Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immunoinflammatory mechanisms are involved. Inflammation is central at all stages of atherosclerosis. It is implicated in the formation of early fatty streaks, when the endothelium is activated and expresses chemokines and adhesion molecules leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium. It also acts at the onset of adverse clinical vascular events, when activated cells within the plaque secrete matrix proteases that degrade extracellular matrix proteins and weaken the fibrous cap, leading to rupture and thrombus formation. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis provided evidence that the immunoinflammatory response in atherosclerosis is modulated by regulatory pathways, in which the two anti-inflammatory cytokines interleukin-10 and transforming growth factor-beta play a critical role. The purpose of this review is to bring together the current information concerning the role of cytokines in the development, progression, and complications of atherosclerosis. Specific emphasis is placed on the contribution of pro- and anti-inflammatory cytokines to pathogenic (innate and adaptive) and regulatory immunity in the context of atherosclerosis. Based on our current knowledge of the role of cytokines in atherosclerosis, we propose some novel therapeutic strategies to combat this disease. In addition, we discuss the potential of circulating cytokine levels as biomarkers of coronary artery disease.

Atherosclerosis is an immunoinflammatory disease elicited by accumulation of lipids in the artery wall and leads to myocardial infarction and stroke. Here, we show that naturally arising CD4(+)CD25(+) regulatory T cells, which actively maintain immunological tolerance to self and nonself antigens, are powerful inhibitors of atherosclerosis in several mouse models. These results provide new insights into the immunopathogenesis of atherosclerosis and could lead to new therapeutic approaches that involve immune modulation using regulatory T cells.

Background-Apoptotic microparticles are responsible for almost all tissue factor activity of the plaque lipid core. We hypothesized that elevated levels of procoagulant microparticles could also circulate in the peripheral blood of patients with recent clinical signs of plaque disruption and thrombosis. Methods and Results-We studied 39 patients with coronary heart disease, including 12 patients with stable angina and 27 patients with acute coronary syndromes (ACS), and 12 patients with noncoronary heart disease. We isolated the circulating microparticles by capture with annexin V and determined their procoagulant potential with a prothrombinase assay. The cell origins of microparticles were determined in an additional 22 patients by antigenic capture with specific antibodies. A cute coronary syndromes (ACS) are severe clinical manifestations of coronary artery lumen occlusion by a thrombus formed on the contact of a ruptured or eroded atherosclerotic plaque. 1,2 Tissue factor (TF) is highly expressed in atherosclerotic plaques, 3 and TF activity of plaques retrieved from patients with unstable angina (UA) is significantly higher than that found in the plaques of patients with stable angina (SA), 4 which suggests that it may significantly determine thrombus formation after plaque disruption. TF activity is highly dependent on the presence of phosphatidylserine (PS), 5 and it has been shown that this anionic phospholipid is redistributed on the cell surface during apoptotic death, 6 conferring to the cell a potent procoagulant activity. 7,8 Interestingly, shed membrane apoptotic microparticles rich in PS are produced in considerable amounts within human atherosclerotic plaques and carry almost all TF activity of the plaque lipid core, 9 indicating that they may largely determine plaque thrombogenicity. In the present study, we hypothesized that high levels of cell-derived microparticles with procoagulant potential could also be detectable in the circulating blood of patients with recent clinical signs of plaque disruption and thrombosis and may therefore contribute to the initiation and perpetuation of the thrombotic process. Methods Patient SelectionTo isolate the circulating microparticles and determine their procoagulant potential, we prospectively included 39 patients with angina and angiographic documentation of coronary artery disease (CAD) and 12 controls. Among patients with CAD, 12 (9 men; mean age 62Ϯ3 years) had SA with no signs of myocardial ischemia at rest, and 27 had ACS: 13 (8 men; mean age 62Ϯ4 years) had UA (Braunwald class III) with documented signs of recent myocardial ischemia at rest, and 14 (10 men; mean age 61Ϯ4 years) had acute myocardial infarction (MI). Cardiovascular risk factors were not significantly different between the 3 groups of patients with CAD, except for hypercholesterolemia, which was more prevalent in patients with SA (PϽ0.02).All coronary patients were receiving aspirin. Patients with ACS received additional standard antithrombotic therapy before blood sampling. Anti-isch...

Abstract-The potential role of anti-inflammatory cytokines in the modulation of the atherosclerotic process remains unknown. Interleukin (IL)-10 has potent deactivating properties in macrophages and T cells and modulates many cellular processes that may interfere with the development and stability of the atherosclerotic plaque. IL-10 is expressed in human atherosclerosis and is associated with decreased signs of inflammation. In the present study, we show that IL-10 -deficient C57BL/6J mice fed an atherogenic diet and raised under specific pathogen-free conditions exhibit a significant 3-fold increase in lipid accumulation compared with wild-type mice. Interestingly, the susceptibility of IL-10 -deficient mice to atherosclerosis was exceedingly high (30-fold increase) when the mice were housed under conventional conditions. Atherosclerotic lesions of IL-10 -deficient mice showed increased T-cell infiltration, abundant interferon-␥ expression, and decreased collagen content. In vivo, transfer of murine IL-10 achieved 60% reduction in lesion size. These results underscore the critical roles of IL-10 in both atherosclerotic lesion formation and stability. Moreover, IL-10 appears to be crucial as a protective factor against the effect of environmental pathogens on atherosclerosis. The full text of this article is available at http://www.circresaha.org. (Circ Res. 1999;85:e17-e24.)

Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages in atherosclerotic plaques. According to the 'response to injury' and 'vulnerable plaque' hypotheses, contractile VSMCs recruited from the media undergo phenotypic conversion to proliferative synthetic cells that elaborate extracellular matrix to form the fibrous cap and hence stabilise plaques. However, recent lineage tracing studies have highlighted flaws in the interpretation of former studies, revealing these to have underestimated both the content and functions of VSMCs in plaques, and have thus challenged our view on the role of VSMCs in atherosclerosis. It is now evident that VSMCs are even more plastic than previously recognised, and can adopt alternative phenotypes including cells resembling foam cells, macrophages, mesenchymal stem cells, and osteochondrogenic cells, which could contribute both positively and negatively to disease progression. In this review, we present the evidence for VSMC plasticity and summarise the roles of VSMCs and VSMC-derived cells in atherosclerotic plaque development and progression. Correct attribution and spatio-temporal resolution of clinically beneficial and detrimental processes will underpin the success of any therapeutic intervention aimed at VSMCs and their derivatives.

Background-Monocytes are critical mediators of atherogenesis. Deletion of individual chemokines or chemokine receptors leads to significant but only partial inhibition of lesion development, whereas deficiency in other signals such as CXCL16 or CCR1 accelerates atherosclerosis. Evidence that particular chemokine pathways may cooperate to promote monocyte accumulation into inflamed tissues, particularly atherosclerotic arteries, is still lacking. Methods and Results-Here, we show that chemokine-mediated signals critically determine the frequency of monocytes in the blood and bone marrow under both noninflammatory and atherosclerotic conditions. Particularly, CCL2-, CX3CR1-, and CCR5-dependent signals differentially alter CD11b ϩ Ly6G Ϫ 7/4 hi (also known as Ly6C hi ) and CD11b ϩ Ly6G Ϫ 7/4 lo (Ly6C lo ) monocytosis. Combined inhibition of CCL2, CX3CR1, and CCR5 in hypercholesterolemic, atherosclerosis-susceptible apolipoprotein E-deficient mice leads to abrogation of bone marrow monocytosis and to additive reduction in circulating monocytes despite persistent hypercholesterolemia. These effects are associated with a marked and additive 90% reduction in atherosclerosis. Interestingly, lesion size highly correlates with the number of circulating monocytes, particularly the CD11b ϩ Ly6G Ϫ 7/4 lo subset. Conclusions-CCL2, CX3CR1, and CCR5 play independent and additive roles in atherogenesis. Signals mediated through these pathways critically determine the frequency of circulating monocyte subsets and thereby account for almost all macrophage accumulation into atherosclerotic arteries. (Circulation. 2008;117:1649-1657.)

Endothelial dysfunction and arterial stiffness are major determinants of cardiovascular risk in patients with end-stage renal failure (ESRF). Microparticles are membrane fragments shed from damaged or activated cells. Because microparticles can affect endothelial cells, this study investigated the relationship between circulating microparticles and arterial dysfunction in patients with ESRF and identified the cellular origin of microparticles associated with these alterations. Flow cytometry analysis of platelet-free plasma from 44 patients with ESRF indicated that circulating levels of Annexin V؉ microparticles were increased compared with 32 healthy subjects, as were levels of microparticles derived from endothelial cells (three-fold), platelets (16.5-fold), and erythrocytes (1.6-fold). However, when arterial function was evaluated noninvasively in patients with ESRF, only endothelial microparticle levels correlated highly with loss of flow-mediated dilation (r ‫؍‬ ؊0.543; P ‫؍‬ 0.004), increased aortic pulse wave velocity (r ‫؍‬ 0.642, P < 0.0001), and increased common carotid artery augmentation index (r ‫؍‬ 0.463, P ‫؍‬ 0.0017), whereas platelet-derived, erythrocyte-derived, and Annexin V؉ microparticle levels did not. In vitro, microparticles from patients with ESRF impaired endothelium-dependent relaxations and cyclic guanosine monophosphate generation, whereas microparticles from healthy subjects did not. Moreover, in vitro endothelial dysfunction correlated with endothelial-derived (r ‫؍‬ 0.891; P ‫؍‬ 0.003) but not platelet-derived microparticle concentrations. In fact, endothelial microparticles alone decreased endothelial nitric oxide release by 59 ؎ 7% (P ‫؍‬ 0.025). This study suggests that circulating microparticles of endothelial origin are tightly associated with endothelial dysfunction and arterial dysfunction in ESRF.J (3,4), a systemic disorder and a key variable in the pathogenesis of atherosclerosis and its complications (5). Moreover, arterial wall stiffening, which is partly influenced by nitric oxide (NO) and the endothelium (6,7), occurs frequently during ESRF and has been reported as an independent predictor of cardiovascular events (7-9) Circulating microparticles (MP) are shed membrane vesicles resulting from apoptosis or activation of several cell types in response to various stimuli (10,11). We previously demonstrated that circulating MP that are isolated from patients with acute coronary syndromes directly induce endothelial dysfunction in vitro and hypothesized that this effect could be of clinical relevance (12). In this study, we sought to extend those earlier observations by investigating the possible relationships between circulating MP levels and in vivo arterial properties in patients with ESRF. In addition, we undertook to determine the cellular origin of the circulating MP associated with these vascular alterations. Materials and MethodsWe included 44 patients with ESRF from the Fleury-Mérogis hemodialysis center. Patients were eligible for inclusion when (1) they had ha...

These results indicate that shed membrane microparticles with procoagulant potential are produced in human atherosclerotic plaques. Apoptosis could be a critical determinant of plaque thrombogenicity after plaque rupture.