins and its molecular effects on intracellular signals.

284 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2009, Vol. 7, No. 4 Smaldone et al.

Statins are also able to reduce INF- induced expression of various costimulatory molecules such as CD40, CD80, and CD86 on lymphocytes, macrophages, and endothelial cells, and inhibit their upregulation during DCs maturation [83, 85, 86]. CD40 acts as a costimulatory molecule that enhances T-cell activation by DCs. A study that demon-strated the colocalization of DCs and T cells in atheroscle-rotic plaques, as well as the expression of MHC II and costimulatory molecules on DCs, suggests that DCs initiate an antigen specific immune response that contributes to the progression of atherosclerosis [87, 88]. Yilmaz et al. also showed that, in contrast to non treated DCs, statin-pretreated DCs exhibit an immature phenotype and a significant lower expression of the maturation-associated markers, CD40, and MHC II molecules. The authors also observed that statins significantly reduced the ability of cytokine-stimulated DCs to induce T-cell proliferation [84].

Statins can also influence another fundamental process of the immune response, the leukocyte extravasation from bloodstream to tissues, normally mediated by chemokines and adhesion molecules [89-91]. There is a great body of evidence demonstrating that statins inhibit the extravasation cascade during acute inflammatory tissue infiltration of granulocytes, for example in non-specific pulmonary in-flammation, chemically induced peritonitis, and myocardial ischemia-reperfusion damage [92-94]. There are also data on the inhibitory effects of statins on immune responses involv-ing recruitment of mononuclear leukocytes, including lym-phocytes [95-97]. Some studies showed that molecular mechanisms underlying the reduced rates

of adhesion of in-

flammatory cells to the endothelium after statin treatment

involve 2-integrin, one of the most important adhesion molecules, also known as leukocytes function antigen (LFA)-1. This integrin plays a role both in adhesion and in activation of T cells [98, 99]. Indeed, statins can selectively inhibit leukocyte adhesion

by direct interactions with the

LFA-1, and there is a quite definitive evidence that these functions are independent from their lipid

lowering action.

By binding to a novel allosteric site within this

2-integrin, rather than targeting HMG-CoA reductase,

statins block

lymphocytes adhesion to the endothelium

in a degree sufficient to suppress the inflammatory response

in murine

models of peritonitis [100, 101].

As far as monocytes/macrophages are concerned, their action depends, beyond

adhesion molecules and chemokines,

on the activity of matrix-degrading enzymes, namely matrix

metalloproteinases (MMPs) [102, 103]. This protease family

may also participate in the weakening of the fibrous cap, and

localize prominently in the plaques’ shoulder, a common site

of rupture [104-108]. Proinflammatory cytokines, such as

interleukin (IL)-1, tumor necrosis factor (TNF)- or CD40L, regulate expression and activation

of MMPs. According to

studies that suggest that statins reduce the migration of cells

found in atheroma, and furthermore, render lesions less likely

to disrupt, these drugs diminish the expression of several

matrix-degrading enzymes implicated in these processes [109, 110]. Indeed, HMG-CoA reductase inhibitors lower the expression and

function of a broad range of MMPs, including

interstitial collagenases

(MMP-1, MMP-13), gelatinases (MMP-2 and MMP-9), and stromelysin

(MMP-3) in most

cell types involved in atherogenesis, including macrophages,

a major source of MMPs in lesions [111-116]. Furthermore,

the enzymatic activity of MMPs depends also on the interac-tion with the endogenous

tissue inhibitors of MMP (TIMPs).

Statins augment the expression of TIMP-1 in human vascular

smooth muscle cells (SMCs) as well as in macrophages, a function

that should limit extracellular matrix breakdown

and, thus, might render lesions less prone to rupture [117].

The mechanisms underlying regulation of MMP/TIMP activ-

ity and imbalance remain uncertain but may involve modula-

tion of nuclear factor- B (NF- B) activity and prenylation of

small signaling Rho proteins [116, 117].

Immunomodulatory effects of statins seem also be due to their ability to induce a specific type of immune response. In a murine model of autoimmune encephalomyelitis, atorvas-tatin induced secretion of Th2 cytokines (IL-4, -5, and -10) and transforming growth factor (TGF)- , whereas secretion of Th1 cytokines (IL-2, IL-12, IFN- , and TNF- ) was sup-pressed [85, 118]. In a murine model of autoimmune retinal disease, it has been shown that lovastatin induced a reduction in T-cell proliferation and a decrease in IFN- production, whereas it had no effect on Th2 cytokine production, and the same result has been reproduced in a recent study on a model of autoimmune uveoretinitis with atorvastatin and lovastatin [119, 120]. These results have been confirmed in vitro with the observation of a lovastatin mediated inhibition of IFN- activity in endothelial cell lines [121]. Furthermore, in pa-tients with unknown cardiovascular disease, pravastatin can reduce proinflammatory cytokine production and, in a recent study, it has been observed that, although it has no effect on Th2 cell functions [122], atorvastatin can reduce Th1 devel-opment in patients with acute myocardial infarction, suggest-ing that reduction of Th1 may be one of the mechanisms through which it improves heart function after acute myo-cardial infarction [123]. Moreover, it was demonstrated in vitro that statins are able to promote the differentiation of Th0 naïve cells towards Th2 phenotype [85, 124]. Taken together, these animal and human findings suggest that statins regulate Th1/Th2 imbalance both in vitro and in vivo. Thus, all these observations could explain the beneficial effect of statins in atherosclerosis, as it has been shown that Th2 cytokines have antiatherogenic properties, and their overexpression protects against atherosclerosis. However, there are different interpretations of these data, and some authors believe that statins only reduce Th1 cytokines secre-tion without actually promoting a Th2 response.

THERAPEUTIC POTENTIAL OF STATINS FOR INFLAMMATORY DISEASES

Recently a great attention has been focused on the possi-bility that these anti-inflammatory and immunomodulatory properties of statins may contribute to their clinical benefits. This concept has gained popularity especially in the last years, after the universal acknowledgement of the central role played by inflammation in the pathogenesis of coronary artery disease, and a number of lines of evidence show the potential for clinically significant pleiotropic effects of stat-ins not only in the cardiovascular science field. Indeed, vari-ous studies tested their potential clinical benefit in “classic” inflammatory diseases, such as rheumatic and other autoim-

Immunomodulator Activity of 3-Hydroxy-3-Methilglutaryl-CoA Cardiovascular & Hematological Agents in Medicinal Chemistry, 2009, Vol. 7, No. 4 285

mune diseases, and other pathological conditions with a great burden of inflammation (Table 1).

Notably, most of these inflammatory conditions have proven to determine a higher risk of developing vascular disease. For example, patients with rheumatoid arthritis (RA), who by definition present a high grade inflammation, are at high risk of cardiovascular complications. Striking parallels can be drawn between the atherosclerotic plaque and synovitis in RA at the tissue level. Similar populations of proinflammatory cells, in particular activated macro-phages and T cells, drive a primarily Th1-mediated response in both pathological processes. It is also increasingly clear that uncontrolled inflammation in the context of various rheumatological disorders predisposes to atherogenesis, contributing to an augmented burden of cardiovascular co-morbidity and premature mortality. So, according to its characteristics, RA represents an ideal model to analyze immunomodulatory effects of statins, and several studies have been carried out both in vitro and in vivo [125, 126].

First of all, it has been demonstrated that T lymphocytes in the inflamed joints of patients with RA preferentially pro-duce Th1 cytokines, namely IFN- and interleukin-2. This Th1-predominant immune disregulation is associated with proliferation of the synovial tissue in patients with RA [127, 128]. A recent in vitro study showed that fluvastatin induces apoptosis in RA synoviocytes through a mitochondrial and caspase-3 dependent pathway and by inhibiting mevalonate pathways, namely the protein geranylgeranylation and RhoA/RhoA kinase pathways. This in vitro fluvastatin-induced apoptosis of synoviocytes was hypothesized to play an important role in the reduction of synovial cell prolifera-tion in patients with RA [129].

As far as the “in vivo” studies are concerned, the first important trial was the TARA (Trial of Atorvastatin in Rheumatoid Arthritis): a double-blind, randomized, placebo-controlled trial evaluating the effects of treatment with atorvastatin, on top of other known disease-modifying agents, in 112 patients with RA. The primary outcome measure was RA disease activity, while secondary outcomes included surrogate markers of vascular risk. In this trial, atorvastatin decreased CRP levels, an acknowledged marker of cardiovascular risk. In addition, other inflammatory and thrombogenic markers such as ESR, IL-6, fibrinogen, VonWillebrand factor and soluble adhesion molecule-1 were lower in the atorvastatin group. The conclusion reached was that statins should be considered as an additive therapeutic option in patients with RA as a mean to reduce the risk of cardiovascular events. However, clinical parameters were not modified by statin therapy in this little trial, namely there were not changes in the health assessment test [19]. Beyond the TARA, data from several other studies reinforce the con-cept that statins may be potentially used as a novel add-on therapy in the treatment of RA, demonstrating a beneficial effect not only on levels of inflammatory and cardiovascular risk markers, but also on endothelial function and activity of the disease. Statins indeed proved to be able to reduce CRP, ESR and TNF- levels, improve endothelium-dependent vasodilatation (notably, without affecting endothelium-independent vasodilatation), reduce aortic stiffness, and

lower disease activity scores and number of swollen joints [130-132].

Beside RA, statins can exert similar beneficial effects also in systemic lupus erythematosus (SLE). Like RA affected patients, SLE patients have a great cardiovascular morbidity and mortality, only in part dependent on tradi-tional risk factors [133]. As in RA, in SLE animal models and in little studies in humans, statins improve endothelial function as demonstrated by improvement of endothelium-dependent vasodilatation and reduction in molecular markers of endothelial dysfunction. Moreover, statins reduce circulat-ing levels of cytokines involved in the pathogenesis of SLE and its complications, such as INF- , TNF- , and IL-6. A study performed in lupus-prone mice suggests that statins may be an effective therapeutic agent: atorvastatin decreased the severity of renal dysfunction and histological glomerular injury, diminished anti-dsDNA titers, and decreased the ex-pression of MHC II antigens on monocytes and B cells [134]. However, data from clinical studies are poor. More-over, it has to be considered that drug-induced SLE is a known and not very rare complication of statin therapy. How statins can induce or worsen SLE is not completely under-stood, but there are two hypothesis: first, statins may trigger cellular apoptosis, causing the release of nuclear antigens into the circulation, thus, enhancing the production of patho-genic autoantibodies, on the other hand, statins may potenti-ate the shift of Th1 to Th2 immune responses, leading to increased B-cell reactivity and production of antibodies. It is not known if these drugs precipitate disease in patients with subclinical disease. Therefore, beyond their possible benefi-cial effect, it is necessary to test statins’ safety and tolerabil-ity in SLE [135, 136].

Statins might be useful also in other autoimmune disor-ders. In Hasimoto’s thyroiditis (HT), oral treatment with simvastatin seems to be beneficial. In 2005, Gullu and coll. randomly assigned 21 patients to simvastatin or to placebo: in the simvastatin group, there was a significant improve-ment in thyroid function and a decrease in lymphocyte autoreactivity (reduction of CD8

+ T cells, activated T cells

and NK). An in vitro sub-study was also performed in the same population, demonstrating an apoptotic effect of statins (at concentrations similar to those reached in vivo) on lym-phocytes. Statins can also reduce HLA-DR expression by HT thyrocytes, which might inhibit the subsequent lymphocyte activation and reduce self-reactivity. However, clinical stud-ies aimed to confirm this hypothesis and testing real clinical effect lack [137].

Statins have also demonstrated beneficial effects in some neurological disorders, in which autoimmunity and inflam-mation play an important pathogenetic role. In experimental autoimmune encephalitis (EAE), a murine model of multiple sclerosis, oral statin treatment at disease onset prevented the development of the disease, and clinical symptoms were reversed when statin treatment was initiated after paralysis was established. These animal studies also revealed that stat-ins have beneficial effects at several steps in the pathogene-sis of EAE including inhibition of myelin antigen presenta-tion, which is required for T-cell activation and differentia-tion into pro-inflammatory encephalitogenic cells and for

286 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2009, Vol. 7, No. 4 Smaldone et al.

Table 1. Studies and Clinical Trials Regarding Use of Statins in Immune/Inflammatory and Infectious Disease

Name (Year) Study Design Setting

(n°pts, Median f/u)

Treatment Results

Studies on Immune/Inflammatory Diseases

TARA (2004) [19] prospective

randomized trial

RA (116 pts, 6 months) atorvastatin 40mg/d (58)

vs placebo (58)

disease activity assessed with

DAS28 (-0.52, -0.87 to -0.17;

p=0.004), n° patients meeting the

DAS28 EULAR response criteria

(OR 3.9, 1.42-10.72; p=0.006),

CRP (by 50%; p<0.0001), ESR

(by 28%; p=0.005), swollen joints

count (-2.16, -3.67 to -0.64;

p=0.0058)

Tikiz et al. (2005)

[129]

prospective

randomized trial

RA (45 pts, 8 weeks) simvastatin 20mg/d (15) vs

quinapril 10mg/d (15) vs

placebo (15)

CRP (from 14 +/- 6 to 7 +/- 3 mg/l;

p = 0.025) and TNF- (from 30 +/- 5

to 16 +/- 4 pg/ml; p = 0.012) and

endothelium-dependent vasodilata-

tion (from 5.3 +/- 1.1% to 8.9 +/-

1.4%; p = 0.025) only in the simvas-

tatin group. No differences in IL-1 ,

IL-6 and endothelium-independent

vasodilatation

Okamoto et al.

(2007) [130]

retrospective

cohort study

RA (4152 pts, 2 years) 279 statin users vs 3873 non

statin users

RA disease activity indicated by

patient's assessment for pain,

physician's assessment, and swollen

joint counts, after corticosteroids

dose adjustment

Mäki-Petäjä et al.

(2007) [131]

prospective

randomized trial

RA (20 pts, 12 weeks) Simvastatin 20mg/d or

ezetimibe 10mg/d each for 6

weeks with crossover

both drugs total and LDL choles-

terol and CRP, disease activity

score (-0.55 +/- 1.01 and -0.67 +/-

0.91; p = 0.002), aortic PWV

(-0.69 +/- 1.15 m/s and -0.71 +/-

0.71 m/s; p = 0.001), and FMD

(1.37 +/- 1.17% and 2.51 +/- 2.13%;

p = 0.001)

Gullu et al. (2005)

[136]

prospective observa-

tional study

HT and subclinical hypothy-

roidism (21 pts, 8 weeks)

simvastatin 20mg/d (11) vs

placebo (10)

fT3, fT4, TSH (p <0.05),

CD4+ and B lymphocytes,

CD8+, NK and activated T

lymphocytes (p <0.05)

Sena et al. (2003)

[141]

prospective observa-

tional pilot study

relapsing-remitting MS

(7 pts, 12 months)

lovastatin 20 to 40 mg/d mean annual relapse rate, n° of

(Gd)-enhancing T1 lesions, n° of

T2-weighted lesions

Paul et al. (2008)

[143]

open label baseline-to-

treatment prospective

observational study

relapsing-remitting MS with

at least 1 (Gd)-enhancing

lesion (41 pts, 9 months)

atorvastatin 80mg/d alone

(25) or associated to

IFN- (16)

n° and volume of MRI lesions

(p= 0.003 and 0.008 in the

atorvastatin group, p= 0.06 and

0.062 in the comedication group)

Jick et al. (2001) [148] population-based,

retrospective nested

case-control analysis

1364 patients from the UK-

based General Practice

Research Database

284 cases with dementia and

1080 controls with untreated

hyperlipidaemia, statin

therapy, other lipid lowering

agents or no hyperlipidaemia

nor lipid lowering drugs use

adjusted relative risk of developing

dementia in statin users

(0.29, 0.13-0.63; p=0.002)

Immunomodulator Activity of 3-Hydroxy-3-Methilglutaryl-CoA Cardiovascular & Hematological Agents in Medicinal Chemistry, 2009, Vol. 7, No. 4 287

Table 1. contd….

Name (Year) Study Design Setting

(n°pts, Median f/u)

Treatment Results

Studies on Immune/Inflammatory Diseases

Wolozin et al.

(2000) [149]

cross-sectional

analysis of hospital

records

60 349 pts from 3 hospital

records

16 592 pts on statin therapy

and 43 757 pts taking other

medications for CVD

or hypertension

prevalence of diagnosis of

probable AD in statin users

Hoglund et al.

(2005) [152]

prospective

observational study

AD (19 pts, 12 months) simvastatin 20mg/d no change in CSF or plasma levels

of A -amyloid, but favor of

the nonamyloidogenic pathway

of APP processing

ADCLT (2005) [156] prospective random-

ized intention-to-treat

pilot study

AD (63 pts, 1 year. All pts

who completed the first 3-

months were considered

evaluable, only 46 completed

the 1-y period)

atorvastatin calcium 80mg/d

(32) vs placebo (31)

benefit assessed with clinical scores,

statistically significant at 6 months

with ADAS-cog and GDS

Studies on Infectious Diseases

Chello et al. [163] prospective

randomized trial

pts undergoing CABG (40

pts, 3 weeks)

atorvastatin 20mg/d (20) vs

placebo (20) in the 3 weeks

before intervention

postoperative IL-6 and IL-8

peak, CD11b expression on

neutrophils and neutrophils-

endothelial adhesion

Gupta et al. (2007)

[164]

prospective cohort

study, propensity

matched subcohort

patients on hemodialysis

(1041 and 214

pts, 3.4 years)

statin users and

non statin users

rates of sespis-related hospitaliza-

tions patient-years (41/1000

vs 110/1000; p<0.001), incidence

of sepsis (RR per 1000 pt-years

0.25, 0.11-0.49)

Hackam et al. (2006)

[165]

propensity matched

retrospective cohort

analysis

acute coronary syndrome,

ischaemic stroke, or

revascularization (69 168 pts)

statin users (34 584)

and non statin users

(34 584)

events of sepsis (71.2 vs 88

per 10 000 pt-years;

p= 0.0003)

Almog et al. (2004)

[166]

prospective

observational cohort

study

acute bacterial infection

presumed or documented

(361 pts)

statin use (82) vs non statin

use (279) before admission

development of severe sepsis

and need for ICU admission (2.4%

and 3.7% vs 19% and 12.2%;

p <0.01 and =0.025)

van de Garde et al.

(2006) [167]

retrospective case

control study

type 1 and 2 DM

(142 175 pts)

patients with CAP

(4719) and matched

controls (15 322)

risk of pneumonia (adjusted

OR: 0.49, 0.35–0.69)

in statin users

Schlienger et al.

(2007) [168]

population-based,

retrospective, nested

case–control analysis

134 262 patients from the

UK-based General Practice

Research Database

patients with CAP (1253)

and controls (4838)

risk of fatal pneumonia

(adjusted OR: 0.47, 0.25–0.88,

p= 0.02) in statin users

Mortensen et al.

(2005) [169]

retrospective

cohort study

patients admitted

withCAP (787)

statin users (110) and

non statin users (677)

30-days mortality (adjusted OR:

0.36, 0.14–0.92)

Majumdar et al.

(2006) [170]

population-based

prospective cohort

study

patients admitted with

CAP (3415)

statin users (325) and

non statin users (3090)

no difference in need for ICU

admission and mortality

EULAR, European League Against Rheumatism; PWV, Peak Wave Velocity; FMD, Flow Mediated Dilatation; HT, Hashimoto’s Thyroiditis; MS, Multiple Sclerosis; AD, Alzheimer’s Disease; CSF, CerebroSpinal Fluid; APP, Amyloid Precursor Protein; ADAS-cog, Alzheimer's Disease Assessment Scale-cognitive subscale; GDS, Geriatric Depression Scale.

leukocytes recruitment into the central nervous system. Moreover, statins are able to reduce in vitro the activation-induced expression of immuno-modulatory molecules on

microglial cells and to reduce their migratory capacity [138-141]. These immunomodulatory effects observed in the murine model of encephalitis seem to translate to human

288 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2009, Vol. 7, No. 4 Smaldone et al.

autoimmune diseases. Two small studies were recently published on the treatment effects of statins in patients with relapsing-remitting multiple sclerosis (MS). An open-label study tested 20 mg lovastatin in seven MS patients with an active disease course with at least two relapses during the previous 2 years. Magnetic resonance imaging (MRI) results indicated decreased inflammation with lovastatin treatment, although no clinical change was observed in this small cohort [142]. In another small, open-label trial, patients were treated with 80 mg simvastatin, the highest FDA approved dose, over 6 months. All patients enrolled had at least one gadolinium-enhancing lesion in the 3-months pre-treatment period. MRI results indicated a decrease of approximately 45% in mean number and volume of the gadolinium-enhancing lesions in the statin-treated patients [143]. Recently, a phase II randomized controlled trial was performed on 41 patients to test safety and tolerability of therapy with 80 mg atorvastatin. The follow-up lasted 9 months, and it was showed that this high-dose was safe and well tolerated, and that atorvastatin, alone or in combination with IFN- , could exert beneficial effect, reducing the vol-ume of gadolinium-enhancing lesions and the development of new lesions [144]. However, in the little observational study conducted on 7 patients by Sena et al., treatment with lovastatin reduced the number of T1 lesions at 2 years follow-up, whereas disability scores remained unchanged and the majority of patients developed new T2 lesions [142]. Thus, despite some encouraging results, it is still not clear if statins can be really useful in the treatment of MS. To better address this issue, a multicenter placebo-controlled trial is currently being conducted. Patients will be treated for 12 months and the composite endpoint will consider both clinical and radiological aspects [145].

Moreover, beside their effect due to the regulation of the immune response, statins appear to have additional immunity independent effects on neuronal and glial cells, which might be of particular importance for recovery in relapsing phases of central nervous system autoimmune disease. Statins have been shown to protect cultured neurons from exocitotoxic death, a form of neuronal death primarily caused by brain ischemia. This statin mediated neuroprotection was signifi-cantly attenuated by co-treatment with either mevalonate or cholesterol, indicating that this effect might be directly correlated to inhibition of neuronal cholesterol biosynthesis [146]. In other studies, lovastatin inhibited degeneration of oligodendrocyte progenitors, a process that is believed to be responsible for impaired remyelination after inflammatory damage of the myelin sheath. Indeed, lovastatin treatment promoted remyelination in the spinal cord of mice with EAE and increased the expression of myelin proteins and transcription factors associated with differentiating oligodendrocytes [146, 147].

These findings might be of therapeutic relevance not only for inflammatory demyelinising CNS disease but also for neurodegenerative disorders, such as Alzheimer’s disease (AD), and other forms of dementia. Indeed, in these diseases, statins seem to show other pleiotropic and potentially benefi-cial effects. Statin treatment has been reported to reduce the risk of dementia possibly by causing a reduction in amyloid-

peptides in the cerebrospinal fluid and brain both in animal

models and in humans, and by promoting the activity of the neuroprotective alpha-secretase ADAM 10 [147-151]. Gellerman and coll., in an in vitro study, found that lovas-tatin can reduce the formation of amyloid-like A plaques in human macrophages by 35% [152]. Interestingly, in a recent report lovastatin have also shown the ability to inhibit, in a dose-dependent manner, the formation of amyloid AA in an in vitro model. In both the studies these effects might be de-pendent on inhibition of farnesyl-derived isoprenoids pro-duction [153]. However, a study in animal models seems to deny these reports [154], and so do some clinical trials. In-deed, results from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) showed no significant effects of pravastatin therapy on slowing cognitive decline [155], and a telephone questionnaire assessing cognitive function in the Heart Protection Study did not point out any beneficial effect of simvastatin [156]. In contrast, the AD Cholesterol-Lowering Treatment (ADCLT) trial, involving 63 patients with AD randomized to 80 mg/d atorvastatin or placebo for 12 months, showed more encouraging results: although the study was relatively small (only 46 subjects completed the trial), atorvastatin therapy was associated with a significant delay in cognitive deterioration assessed by the Alzheimer’s Disease Assessment Scale-Cognition scores [157]. Surely, these contrasting results support the need to carry out more definitive studies in this area. By this way, the Atorvas-tatin/Donepezil in Alzheimer's Disease (LEADe) study has recently termed: in this study it has been tested the effect of atorvastatin on top of therapy with donepezil in a large popu-lation of elderly with dementia, but the results are still un-published [158].

These data, although not completely confirmed and in need of clarification with larger trials, show that statins can be useful in a large variety of pathological conditions, in which inflammation is involved, even if apparently far from the ones in which statin use is currently indicated.

For example, statin therapy seems to be beneficial also in sepsis treatment. Indeed, beyond pathogen virulence, there are many other factors that participate in the pathogenesis of sepsis and that determine its outcome, in particular the in-flammatory response of the host. A successful inflammatory response eliminates the invading microorganisms without causing lasting damage, while Systemic Inflammatory Re-sponse Syndrome (SIRS) develops when the initial appropri-ate response becomes amplified, and then aberrant [159]. Several animal models have been used to examine the effects of statin therapy in sepsis. In a murine model of LPS-induced sepsis, pre-treatment with cerivastatin significantly improved 7-days survival. The treatment also reduced serum levels of TNF- and IL-1 at 2 h and NO, nitrite, and nitrate at 8 h [160]. In the mouse cecal ligation and puncture (CLP) model of polymicrobial sepsis, pre-treatment with simvastatin sig-nificantly increased both the 3-days survival rate (from 26% to 73%) and the average duration of survival (from 28 to 108h) [161]. This improvement was associated with a pres-ervation of cardiac function and hemodynamic status, which were severely impaired in untreated CLP mice. As one of the underlying mechanisms, the authors found that the increased mononuclear cell adhesiveness in septic mice, an important contributor to sepsis pathophysiology, was partially inhibited

Immunomodulator Activity of 3-Hydroxy-3-Methilglutaryl-CoA Cardiovascular & Hematological Agents in Medicinal Chemistry, 2009, Vol. 7, No. 4 289

by statin treatment. Subsequent CLP studies in mice demon-strated that this effect was seen with simvastatin, atorvas-tatin, and pravastatin but not with fluvastatin [162, 163]. Taken together, these studies provide significant evidence to support the immunomodulatory effect of statins in sepsis and suggest that this is a class effect of these drugs.

Some studies have also been carried out in humans. Sys-temic inflammatory response frequently occurs after coro-nary artery bypass surgery, and it is strongly correlated with the risk of postoperative morbidity and mortality. In a dou-ble-blind, placebo-controlled, randomized study, 20 mg atorvastatin for 3 weeks before surgery significantly reduced IL-6 and IL-8 release and neutrophil adhesion to the venous endothelium in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass [164]. In a prospective observational cohort study of 361 consecutive patients ad-mitted with suspected or documented acute bacterial infec-tion, severe sepsis developed in 19% of patients not on pre-vious statin treatment compared with only 2.4% of the pre-treated patients [165]. More recently, a study that used pro-pensity-based matching, which accounted for each individ-ual’s likelihood of receiving a statin, yielded a cohort of 69.168 patients with cardiovascular disease, half of whom received a statin and half did not. They found that patients receiving statins had a 19–25% lower incidence of sepsis, severe sepsis, or fatal sepsis than the controls [166]. Another prospective observational study examining 361 patients with suspected infection attending the emergency department found that the 82 patients on statin therapy had a clinically and statistically significant reduction in mortality [167]. However, these data are not yet conclusive and there are some question to answer before starting to use statins in sep-sis. Beyond sepsis, the relation between statin use and infec-tious diseases has been studied in other settings: an examina-tion of the UK General Practice Research Database per-formed to identify the susceptibility to community acquired pneumonia among diabetic patients in relation to statin as-sumption, observed a correlation between statin use and re-duction of the risk of pneumonia in this population. This effect persisted after adjustment for confounding factors and in sub-group analyses [168]. Three other studies investigated the correlation between statin therapy and CAP outcome: two retrospective studies showed a better outcome in statin users, while a prospective study showed no benefit in pa-tients on statin therapy admitted to hospital with CAP [169-171].

In conclusion, even if in many cases available data are still too little to justify their use on large scale, the further comprehension of the action and the pleiotropic effects of statins has made us able to broaden our view about the pos-sible fields of employment of these drugs, some of which were completely unexpected until a few years ago. It is to be hoped that this will lead to fully exploit their several lipid independent beneficial effects.

CONCLUSIONS

Statins have initially revolutioned the treatment of hyper-cholesterolemia, and are now known to exert beneficial ef-fects by reducing cardiovascular morbidity and mortality in primary and secondary prevention not only in hypercoles-

terolemic patients. During the last decade several studies in vitro and in vivo have described the pleiotropic effects of statins, independent from their lipid-lowering effects, includ-ing improvement of endothelial function, stabilization of atherosclerotic lesions and inhibition of platelet aggregation. These pleiotropic effects are probably effective in ACS, where they seem to be at least in part responsible of the in-creased and rapid benefits of early high-dose statin treat-ment. These observations remark the central position filled by statins in the scenario of cardiovascular drugs.

Statins have also demonstrated to inhibit the activation of the immune response. This finding raises the question of whether statins might be used as immunomodulatory agents in inflammatory and degenerative diseases such as RA, MS, and others. In most cases, they are safe and tolerable and seem to be effective, however, data mainly come from ob-servational studies and small randomized trials. Thus, evi-dence is still too weak to justify a use on large scale, but it is a fact that a very promising research path has been traced, and future studies may lead us to profit from the beneficial properties of statins also in other fields beyond cardiovascu-lar medicine.

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Received: March 21, 2009 Revised: July 13, 2009 Accepted: July 28, 2009