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Pathogenetic and Immunological Paradigm of Atherosclerotic Plaque

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Plaque

G. C

ALCARA

, C. C

ORNO

Atherosclerosis is the ‘mother’ of ischaemic cardiopathy, of cerebrovascular disease, and of peripheral vasculopathy, and consequently is the indirect cause of the majority of deaths and disability in the world. The general view of the atherosclerotic process has changed; attention to the chronic degener- ative aspects has been replaced by the dominant hypothesis that considers atherosclerosis to be an inflammatory process of the arterial vascular wall [1, 2]. Atherosclerotic plaque thus represents a specific inflammatory response of the arterial wall to various damaging phlogogenic stimuli identified in the classical risk factors, such as hypercholesterolaemia, arterial hypertension, diabetes mellitus, cigarette smoking, obesity, being male (men are more at risk than women), insufficient physical activity, a history of atherosclerosis in the family, and ageing.

The 25% of patients who suffer cardiovascular problems during youth show none of the classical risk factors. Clinical research has identified at least a hundred additional conditions that may better indicate a tendency to future cardiovascular events. Among the well known and highly studied are homocysteine, lipoprotein (a), oxidative stress, fibrinogen, factor VII, protein C–reactive (PCR), adhesion molecules, and advanced glycation end-prod- ucts.

Endothelial anatomical injury is not necessary for the start-up of the ath- erosclerotic plaque, but it is a consequence of functional alteration of the endothelium (endothelial dysfunction) [3]. The endothelium represents the critical cellular interface that governs the homoeostasis of the arterial wall.

Under physiological conditions the effect of the paracrine endothelial sub- stances consists in:

Divisione di Medicina Interna Ospedaliera, Garibaldi Hospital, Catania, Italy

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− Maintenance of blood fluidity (function: anti-aggregation and anticoagu- lant)

− Maintenance of normal vascular tone

− Control of vascular inflammatory process and smooth muscle cell prolif- eration (function: antiphlogistic)

The endothelial activation involves a pro-coagulant effect due to a major synthesis of tissue factor that, associated with a reduced synthesis of throm- bomodulin, heparin, and heparan sulphate, reduces the anticoagulant poten- tial. The reduced synthesis of tissue plasminogen activator (tPA) and the increased level of PAI-1 reduces the fibrinolytic potential of the endotheli- um.

The functional control alteration of the vascular tone is due to reduced production of nitric oxide and of PGI

2

. The immunophlogistic effect is due to:

− Production of endothelial chemotactic factors (M-CSF, GM-CSF), a high- er expression of adhesion molecules (ELAM, ICAM, E-selectin) that facil- itate the migration from the lumen to the vessel wall of inflammatory cells (leucocytes) [4]

− Production of inflammatory cytokines (IL-1, TNF-α)

− Production of growth factors (PDGF, TGF-β, PGF-basic)

The onset, progression, and consequent clinical manifestation of athero- sclerotic plaque represents the inflammatory process of the arterial wall acti- vated by risk factors.

Take the low-density lipoproteins (LDL), one of the classical risk factors.

The early events of the atherosclerotic process are characterised by the migration of monocytes from the lumen to the arterial wall [5], helped by the endothelial expression of adhesion molecules and by the risk factors, in this case the oxidated LDL. The involvement of the adhesion molecules in the migration happens in three phases. The first phase is facilitated by the inter- action between the E-selectin of the endothelium and the glycosidic ligand cells of the monocyte membrane. It is characterised by monocyte rolling.

The second phase is facilitated by the interaction between MCP1 of the endothelium and the monocyte serpentine receptors that cause some modi- fications facilitating the interaction among the monocyte LFA-1, Mac-1, and VLA-4 and ICAM, VCAM, and PECAM of the endothelium that is the basis of the stop, flattening, and diapedesis of the monocytes (third phase).

Migrated into the vessel wall, the macrophage–monocytes express the

scavenger receptors that interact with the modified LDL, becoming trans-

formed into foam cells [6] that, activating themselves, produce proinflamma-

tory cytokine and grow th factors. These interact accordingly with the

endothelial receptors and the smooth muscle cells that migrate to the intima

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and are able to secrete collagen fibres. The progression of the plaque is char- acterised by the migration of subsets of Th1 lymphocytes assisted by adhe- sion molecules whose increased expression is induced by cytokines (IL-1, TNF- α) produced by the activated macrophages (Fig. 1).

Still to be clarified is the simultaneous appearance of the adhesion and endothelial molecules that diffuse and represent traffic signals for the migra- tion of the leucocytes from the lumen to the vessel walls. Since each gene synthesises a single protein molecule, their ‘coordinated’ activation must be due to the involvement of one or a few transcription factors (NF). The NF-kB system [7] is made of heterodimeric proteins caught in the cytoplasm, linked to a kB inhibitor (IkB), and it has been documented that the various risk fac- tors that increase the production of the adhesion molecules act to start the oxidative stress, producing reactive species of the O

2

superoxide anion and peroxide H. The reactive oxygen species (H

2

O

2

, O

2

) cause degradation of the NF inhibitors, making them available to interaction with the promoter region of the genes for adhesion molecule synthesis (Fig. 2) [8].

The subsequent interaction between macrophage and Th1 lymphocyte causes the lymphocyte production of IFN-γ that has an important role in the instability of the plaque.

Fig. 1. Early events of the atherosclerotic process

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The biological effect of the IFN- γ is to attach to the macrophage and to the smooth muscle cells, causing increased production of matrix metallopro- teinase and inhibition of the proliferation of CML with consequently reduced production of collagen and amorphous fundamental substance [9].

Enhanced MMP9 production by macrophages in symptomatic plaques is caused by the enhancement in PGE2 synthesis as a result of the induction of the functionally coupled COX2/mPGES–1. This causes early degradation of the fibrous component which, associated with reduced production of the fibrotic component, causes degradation of the fibrous cap and thus a fissur- ing or rupture of the plaque (Fig. 3).

The physiopathological events responsible for transforming a fissured plaque into a clinical manifestation are characterised by an interaction between the tissutal factor (TF) of macrophagic source and factor VIIa, which through the activation of factor X causes the formation of the ‘activa- tor complex of prothrombin’ (Xa, Va, platelet membrane phospholipids, Ca

2+

), with production of thrombin and consequently of fibrin and forma- tion of thrombus. Furthermore, the increased endothelial production of PAI- 1 reduces the spontaneous fibrinolytic activity.

Fig. 2.Nuclear factor system kB (NF-kB) and production of adhesion molecules

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The role of the platelets in the progression to and during the course of atherosclerotic disease has recently been emphasised. The interaction between the CD40L of platelet production and the CD40 expressed on the endothelial cells and on the macrophages is involved in the pathogenesis of atherosclerosis, provoking a complex of inflammatory reactions with endothelial production of VCAM-1, ICAM-1, E-selectin, MCP1 and produc- tion of reactive oxygen species from macrophage activation, legitimating the role of CD40L inflammatory marker as predictive criteria risk for cardiovas- cular events [10]. The platelet activation is preceded by recruitment and acti- vation of polymorphonuclear neutrophils (PMNs), despite their apparent insignificance in coronary atherogenesis, has been shown an increased degranulation within the coronary circulation in acute coronary syndrome.

One of the principal mediators secreted on PMN activation is myeloper- oxidase, w hich displays potent pro-atherogenic proper t ies [11].

Myeloperoxidase can oxidise LDL cholesterol, amplifying and perpetuating foam cell formation, activate metalloproteinase, and consume endothelium- derived nitric oxide.

Fig. 3. Role of IFN- γ in plaque instability

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Conclusions

Inflammation plays a key role in atherosclerosis. A number of different bio- markers of inflammation are measurable in blood. These include cytokines, chemokines, soluble adhesion molecules, and acute-phase reactants. The first three of these groups of molecules are not routinely available in clinical laboratories. In contrast, however, C-reactive protein is readily measurable, and numerous clinical studies have demonstrated its usefulness as a marker of atherosclerotic risk [12, 13]. Other independent predictive risk factors of cardiovascular events are: myeloperoxidase, serum CD40L (sCD40L), adiponectin, and vWF.

Given its pro-inflammatory properties, myeloperoxidase, produced by the activated PMNs, could be utilised as a marker and mediator of vascular inflammation, confirming the importance of activated PMNs in the phys- iopathology of the acute coronary syndrome.

The different combinations of immunocompetent cells (macrophage- –monocytes and T lymphocytes), of the vascular wall cells, of atheronecrotic material, and of fibrous material regulated by cytokines and growth factors produced by the same cells, allow us to say that every plaque is different from the next. This combination is responsible for the clinical manifestations of coronary atherosclerosis that affect only 5–10% of the individuals who have these lesions.

This hypothesised physiopathological and pathogenetic paradigm is a useful reference point for therapeutic strategies and prevention.

References

1. Moneta I, De Caterine R (1996) Aspetti infiammatori delle fasi iniziali dell’atero- sclerosi. G Ital Cardiol 25:225–239

2. Glass CK, Witztum JL (2001) Atherosclerosis: the road ahead. Cell 104:503–516 3. Gimbrone MA Jr, Kume N, Cybulsky M (1993) Vascular endothelial dysfunction

and the pathogenesis of atherosclerosis. In: Weber P, Leaf A (eds) Atherosclerosis reviews. New York, Raven Press

4. Cybulsky M, Gimbrone MA Jr (1992) Endothelial leukocyte adhesion molecules in acute inflammation and atherogenesis. In: Simionescu N, Simionescu M (eds) Endothelial cell dysfuctions. New York, Plenum Press, pp 129–140

5. Libby P, Clinton S (1993) The role of macrophages in atherogenesis. Curr Opin Lipidol 4:355–363

6. Gerrity R (1981) The role of monocyte in atherogenesis I. Transition of blood from monocytes into foam cells in fatty lesions. Am J Pathol 103:181–190

7. Collins T (1993) Endothelial nuclear factor-kB and initiation of the atherosclerotic lesion. Lab Invest 68:499–508

8. Jander S, Sitzer M, Schumann R et al (1998) Inflammation in light grade carotid

stenosis: a possible role for macrophages and T cells in plaque destabilisation,

Stroke 29:1625–1630

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9. Shankaravan UT, Lai WC, Netzel-Arnett S et al (2001) Monocyte membrane type 1- matrix metalloproteinase. Prostaglandin dependent regulation and role in metallo- proteinase-2 activation. J Biol Chem 276:1907–1032

10. Cipollone F, Ferri C, Desideri G et al (2003) Preprocedural level of soluble CD40L is predictive of enhanced inflammatory response and restenosis after coronary angioplasty. Circulation 108:2776–2782

11. Baldus S, Heeschen C, Meinertz T et al (2003) Myeloperoxidase serum levels pre- dict risk in patients with acute coronary syndromes. Circulation 108:1440–1445 12. Paul A, Ko KW, Li L et al (2004) C-reactive protein accelerates the progression of

atherosclerosis in apolipoprotein E-deficient mice. Circulation 109:647–655 13. Ridker PM, Rifai N, Rose L et al (2002) Comparison of C-reactive protein and low-

density lipoprotein cholesterol levels in the prediction of first cardiovascular

events. N Engl J Med 347:1557–1565

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