Coagulation Factor Xa Stimulates Interleukin-8 Release in Endothelial Cells and Mononuclear Leukocytes

Abstract

Objective-In acute myocardial infarction (AMI), proinflammatory plasma C-reactive protein values are strongly associated with postinfarction morbidity and mortality. So far, the cause of these inflammatory changes is not well understood. Therefore, we sought to investigate the relationship between the activation of coagulation and subsequent systemic inflammatory changes in AMI. Methods and Results-Factor Xa (FXa) bound to tissue factor pathway inhibitor and prothrombin fragments F1ϩ2 (F1ϩ2) were used as a measure for activated coagulation. To assess systemic inflammatory changes, plasma interleukin (IL)-6 and IL-8 concentrations were analyzed by immunoassay. Blood samples were taken from 21 patients with AMI and 20 patients with stable angina pectoris. In AMI, tissue factor pathway inhibitor FXa but not F1ϩ2 plasma levels were associated with circulating IL-8 (Pϭ0.01). In vitro experiments revealed that FXa stimulated IL-8 and monocyte chemoattractant protein-1 release and RNA expression in endothelial cells and mononuclear leukocytes by activation of protease-activated receptor-1. Key Words: coagulation Ⅲ myocardial infarction Ⅲ inflammation Ⅲ cytokines T he main initiator of the extrinsic coagulation cascade is tissue factor (TF), the receptor and cofactor for plasma coagulation factor VII/VIIa. Under physiological conditions TF is mainly expressed at extravascular sites. However, TF is induced by several inflammatory mediators such as interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. 1,2 In acute myocardial infarction (AMI), disruption of atherosclerotic plaques exposes TF-positive cells within the plaque-to-plasma clotting factors and initiates local thrombosis with subsequent occlusion of the coronary vessel. 3 In addition, increased TF expression occurs on circulating monocytes and microparticles in acute coronary syndromes and may thereby contribute to activation of coagulation. 4 -6 A soluble form of TF within the circulating blood may also support coronary thrombosis. 7 Stimulation of the TF-thrombin pathway does not only occur at the site of the plaque but also within the ischemic myocardium where activated coagulation factors may enhance inflammatory responses and deteriorate infarct size. 8 The endogenous Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI)-1 inhibits initiation of TF-induced blood coagulation. TFPI binds and inactivates factor Xa (FXa). The TFPI-FXa complex then binds and inactivates FVIIa. Increased levels of the TFPI-FXa complex may reflect both increased FXa generation and increased TFPI concentrations. 9 In addition to the full length TFPI, most of the plasma TFPI circulates in truncated forms that are bound to plasma lipoproteins. These truncated forms lack their C-terminal domains and exhibit reduced affinity for vascular wall proteolysis. Conclusion-OurBinding of the serine protease FVII to TF results in generation of the coagulation protease FXa and subsequently thrombin, both known to induce cell signaling. FXa shows dose-dependent inductio...

High plasma levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and interleukin-8 (IL-8) characterize patients prone to ventricular fibrillation complicating myocardial infarction

“…There are two other pathophysiological facets underlining the hypothesis that IL-8 is a potential profibrillatory marker. Firstly, there is a bidirectional link between IL-8 and coagulation (5). IL-8 exerts a procoagulant activity by induction of tissue factor expression in circulating monocytes (37).…”

“…Formation of intracoronary thrombi during myocardial ischemia requires thrombin which is not only necessary for the coagulation cascade, but also interacts with cardiomyocytes via protease-activating receptors and has arrhythmogenic properties in ventricular myocytes (4). Thrombin also induces interleukin-8 (IL-8) production in endothelial and mononuclear cells probably by this classic thrombin receptor (5). In vitro studies with human whole blood revealed that coagulation activation triggers IL-8 release to be positively correlated with the measurement of thrombin-antithrombin complexes, indicating that IL-8 is a key proinflammatory mediator of the crosstalk between coagulation and inflammation (6,7).…”

Overexpression of Insulin-Like Growth Factor-2 in Expanded Endothelial Progenitor Cells Improves Left Ventricular Function in Experimental Myocardial Infarction

“…Three to four confluent plates (corresponding to 3-4 × 10 5 cells per 100-mm dish) were lysed using TriZol (Invitrogen, Karlsruhe, Germany), and total RNA was extracted with an RNeasy Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions. Reverse transcription and semiquantitative [19] and quantitative PCR [20] were performed as described before. The primers for semiquantitative PCR (GAPDH and IGF-2) were obtained from Applied Biosystems (Darmstadt, Germany) and MWG Biotech (Munich, Germany), respectively.…”

Soluble Tissue Factor Emerges From Inflammation

“…Coagulation factors activate proteaseactivated receptors (PARs) on mononuclear or endothelial cells and thereby contribute to cytokine generation or inflammatory cell apoptosis. 2,3 Elegant experiments in genetically modified mice identified the key role of TF and PARs in coagulation-induced inflammation during endotoxemia. A decrease in TF activity in low TF or a PAR-2 deficiency in combination with thrombin inhibition abrogated systemic inflammatory changes.…”

“…TF antigen in plasma is found to be elevated in a number of disease states associated with increased activation of the coagulation. 3 However, this circulating extracellular TF consists of 2 forms in addition to soluble secreted TF: truncated forms and procoagulant microparticles (MP). 6 MPs are small membrane vesicles, released from blood cells or endothelial cells on activation by cytokines, shear stress, or apoptosis.…”