Leukocyte recruitment and the expression of pro-inflammatory
cytokines are prevalent characteristics of early
atherogenesis. Recently, several inflammatory mediators have been linked to
atheroma formation and inflammatory pathways have been shown to promote
thrombosis. The discovery of mast cells, activated T lymphocytes and macrophages in atherosclerotic lesions, the detection of
human leukocyte antigen class II expression, and the finding of local secretion of several
cytokines all suggest the involvement of immune and inflammatory mechanisms in the pathogenesis of
atherosclerosis. Recent research suggests activation of
protease activated receptors (PAR) on the surface of endothelial cells may play a role in general mechanisms of
inflammation. In previous studies, our laboratory has demonstrated that
thrombin (which activates PAR-1) and
tryptase (which activates PAR-2) stimulation of endothelial cells results in activation of
calcium-independent
phospholipase A(2) (
iPLA(2)).
iPLA(2) plays a critical role in the synthesis of membrane
phospholipid-derived inflammatory mediators such as
arachidonic acid,
platelet activating factor (PAF), and
prostaglandins, all demonstrated to be central in both the initiation and propagation of the inflammatory response. Activation of
iPLA(2) results in release of
choline lysophospholipids from endothelial cells, these metabolites may contribute to the initiation of ventricular arrhythmias following
myocardial ischemia as a direct result of incorporation into the myocyte sarcolemma. This biochemical event represents a direct link between occlusion of a coronary vessel and the nearly immediate initiation of arrhythmogenesis often seen in
myocardial ischemia.