X

Adapted with permission from Ridker PM. Circulation 2001;103:1813-1818.

Patients with unstable angina demonstrate high concentrations of tissue factor antigen and activity within coronary atherectomy specimens (98), and it has been suggested that this potent procoagulant protein found within the lipid core may be released from macrophages during cell death or in the form of shed vesicles (99) (Fig. 12).

The impact of therapies designed to reduce myocardial ischemia or attenuate thrombotic potential on endothelial performance must be considered. One frequently used agent, unfractionated heparin, exerts prothrombotic effects by adversely affecting

Pictures Myocardial Infarction

viiyvila

■y Thrombin lXa/Xa

Fig. 12. Tissue factor is a strong stimulus for intravascular coagulation, particularly after plaque disruption. In addition to activating factor X directly (extrinsic coagulation cascade) the TF-VIIa complex generates thrombin (and the conversion of fibrinogen [FgN] to fibrin) via the extrinsic coagulation cascade by factor IX activation (cascade cross-talk).

Tissue Factor mRNA Activity viiyvila

■y Thrombin lXa/Xa

Fgn Fibrin

Fig. 12. Tissue factor is a strong stimulus for intravascular coagulation, particularly after plaque disruption. In addition to activating factor X directly (extrinsic coagulation cascade) the TF-VIIa complex generates thrombin (and the conversion of fibrinogen [FgN] to fibrin) via the extrinsic coagulation cascade by factor IX activation (cascade cross-talk).

endothelial-mediated thromboresistance to tissue factor, which is an important trigger for thrombosis in atherosclerotic coronary artery disease. Under normal circumstances, TFPI is released from endothelial cells, neutralizing the tissue factor, VIIa complex and factor Xa. Unfractionated heparin causes a release of TFPI (100), contributing to its overall anticoagulant effects; however, prolonged administration depletes intracellular storage pools, compromising both anticoagulant potency and thromboresistance capacity. This phenomenon may help explain the limitations of unfractionated heparin in acute coronary syndromes and the clustering of thrombotic events that follow its abrupt discontinuation (101).

Thrombin, a multifunctional serine protease generated at sites of vascular injury, is a potent platelet activator and possesses a variety of actions on inflammatory cells, the vascular endothelium, and smooth muscle cells. Arterial wall-associated thrombin activity is expressed following coronary angioplasty (102), and thrombin bound to the subendothelial extracellular matrix is functionally active, localized, and protected from inactivation by circulating inhibitors (103).

The multiple cell-activating functions of thrombin contribute to hemostatic, inflammatory, proliferative, and reparative responses of injured vessel walls (Fig. 13). In human atheroma, a functional thrombin receptor is expressed in regions rich in macrophages and smooth muscle cells. Local thrombin generation in areas of dysfunctional endothelium and either fissured or ruptured atherosclerotic plaques activates surrounding cells, thereby contributing to plaque growth, inflammation, and thrombosis (104).

Cultured endothelial cells exposed to monocytes release less nitric oxide, and the monocyte-derived cytokines, IL-1, and TNF-a, down-regulate nitric oxide synthase (105). Overall, the adhesion of monocytes to endothelial cells, as well as their secretory products, diminishes the steady-state levels of nitric oxide synthase, an event associated with an attenuated release of biologically active nitric oxide. The observed suppression is both monocyte concentration and time-dependent (106).

Thrombin

Monocytes

Neutrophil And Myocardial Infarction

Fig. 13. Beyond serving as the pivotal enzyme for all coagulation processes, thrombin exhibits a broad range of direct cellular activating (and inhibiting) properties as well. Platelet, monocyte, and neutrophil activation (and interactions) may be particularly important in the determination of an inflammatory-pro-thrombotic environment. Thrombin's effect on dysfunctional endothelial cells includes increased PAI-1 secretion and decreased APC secretion. Thrombin-mediated platelet-derived growth factor (PDGF) synthesis participates in smooth muscle cell migration and plaque growth. PGI2 and tPA secretion are decreased as well. The latter may also be functionally defective (impaired fibrinolytic potential).

Fig. 13. Beyond serving as the pivotal enzyme for all coagulation processes, thrombin exhibits a broad range of direct cellular activating (and inhibiting) properties as well. Platelet, monocyte, and neutrophil activation (and interactions) may be particularly important in the determination of an inflammatory-pro-thrombotic environment. Thrombin's effect on dysfunctional endothelial cells includes increased PAI-1 secretion and decreased APC secretion. Thrombin-mediated platelet-derived growth factor (PDGF) synthesis participates in smooth muscle cell migration and plaque growth. PGI2 and tPA secretion are decreased as well. The latter may also be functionally defective (impaired fibrinolytic potential).

Nitric oxide is generated under basal conditions by vascular endothelial cells, and several lines of evidence suggest that the continuous tonic release of nitric oxide is important in maintaining normal vasoreactivity and thromboresistance by means of its potent vasodilating and platelet-inhibiting potential, respectively.

Monocytes and macrophages from atheromatous plaques exhibit a coagulant response to a variety of stimuli, including IL-1 and products of activated lymphocytes (107). Monocytes from patients with unstable angina express significant procoagulant activity; however, they must first bind to lymphocytes (108). In addition, only activated lymphocytes can stimulate monocyte procoagulant activity.

The impact of T lymphocytes on atherosclerotic disease progression and expression is supported by studies showing a relationship between immune-mediated IFN-y signaling and acute coronary syndromes. Monocytes from patients with acute coronary syndromes exhibit a molecular fingerprint of recent activation (transcription of STAT [transcription-1 proteins], up-regulation of inducible genes (D64 and IP-10) (109), and monoclonal T cell populations have been detected in atherosclerotic plaques obtained from patients with fatal MI (110). Although there is little question that antigen-specific stimulation is of paramount relevance in atherogenesis, an alternate pathway of T cell activation, independent of antigen presentation, might involve IL-15-A, a macrophage-released cytokine that shares biologic similarities with IL-2 and induces proliferation of mature T cells, generation of cytotoxic T cells, induction of CD 40 ligand expression, and release of proinflammatory cytokines (111).

Smooth Muscle Cells

The smooth muscle cell is ubiquitous in its role as both a pro-atherosclerotic and pro-thrombotic mediator. Similar to endothelial cells and monocytes, smooth muscle cells

Myocardial Muscle Cells

Fig. 14. The dysfunctional vascular endothelium, transformed intima, and modified cellular components of the developing plaque are a virtual warehouse of inflammatory proteins and expressed receptors that mediate the adhesion of cells to one another and to structural components of the cell surface matrix. ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; PECAM, platelet endothelial cell adhesion molecule; vWF, von Willebrand factor; GP, glycoprotein.

Fig. 14. The dysfunctional vascular endothelium, transformed intima, and modified cellular components of the developing plaque are a virtual warehouse of inflammatory proteins and expressed receptors that mediate the adhesion of cells to one another and to structural components of the cell surface matrix. ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; PECAM, platelet endothelial cell adhesion molecule; vWF, von Willebrand factor; GP, glycoprotein.

express tissue factor (112). In addition, they can release inflammatory cytokines in response to thrombotic activation that activate platelets and/or monocytes (113).

Cell Adhesion Molecules

In both physiologic and pathologic states, cell surface receptors mediate the adhesion of cells (endothelial cells, monocytes, lymphocytes, neutrophils, smooth muscle cells, platelets) to one another and to structural components of the extracellular matrix. To date, six families of cell adhesion molecules have been described—integrins, selectins, immunoglobulins, adhesion molecules, proteoglycans, and mucins (Fig. 14).

Integrins comprise a superfamily of heterodimeric transmembrane proteins composed of noncovalently associated a- and b-subunits (Table 5). To date, 8 b-subunits and 12 a-subunits have been identified (114,115). Integrins have been grouped according to their composition, which typically includes various combinations of a-subunits joined with a common b-subunit. Most integrins that bind matrix molecules recognize the tripeptide Arg-Gly-Asp (RGD) that can be found in fibrinogen, fibronectin, fibronectin, vitronectin, laminin, and type 1 collagen. Not all cellular interactions with matrix proteins are mediated by their RGD sequence.

Selectins are composed of a lectin domain, an epithelial growth factor domain, and complement regulatory-like molecules. P- and E-selectins bind to common sites of carbohydrates, and C-selectin binds to mucin-like endothelial cell glycoproteins. P-selectin (CD62, granule membrane protein, platelet activation-dependent granule external membrane protein) can be found within platelet a-granules and endothelial cells (Weibel-Palade bodies). Because P-selectin binds to monocytes and neutrophils, it is felt to play an important role in platelet-leukocyte and endothelial cell-leukocyte interactions. The interaction of fibrinogen and P-selectin may have a particularly important role in regulating inflammatory and thrombotic responses (Table 6).

Members of the immunoglobulin superfamily, including intercellular adhesion molecules (ICAM-1, ICAM-2) and vascular cell adhesion molecules (VCAM) play an

Table 5

Major Integrins and Their Ligands that Contribute to Atherothrombosis

Table 5

Major Integrins and Their Ligands that Contribute to Atherothrombosis

Integrin

Ligands

VLA integrins

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