The therapeutic potential of phospholipase A2 inhibitors in cardiovascular disease.
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.
White
M C
MC
Department of Pathology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
McHowat
J
J
D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology; D003331:Coronary Vessels / Q000201:enzymology; D042783:Endothelial Cells / Q000201:enzymology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000502:physiology; D054467:Phospholipases A2; D010743:Phospholipids / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D010743:Phospholipids; D010741:Phospholipases A; D054467:Phospholipases A2