Elsevier

Atherosclerosis

Volume 240, Issue 2, June 2015, Pages 497-509
Atherosclerosis

Review
Novel anti-inflammatory therapies for the treatment of atherosclerosis

https://doi.org/10.1016/j.atherosclerosis.2015.04.783Get rights and content

Highlights

  • Inflammation acts by different pathways to contribute to atherogenesis.

  • Clinical trials of novel anti-inflammatories suggested their potential utility for CAD.

  • IL-1β, Il-6, P-selectin, 5-LO and TNF-α are possible targets of therapy.

  • Immune cells, serpin, colchicine, methotrexate and HDL may reduce atherosclerosis.

Abstract

The underlying role of inflammation in atherosclerosis has been characterized. However, current treatment of coronary artery disease (CAD) predominantly consists of targeted reductions in serum lipoprotein levels rather than combating the deleterious effects of acute and chronic inflammation. Vascular inflammation acts by a number of different molecular and cellular pathways to contribute to atherogenesis. Over the last decades, both basic studies and clinical trials have provided evidence for the potential benefits of treatment of inflammation in CAD. During this period, development of pharmacotherapies directed towards inflammation in atherosclerosis has accelerated quickly. This review will highlight specific therapies targeting interleukin-1β (IL-1β), P-selectin and 5-lipoxygenase (5-LO). It will also aim to examine the anti-inflammatory effects of serpin administration, colchicine and intravenous HDL-directed treatment of CAD. We summarize the mechanistic rationale and evidence for these novel anti-inflammatory treatments at both the experimental and clinical levels.

Introduction

Atherosclerosis is an inflammatory disease that results in the development of plaques and progressive stenosis of the coronary arteries. Inflammation has been implicated in every stage of atherosclerosis, ranging from onset of plaque to rupture. Traditional models of inflammation begin with endothelial cell dysfunction within the vascular wall resulting in up-regulation of leukocyte adhesion molecules followed by infiltration of cholesterol and diapedesis of monocytes across the arterial intima, with subsequent development of pro-inflammatory foam cells and eventual atherosclerotic plaque formation [1], [2], [3]. The use of P-selectin and leukotriene inhibitors, intravenous HDL, serpins and colchicine have all been proposed as therapeutic options to impede different steps in the inflammatory process in atherosclerosis [4].

Other inflammatory pathways have been elucidated more recently. The role of cytokines that promote atherosclerosis, including Interleukin-1β (Il-1β), IL-6 and tumor necrosis factor-α (TNF-α), has become increasingly clear. Additionally, the importance of immune cells, particularly T-helper and regulatory T-cells, has been noted in atheroma development, altering traditional mechanistic views of vascular inflammation. Current evidence has also highlighted the role of innate, adaptive and humoral immunity in atherogenesis. These inflammatory pathways serve as burgeoning targets for future therapy.

Despite the efficacy of therapies targeting serum lipid abnormalities, atherosclerosis remains the most significant cause of death in the world [5]. The potential benefit of targeting inflammation in atherosclerosis may be demonstrated by examining cardiovascular outcomes in patients receiving 1) statins for coronary artery disease (CAD) and 2) therapy for systemic inflammatory conditions. In patients with known CAD, a dose-dependent decrease in LDL-cholesterol (LDL-C) levels and concurrent reduction in cardiovascular events has been associated with statin use. However, the TNT and IDEAL trials suggested that despite treatment with high-dose statins and concurrent reductions in LDL-C levels, the risk of ischemic events still exists in CAD patients, with event rates ranging between 8.7% and 9.3% over ∼5-year median follow-up, suggesting potential utility for additional therapies targeting atherosclerosis [6], [7]. Outside this lowering effect on LDL-C, the potential anti-inflammatory effects of statins were examined in the Jupiter trial. Major cardiovascular events were significantly reduced in patients without overt hyperlipidemia but with elevated high-sensitivity C-reactive protein (hs-CRP) levels when treated by rosuvastatin [8]. A secondary analysis of this study demonstrated that patients with reductions of both hs-CRP levels <2 mg/L and LDL-C < 1.8 mmol/L had greater clinical benefit when compared with those who achieved just one of this targets [9].

In patients with underlying chronic systemic inflammatory conditions, such as rheumatoid arthritis (RA), systemic lupus erythematosus, psoriasis and inflammatory bowel disease, rates of myocardial infarction (MI) are increased when compared with those in the general population. In these patients, vascular inflammation is noted early in disease with diminished nitric oxide production causing endothelial dysfunction, demonstrated by impaired flow-mediated coronary dilation, and further propagation of the inflammatory cascade results in premature atherosclerotic plaque formation. Treatment of systemic extra-cardiac conditions with anti-inflammatory therapies such as methotrexate and TNF-α inhibitors has been associated with possible reductions in the development of CAD and cardiovascular outcomes [10], [11].

This review attempts to highlight therapies targeting components of traditional and emerging inflammatory pathways involved in atherogenesis, including inhibition of IL-1β, IL-6, TNF-α, P-selectin and 5-lipoxygenase (5-LO), as well as examining the potential utility of serpin, intravenous HDL, methotrexate and colchicine treatments. It also summarizes pre-clinical evidence for therapies that promote atheroprotective immunity, including T-cell-targeted treatments and immunization strategies against atherosclerosis.

The IL-1 family of proteins consists of IL-1α and IL-1β, proinflammatory cytokines which act on endothelial and vascular smooth muscle cells (VSMCs). IL-1α proteins bind to an IL-1 receptor. IL-1 receptor type II and IL-1 receptor antagonist (IL-1Ra) serve as competitive inhibitors to counter the effects of IL-1α and IL-1β [12]. After synthesis, IL-1α is predominantly bound to the plasma membrane of producing cells and acts locally. In contrast, IL-1β is secreted into the plasma, predominantly by monocytes and macrophages, and acts systemically [13]. IL-1β plays an important role in up regulating leukocyte adhesion molecules on endothelial cells, proliferation of VSMCs and production of other cytokines [14], [15] which have all been implicated in the development of atherosclerosis (Fig. 1) [13].

IL-1β was found to be elevated in porcine models immediately after angioplasty and was suggested to play a role in inflammation after arterial injury. IL-1 Ra deficient mice, which are exposed to the excessive effects of IL-1β, have increased neointimal thickening after endothelial injury due to balloon angioplasty-related injury and increased vascular inflammation [16], [17]. Direct intracoronary administration of Il-1 had similar increase in neointimal thickening and arterial vasospasm in porcine models [18].

Inhibiting the actions of Il-1β has been shown to attenuate plaque growth in animal models. Reduced intimal thickening was noted after carotid artery injury in mice deficient of IL-1β and type 1 IL-1 receptor [19]. Administration of IL-1Ra to ApoE knockout mice resulted in attenuation of fatty lesion formation (Table 1) [20]. Ablation of the IL-1 receptor in mice predisposed to atherosclerosis also attenuated plaque progression [21]. Furthermore, a single administration of the IL-1β modulator gevokizumab improves endothelial regrowth and reduces neointima formation in rats following carotid denudation (Table 1) [22]. In addition to its role in atherosclerosis, IL-1 may affect myocardial remodeling after MI. In animal models, use of IL-1β trap or administration of type 1 IL-1 Ra have been shown to reduce myocardial dysfunction by preventing apoptosis and fibrosis associated with post–MI remodeling (Table 1) [23], [24], [25].

In humans, arteries with atherosclerotic lesions have greater IL-1β concentrations when compared to normal coronary arteries [26]. Despite this, causality between arterial IL-1β levels and development of atherosclerosis has not been determined. In contrast with animal studies, IL-1Ra levels have been noted to be higher in patients with acute coronary syndrome (ACS) in comparison to asymptomatic patients or those with chronic stable CAD [27]. Increased plasma levels of IL-1Ra at the time of PCI have also been associated with major adverse cardiovascular events in patients with symptomatic CAD [28]. Higher levels may be attributed to increased production of IL-1Ra by myocytes at infarct border zones in response to tissue injury caused by IL-1-related pathways [29]. It remains to be seen whether higher levels of IL-1β and its receptors merely serve as a surrogate markers for disease or whether they are involved in causal pathways regulating CAD development. Polymorphisms of IL-1Ra have been associated with increased risk of restenosis (>50% luminal narrowing) after percutaneous coronary intervention (PCI) in a large cohort of individuals with single-vessel disease [30], but these associations are not consistent and have conflicted with a subsequent meta-analysis [31].

Clinically, administration of anakinra, a non-glycosylated form of human recombinant IL-1Ra that competitively inhibits the actions of IL-1β, to patients with rheumatoid arthritis but no known CAD was associated with improved coronary flow reserve, endothelial function and reduced levels of inflammatory biomarkers compared to placebo [32]. In this study, parameters of left ventricular function, including mitral annular systolic velocity and E-to-EM ratio, were improved in patients receiving anakinra at 30 days. In the larger clinical MRC-ILA-HEART Study, therapy with anakinra early after ACS patients did not reduce hs-CRP or subsequent cardiac events (Table 2) [33]. Currently, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) is a large clinical trial examining the effects of the selective human monoclonal IL-1β antibody, canakinumab, on rates of recurrent cardiovascular events in stable post–MI patients who have persistently elevated hsCRP (>2 mg/L) (Table 2) [34]. Canakinumab has been shown to reduce IL-6 and fibrinogen, both inflammatory markers, in patients with diabetes and high cardiovascular disease risk [35].

Other members of the interleukin family are also thought to be involved in the initiation and progression of atherosclerosis. Interleukin-6 (IL-6) plays a prominent role in the development of atherosclerotic plaques, as well as plaque rupture. Although IL-6 is expressed at low levels in healthy individuals, it is up-regulated in the setting of inflammation and further propagates the inflammatory response in atherosclerosis and other chronic systemic inflammatory disorders.

IL-6 is produced most commonly by macrophages in atherosclerotic plaques and also by endothelial cells, fibroblasts and adipose tissue [36], [37]. IL-6 acts by binding to IL-6 receptors (IL6R) and then complexing with gp130, a transmembrane molecule, leading to the activation of JNK, ERK and p38MAPK signaling systems. It promotes endothelial dysfunction, VSMC migration and macrophage transition to foam cells (Fig. 1) [38]. IL-6 is also involved in the acute phase response to inflammation, including the regulation of C-reactive protein.

In vitro, free cholesterol loaded macrophages were shown to be sources of significant IL-6 synthesis and production. In human VSMCs cultures, administration of angiotensin II has been noted to increase IL-6 production [39]. The combined treatment of IL-6 with its soluble receptor resulted in increased production of MCP-1 in human mesangial cell [40]. Similarly, the addition of soluble IL-6 receptors to thrombin activated umbilical vein endothelial cells resulted in increased synthesis of MCP-1 [41]. Combined IL-6 and receptor treatment also stimulated ICAM-1 and VCAM-1 production in endothelial cells [42], whereas antibodies directed at IL-6 prevented the increase in MCP-1. Finally, incubation of IL-6 with isolated peritoneal macrophages resulted in increased oxidized LDL degradation [38].

IL-6 mRNA was detected in apoE knockout mice but could not be found in wild-type controls [37]. Immunohistological staining of aortic tissue in apoE knockout mice revealed expression of IL-6 to be localized to macrophages. Administration of IL-6 antibodies to apoE knockout mice prevented angiotensin II mediated oxidized LDL uptake in macrophages and synthesis of CD36, which is highly expressed in foam cells [38]. In contrast treatment with recombinant IL-6 in apoE knockout mice has been shown to increase aortic fatty streaks by 1.9–5.1 folds when compared with mice administered saline [43]. Surprisingly, atheroprotective effects of IL-6 have also been suggested based on animal model studies. In apoE and IL-6 double knockout mice, atherosclerotic plaque formation was increased significantly when compared with apoE knockout alone, IL-6 knockout alone and wild type mice [44]. Additionally, IL-6 knockout mice have been noted to develop larger fatty streak lesions when compared with wild-type mice after being fed an atherogenic diet [45].

Increased serum IL-6 levels have been described in patients with unstable angina. Increased IL-6 levels noted within 48 h of hospitalization for unstable angina was associated with worsened prognosis [46]. In patients receiving thrombolysis for acute MI, elevated serum IL-6 levels portended to worsen in-hospital and 12-month outcomes [47]. In healthy males, increased circulating levels of IL-6 were associated with increased future risk of MI [48]. In a population of healthy older (≥65 years) adults, higher levels of circulating IL-6 was associated with increased long-term cardiovascular and non-cardiovascular mortality [49]. Increased post-PCI levels of IL-6 have been associated with higher rates of restenosis [50]. However, based on this evidence it currently remains unclear as to whether IL-6 serves merely as a surrogate marker for increased risk or has true causative effects on atherosclerotic progression.

Genome-wide associated studies (GWAS) have shed light on inflammation-related gene loci that may be associated with the development of CAD. These studies have noted the ABO locus on the chromosome 9q34 to be associated with CAD and plasma levels of IL-6 (as well as E-selectin) [51]. The Asp358Ala is an IL-6 receptor loss-of-function gene polymorphism that has been associated with a reduction in CAD risk [52]. A meta-analysis involving 33514 individuals noted that the most commonly studied IL-6 gene polymorphism (−174G > C) was associated with development of atherosclerosis in non-Caucasians and population-based subgroups [53].

Although a monoclocal antibody to IL-6 is clinically available for the treatment of rheumatoid arthritis, there have been thus far no clinical trials examining targeted anti-IL-6 therapy for atherosclerosis. Further study may be needed to clarify and isolate selective pro-atherosclerotic pathways before IL-6 targeted treatment is attempted.

Selectins are cell surface glycoproteins expressed by platelets and endothelial cells that play an integral role in mediating cell–cell interaction. P-selectin is a member of the selectin protein family, along with L- and E-selectin, and is found in α granules of platelets and Weibel-Palade bodies of endothelial cells [54]. P-selectin binds to and acts via its major ligand, protein selected glycoprotein ligand-1 (PSGL-1), expressed by leukocytes [55]. The initial step of leukocyte rolling along the vascular endothelium and activation of platelets in early atherosclerosis development is in part mediated by selectins (Fig. 1) [54]. P-selectin also plays a role in fibrin formation [56], as well as influencing size and stability of thrombi after ACS [57].

The role of P-selectin in atherosclerosis has predominantly been derived from animal model studies. Increased expression of P-selectin has been noted in the aortas of hypercholesterolemic rats [58]. In P-selectin knockout mice, atherosclerotic plaque growth and neointimal thickening was reduced in ApoE and LDL-receptor deficient animals [59], [60]. In vitro, inhibition of P-selectin has been shown to reduce platelet aggregation and platelet-leukocyte adhesion [61]. In vivo, using various animal models, inhibition of P-selectin, or its ligand PSGL-1, may lessen arterial neointimal thickening after angioplasty and accelerate thrombolysis (Table 1) [62], [63], [64], [65], [66]. In addition to its role in atherosclerosis, post–MI administration of P-selectin inhibitors via an intracoronary infusion has been associated with reduced infarct size and lessened ischemic-reperfusion injuries [66].

In humans, increased expression of P-selectins has been noted in the endothelium covering fatty streaks and atherosclerotic plaques based on immunohistochemical analysis [67]. Higher plasma levels of P-selectin have also been found in patients with unstable angina when compared to those with stable CAD, as well as after PCI [68], [69]. Increased plasma levels of P-selectin have been associated with cardiovascular mortality and sudden cardiac death in male dialysis patients [70].

Thus far, two clinical trials have examined the effects the P-selectin antibody inclacumab in patients with CAD. The SELECT-Acute Coronary Syndrome (SELECT-ACS) trial showed that inclacumab significantly reduced peri-PCI myocardial injury (reflected by changes in troponin and CK-MB) after NSTEMI (Table 2) [71]. In the SELECT-Coronary Artery Bypass (CABG) Surgery trial, inclacumab was administered to patients undergoing saphenous vein grafting (SVG). The results of the latter trial have not yet been reported.

Leukotrienes are a class of eicosanoids derived from arachidonic acid metabolism that have been shown to play a prominent role in the development of inflammatory diseases, including asthma [72], [73]. In atherosclerosis, 5-lipoxygenase (5-LO) has emerged as a potential therapeutic target for reduction of plaque inflammation [74], [75]. 5-LO helps to regulate the production of 2 major leukotrienes classes, leukotriene B4 (LTB4) and the cysteinyl leukotrienes (LTC4, D4, and E4) [76]. LTB4 has been shown to play a role in increased leukocyte adhesion to vascular endothelium, as well as proliferation and migration of VSMCs (Fig. 1) [77]. Cysteinyl leukotrienes allow for increased vascular constriction and permeability, while also reducing myocardial contractility and blood flow [78], [79].

In mice, 5-LO has been identified as a gene that contributes to atherosclerosis in hypercholesterolemic mice [80]. Inhibition of 5-LO attenuates plaque progression in mice models prone to atherosclerosis (Table 1) [81]. In addition, inhibition of 5-LO in hypercholesterolemic rabbits reduces neointimal thickening and macrophage infiltration after femoral arterial injury (Table 1) [82]. Similarly, inhibition of cysteinyl leukotrienes and its major receptor (BLT1) also decreases neointimal thickening and reduces foam cell and lipid infiltration in the arterial wall [83], [84].

Clinical analysis has revealed increased expression of 5-LO in the atherosclerotic plaques of patients with CAD that may be prone to rupture [85]. 5-LO expressing cells were also found to be more common in late vs. early stages of coronary artery disease [74]. Expression of 5-LO was notably higher in the carotid plaques of patients who had recent cardiac ischemic events [75]. Genetic analyses have demonstrated that 5-LO and 5-LO activating protein (FLAP) gene polymorphisms may result in almost 2-fold increase in the risk of MI [86].

VIA-2291 is a 5-LO inhibitor that was previously studied in several clinical trials for asthma [87]. More recently, VIA-2291 was examined in a placebo-controlled, double-blinded trial involving 191 patients randomized 3 weeks after a recent ACS (Table 2) [76]. Administration of VIA-2291 was associated with marked dose-related decreases in plasma LTB4 and urine LTE4 after 12 weeks of treatment. The subgroup of patients who were followed for 24 weeks revealed a significant reduction in hs-C reactive protein when treated with VIA-2291 compared to placebo. On CT angiography performed at 24 weeks, significantly fewer patients developed new coronary plaques when receiving VIA-2291 compared with placebo (27.8% vs. 4.8%). Non-calcified plaque volume was also substantially reduced in patients treated with VIA-2291 when compared to placebo (p < 0.01).

Serine protease inhibitors, termed serpins, are a family of glycoproteins which are found in both primitive organisms, such as viruses and bacteria and various mammalian species in which they represent between 2 and 10% of all circulating proteins [88]. In mammals, serpins exhibit both antithrombotic and prothrombotic effects, while in viruses serpins demonstrate anti-inflammatory and anti-thrombotic properties making them an ideal therapeutic target for cardiovascular disease (Fig. 2) [89]. In vitro, infusion of the viral serpin, Serp-1, was shown to complex with and inhibit the actions of urokinase-type plasminogen activators (uPA), tissue plasminogen activator (tPA), plasmin and factor Xa [90], [91], [92].

In animal models, Serp-1 has reduced early activation and infiltration of monocytes/macrophages after arterial injury, stent implantation and transplantation [88], [93], [94]. Serp-1 also inhibited the action of thrombolytic and thrombotic proteases and attenuated arterial plaque progression [95]. Local administration of Serp-1 at the site of balloon angioplasty-induced injury reduced neointimal expansion and plaque growth in rabbits at 4 weeks of follow-up (Table 1) [93]. In human cell lines, administration of Serp-1 reduced adhesion, activation and migration of monocytes [96].

A recent randomized, placebo-controlled trial involving 48 ACS patients undergoing coronary stent implantation found that intravenous administration of Serp-1 reduced troponin and CK-MB rise after PCI (Table 2) [97]. Of note, post-procedural levels of cardiac biomarkers have been associated with worsened prognosis.

More recently, a second protein from the serpin superfamily, named Serp-2, has also been shown to reduce T-cell-mediated apoptosis and vascular inflammation in in vivo mouse and rat models [98]. Additionally, preliminary in vitro mice studies suggested that Serp-2 administration may be associated with a pan-arterial reduction in plaque growth rather than just at sites of arterial injury [98].

Therapies targeting reduction of serum LDL-C levels have been associated with significant decreases of morbidity and mortality attributable to atherosclerosis. In contrast with LDL-C, there is an inverse correlation between serum high-density lipoprotein (HDL-C) levels and cardiovascular events, suggesting that treatments aimed at augmenting HDL-C levels or function could be beneficial; however causality between low HDL-C levels and worsened cardiovascular outcomes has not been established. HDL has been shown to be involved in so-called reverse cholesterol transport, whereby cholesterol is transported from foam cells to the liver. Anti-inflammatory properties of HDL have also been described, with reduction of the synthesis of vascular endothelial adhesion molecules and pro-inflammatory chemokines, as well as possible attenuation in the production of foam cells (Fig. 3, Table 1) [99], [100], [101].

In early animal studies, combined infusion of HDL/very high-density lipoproteins (VHDL) resulted in regression of aortic wall plaque size and decreased lipid deposition in cholesterol-fed rabbits [102], [103]. In vitro models have suggested that reconstituted HDL (rHDL) administration is associated with reductions in monocyte migration and neutrophil adhesion to human endothelial cells [104], [105]. Similar studies have also demonstrated that pre-incubation of rHDL with human monocytes and coronary endothelial cells results in attenuated expression of chemokines and chemokine receptors, which in turn are associated with monocyte recruitment and early atherosclerosis development [106]. rHDL infusion has been shown to attenuate neointimal thickening and production of vascular endothelium adhesion molecules after carotid injury in ApoE knockout mice [100]. Infusion of rHDL in rabbit vascular injury models also prevented neutrophil infiltration, vascular endothelial adhesion protein synthesis and chemokine protein expression at injury site [107].

In cholesterol-fed rabbits, intravenous infusion of ApoA1 Milano [108] after balloon- or electrically-induced peripheral arterial injury significantly reduced neointimal thickening, VSMC proliferation and macrophage and lipid content at the injury site when compared with placebo [109], [110], [111], [112]. A single high dose of ApoA1 Milano has also been shown to mobilize cholesterol from tissue sources, thereby promoting reverse cholesterol transport in ApoE-deficient mice [112]. Treatment of rabbits with ApoA1 Milano infusions was associated with a 5% regression in aortic plaques when comparing pre- and post-treatment (5-week) imaging using MRI (Table 1) [113]. In comparison to administration of wild-type HDL infusion of ApoA1 Milano in rabbits appears to have been associated with superior anti-inflammatory effects, with notably reduced plaque macrophage density and chemokine levels [114].

Intravenous administration of rHDL has also been noted to cause reductions in lipid content, macrophage size, vascular adhesion molecules and inflammatory markers in atherectomized plaques of superficial femoral arteries when compared with placebo [115]. In diabetic patients, rHDL infusion also reduced vascular adhesion of monocytes and neutrophils [116]. Four clinical studies evaluated different forms of intravenous HDL infusions using intravascular ultrasound imaging [117], [120], [119], [118]: reductions in coronary plaque burden were observed at follow-up when compared to baseline, but none of these studies established statistical significance compared to placebo. Large clinical trials using the cholesterylester transfer protein (CETP) inhibitors torcetrapib (ILLUMINATE) and dalcetrapib (DAL-Outcomes) have not shown significant benefit on clinical outcomes despite significant increases in plasma HDL-cholesterol [121], [122]. Interestingly, CETP inhibitors have been shown not to reduce plasma levels of hs-C reactive protein [122], [123].

Colchicine may reduce inflammatory responses associated with atherosclerosis by inhibiting vascular endothelial surface protein synthesis, cytokine production and monocyte migration (Fig. 3) [124], [125]. In vitro, colchicine has been noted to down regulate E-selectin from endothelial cells and synthesis of IL-2 from T-cells [125]. Colchicine has been shown to reduce the proliferative and migratory activity of human VSMCs from coronary and peripheral atherosclerotic lesions [126]. In animal models of atherosclerosis, colchicine attenuated lipid deposition in aortic plaques [127].

Clinically, colchicine has been reported to reduce the incidence of ischemic heart disease in patients with Familial Mediterranean Fever (FMF), a hereditary inflammatory disorder [128]. In addition, carotid intima-media thickness was shown not to be different in patients with FMF receiving colchicine and healthy controls [129], suggesting that the anti-inflammatory effects of colchicine may attenuate atherosclerosis development. Colchicine has been shown to reduce the risk of recurrences of pericarditis after the initial episode as well as the risk of the post-pericardiotomy syndrome [130].

In patients with stable CAD and those with ACS, colchicine has been shown to significantly reduce hs-CRP [131], [132]. Furthermore, colchicine was recently examined in the LoDoCO study, a prospective, randomized multicenter trial involving 532 patients with clinically stable CAD (Table 2) [133]. The LoDoCo study, patients receiving 0.5 mg daily of colchicine had a reduction of 67% (p < 0.001) in the rates of major adverse coronary events (composite of ACS, out-of-hospital cardiac arrest, and noncardiac embolic stroke) after 3 years of follow-up. Clearly, larger studies focused on hard cardiovascular outcomes should be conducted with colchicine in patients with atherosclerotic heart disease.

Section snippets

Methotrexate

Methotrexate is a dihydrofolate reductase inhibitor that prevents the synthesis of nucleotides and serves as a chemotherapeutic agent at high doses. At low-doses, methotrexate is frequently used to target inflammation in systemic inflammatory disease such as collagen vascular diseases. The inflammatory pathways involved in such systemic diseases, notably RA, resemble those described in atherosclerosis.

Administration of methotrexate reduces cellular responses to IL-1 while increasing production

Conclusion

The current paradigm for treatment of atherosclerosis is centered on statin use and targeting abnormal lipid levels. However, the importance of inflammation in atherosclerosis has been increasingly suspected and anti-inflammatory therapies have been proposed as possible adjuncts to current therapy. Evaluation of these therapies should focus on different pro-inflammatory pathways that appear to be involved in the atherosclerotic process. Despite the obvious complexity of these pathways, a number

Conflicts of interests

The authors have no conflicts of interest to disclose.

Funding

Philippe L. L'Allier has received research grants from Desgroseillers-Bérard Chair in interventional cardiology, and is supported by the Montreal Heart Institute Foundation. Vincent Spagnoli has received research grants from French Federation of Cardiology.

References (196)

  • T.B. Harris et al.

    Associations of elevated interleukin-6 and c-reactive protein levels with mortality in the elderly

    Am. J. Med.

    (1999)
  • Y.W. Yin et al.

    Influence of interleukin-6 gene -174g>c polymorphism on development of atherosclerosis: a meta-analysis of 50 studies involving 33,514 subjects

    Gene

    (2013)
  • R.J. Jaumdally et al.

    Platelet activation in coronary artery diseaseintracardiac vs peripheral venous levels and the effects of angioplasty

    CHEST J.

    (2007)
  • J.C. Tardif et al.

    Effects of the p-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-st-segment elevation myocardial infarction: results of the select-acs trial

    J. Am. Coll. Cardiol.

    (2013)
  • J.-H. Choi et al.

    Anti-atherogenic effect of bhb-tzd having inhibitory activities on cyclooxygenase and 5-lipoxygenase in hyperlipidemic mice

    Atherosclerosis

    (2010)
  • H. Chen et al.

    Viral serpin therapeutics from concept to clinic

    Methods Enzym.

    (2011)
  • P. Nash et al.

    Inhibitory specificity of the anti-inflammatory myxoma virus serpin, serp-1

    J. Biol. Chem.

    (1998)
  • D.A. Lomas et al.

    Inhibition of plasmin, urokinase, tissue plasminogen activator, and c1s by a myxoma virus serine proteinase inhibitor

    J. Biol. Chem.

    (1993)
  • A. Lucas et al.

    Transplant vasculopathy: viral anti-inflammatory serpin regulation of atherogenesis

    J. Heart Lung Transplant.

    (2000)
  • P. Dimayuga et al.

    Reconstituted hdl containing human apolipoprotein a-1 reduces vcam-1 expression and neointima formation following periadventitial cuff-induced carotid injury in apoe null mice

    Biochem. Biophys. Res. Commun.

    (1999)
  • P. Libby et al.

    Inflammation and atherosclerosis

    Circulation

    (2002)
  • M. Navab et al.

    The yin and yang of oxidation in the development of the fatty streak a review based on the 1994 george lyman duff memorial lecture

    Arteriosclerosis Thrombosis Vasc. Biol.

    (1996)
  • J.C. LaRosa et al.

    Intensive lipid lowering with atorvastatin in patients with stable coronary disease

    N. Engl. J. Med.

    (2005)
  • T.R. Pedersen et al.

    Incremental decrease in end points through aggressive lipid lowering (ideal) study group. High dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the ideal study: a randomized controlled trial. Multicenterstudium

    JAMA: J. Am. Med. Assoc.

    (2005)
  • P.M. Ridker et al.

    Rosuvastatin to prevent vascular events in men and women with elevated c-reactive protein

    N. Engl. J. Med.

    (2008)
  • C. Barnabe et al.

    Systematic review and meta-analysis: anti-tumor necrosis factor alpha therapy and cardiovascular events in rheumatoid arthritis

    Arthritis Care & Res.

    (2011)
  • V.P. van Halm et al.

    Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study

    Arthritis Res. Ther.

    (2006)
  • K. Isoda et al.

    The effect of interleukin-1 receptor antagonist on arteries and cholesterol metabolism

    J. Atheroscler. Thrombosis

    (2006)
  • C.A. Dinarello

    Immunological and inflammatory functions of the interleukin-1 family

    Annu. Rev. Immunol.

    (2009)
  • M.P. Bevilacqua et al.

    Interleukin-1 activation of vascular endothelium. Effects on procoagulant activity and leukocyte adhesion

    Am. J. Pathology

    (1985)
  • M. Tamaru et al.

    Interleukin-1β induces tissue-and cell type–specific expression of adhesion molecules in vivo

    Arteriosclerosis Thrombosis Vasc. Biol.

    (1998)
  • K. Isoda et al.

    Deficiency of interleukin-1 receptor antagonist promotes neointimal formation after injury

    Circulation

    (2003)
  • F. Merhi-Soussi et al.

    Interleukin-1 plays a major role in vascular inflammation and atherosclerosis in male apolipoprotein e-knockout mice

    Cardiovasc. Res.

    (2005)
  • H. Shimokawa et al.

    Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor

    J. Clin. Investigation

    (1996)
  • R. Elhage et al.

    Differential effects of interleukin-1 receptor antagonist and tumor necrosis factor binding protein on fatty-streak formation in apolipoprotein e–deficient mice

    Circulation

    (1998)
  • H. Chi et al.

    Interleukin-1 receptor signaling mediates atherosclerosis associated with bacterial exposure and/or a high-fat diet in a murine apolipoprotein e heterozygote model pharmacotherapeutic implications

    Circulation

    (2004)
  • B.W. Van Tassell et al.

    Interleukin-1 trap attenuates cardiac remodeling after experimental acute myocardial infarction in mice

    J. Cardiovasc. Pharmacol.

    (2010)
  • A. Abbate et al.

    Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction

    Circulation

    (2008)
  • J. Galea et al.

    Interleukin-1β in coronary arteries of patients with ischemic heart disease

    Arteriosclerosis Thrombosis Vasc. Biol.

    (1996)
  • G. Patti et al.

    Interleukin-1 receptor antagonist: a sensitive marker of instability in patients with coronary artery disease

    J. Thrombosis Thrombolysis

    (2002)
  • A. Abbate et al.

    Alterations in the interleukin-1/interleukin-1 receptor antagonist balance modulate cardiac remodeling following myocardial infarction in the mouse

    PloS One

    (2011)
  • S.E. Francis et al.

    Interleukin-1 receptor antagonist gene polymorphism and coronary artery disease

    Circulation

    (1999)
  • L. Zhou et al.

    Associations between interleukin-1 gene polymorphisms and coronary heart disease risk: a meta-analysis

    PLoS One

    (2012)
  • I. Ikonomidis et al.

    Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis

    Circulation

    (2008)
  • A.C. Morton et al.

    15 investigation of il-1 inhibition in patients presenting with non-st elevation myocardial infarction acute coronary syndromes (the mrc ila heart study)

    Heart

    (2011)
  • P.M. Ridker

    Closing the loop on inflammation and atherothrombosis: why perform the cirt and cantos trials?

    Trans. Am. Clin. Climatol. Assoc.

    (2013)
  • P.M. Ridker et al.

    Effects of interleukin-1β inhibition with canakinumab on hemoglobin a1c, lipids, c-reactive protein, interleukin-6, and fibrinogenclinical perspective a phase iib randomized, placebo-controlled trial

    Circulation

    (2012)
  • D.A. Sukovich et al.

    Expression of interleukin-6 in atherosclerotic lesions of male apoe-knockout mice: Inhibition by 17beta-estradiol

    Arteriosclerosis Thrombosis Vasc. Biol.

    (1998)
  • S. Keidar et al.

    Angiotensin ii administration to atherosclerotic mice increases macrophage uptake of oxidized ldl: a possible role for interleukin-6

    Arteriosclerosis Thrombosis Vasc. Biol.

    (2001)
  • R. Kranzhofer et al.

    Angiotensin induces inflammatory activation of human vascular smooth muscle cells

    Arteriosclerosis Thrombosis Vasc. Biol.

    (1999)
  • Cited by (122)

    • Kv1.3 Channel Is Involved In Ox-LDL-induced Macrophage Inflammation Via ERK/NF-κB signaling pathway

      2022, Archives of Biochemistry and Biophysics
      Citation Excerpt :

      An imbalance in cholesterol metabolism, especially modified LDL, can lead to macrophage dysfunction, altered nuclear receptor activation, an inflammatory response, and ultimately AS. Macrophages not only assemble lipids but also release TNF-α, IL-1β, IL-6, and other proinflammatory cytokines [24], which further irritate the vascular endothelium and promote disease progression [25]. In line with this, our study also found that ox-LDL induced an increase in IL-6 and TNF-α levels in macrophages.

    View all citing articles on Scopus
    View full text