The molecular mechanisms of the thrombotic complications of atherosclerosis

Abstract

Our evolving knowledge of the cellular and molecular mechanisms underlying atherosclerosis has helped uncover the underlying causes behind thrombotic complications of this disease. Most fatal coronary thrombosis result from fibrous cap rupture or superficial erosion. Recent research has established a role for matrix metalloproteinases in the regulation of aspects of plaque structure related to propensity to disrupt and provoke thrombosis. Inflammatory pathways impinge on proteinase activity and aspects of oxidative stress that may favour plaque disruption. Novel molecular imaging strategies may permit visualization of proteinase activity in vivo, providing a new functional window on pathophysiology.

1

Fibrous cap rupture and superficial erosion. Rupture of the fibrous cap (left) triggers two-thirds to three-quarters of all cases of fatal coronary thromboses. Superficial erosion (right) takes place in one-fifth to one-quarter of fatal coronary thromboses. Certain populations, such as individuals with diabetes and women, appear to have superficial erosion more frequently as a mechanism of plaque disruption and thrombosis. (Libby P, Theroux P. Circulation 2005;111:3481-3488.)

2

Collagenolysis in human atheromatous and fibrous plaques. Immunofluorescence for collagenase-cleaved type I collagen neoepitope (FITC, green; top left) and collagen type I (Texas red; top right) revealed cleaved collagen in the shoulder area. Adjacent sections were stained immunohistochemically for MMP-1 and -13, as well as for human Mϕ (bottom). (Sukhova GK et al. Circulation 1999;99:2503-2509.)

3

Inflammation regulates metabolism of fibrillar collagen, which may influence atherosclerotic plaque disruption. The T-lymphocyte releases proinflammatory cytokines such as IFN-γ (lower left) that inhibit SMCs from producing the new collagen required to lay down the collagenous matrix of the plaque's fibrous cap, which protects the plaque from rupture. The T-cell-derived cytokine CD40L stimulates mononuclear phagocytes (center) to elaborate interstitial collagenases including MMP-1, MMP-8, and MMP-13, which catalyze the initial proteolytic cleavage of the intact collagen fibril. The cleaved collagen can then undergo additional degradation by gelatinases such as MMP-9. In this way, inflammation can threaten the stability of atherosclerotic plaques; increase their tendency to rupture; and, hence, cause thromboses that trigger most acute coronary syndromes. TGFβ, transforming growth factor β. (Libby P., In: Morrow D, editor. Contemporary Cardiology, 2006)

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The relationship between thrombosis and inflammation. Thrombin stimulation prompts secretion of platelet, endothelial cell, and smooth muscle cell factors that trigger macrophages to produce tissue factor, pro-inflammatory cytokines, lipid mediators of inflammation, and reactive oxygen species. Via these mechanisms, thrombin inititates vascular inflammation, which promotes additional thrombin production through amplification loops that perpetuate atherogenic signals. (Croce K., Libby P. Curr Opin Hematol 2007;14:55)

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Potential mechanisms of superficial erosion leading to coronary thrombosis. Death of endothelial cells, for example by apoptosis, may cause desquamation and facilitate thrombosis as platelets encounter subendothelial pro-aggregatory collagen. Lysis of basement membrane (type IV) collagen by type IV collagenase (MMP-2) activated by inflammatory mediators may accelerate endothelial apoptosis and desquamation as well by severing attachment of the cells to the basement membrane. The endothelial cells attach to their subjacent matrix in part through membrane integrins, represented here by alpha and beta. (Libby P., In: Topol EJ, editor. Acute Coronary Syndromes, 2^nd ed., 2000)

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Thrombotic determinants in coronary atherosclerotic plaques. Formation, extenet, and duration of coronary thrombi produced by mechanisms such as those outlined in Figure 1 rely on both solid-state factors in the plaque itself and fluid-phase determinants in blood. See text for further explanation. (Libby P, Theroux P. Circulation 2005;111:3481-3488.)