Although atherosclerosis is considered a chronic inflammatory disease, its precise role in plaque progression, rupture, and thrombosis is unclear. Because no satisfactory animal model of human plaque rupture currently exists, we rely on autopsy material collected from sudden coronary death victims for study. A considerable amount of research has focused on the effects of matrix degradation within the fibrous cap as potential mechanisms of plaque instability and rupture. Alternatively, a growing body of literature suggests that apoptotic cell death of smooth muscle cells and macrophages are critical for plaque progression and instability. Smooth muscle cells genetically programmed to undergo apoptosis in-vivo have been shown to up regulate the proinflammatory cytokines MCP-1 and IL-8 causing an extensive infiltration of macrophages in experimentally induced lesions. Observations in our laboratory have demonstrated activated caspase-1 in macrophages at plaque rupture sites, while little caspase-1 was detected in the fibrous cap of stable plaques. Caspase-3, another pro-death mediator has also been detected in advanced lesions of atherosclerosis. Caspases may be critical to disease progression and plaque instability since they are directly involved in the processing and maturation of inflammatory cytokines. We believe that monocyte recruitment into the fibrous cap is a critical event, leading to plaque instability. Infiltration of the fibrous cap by monocyte/macrophages may be provoked by proinflammatory signals from apoptotic cell within the lesion itself.
The specific aims of this project are (1) the role of smooth muscle cell and macrophage death, including the identification of the upstream and down stream pathways of caspase 1 in the formation of early and late apoptotic compartments (cores) in the human atherosclerotic plaque (2) The role of proinflammatory cytokines in luminal and abluminal macrophage migration in apoptotic cores (3) The role of myeloperoxidase expressing macrophages in plaque rupture and thrombosis, and interaction with EMAP II. (4) The role of extracelllar matrix (hyaluronan, versican, biglycan and decorin), suppressors of inflammation (TSG-6, PAI-2), and endothelial cell apoptosis in acute thrombosis: alternate pathway of luminal thrombosis due to plaque erosion and (5) The correlation of novel peripheral markers of inflammation with the pathology of plaque instability. Our detailed studies of human coronary disease should provide insight into the mechanisms involved in the final pathway of plaque rupture and erosion that may help design newer modalities of treatment to reduce the mortality and morbidity of coronary heart disease.
