Review Articles in 2002

The cytokine, TNF, participates in virtually every aspect of stroke. Its effects, however, often appear contradictory. Analysis of the current model for TNF receptor signaling and TNF interactions with other stroke mediators helps to resolve some of these apparent discrepancies.

The participation of platelets in atherogenesis and the subsequent formation of occlusive thrombi depend on platelets' adhesive properties and the inability to respond to stimuli with rapid activation. By understanding the multifaceted mechanisms involved in platelet interactions with vascular surfaces and aggregation, new approaches can be tailored to selectively inhibit the pathways most relevant to the pathological aspects of atherothrombosis.

Specialized functions of macrophages have evolved to protect the body from infection. However, the same mechanisms that enable phagocytosis of pathogens and activation of leukocytes also permit the uptake of lipoproteins and release of reactive oxygen species and immune mediators that collectively contribute to atherosclerosis. New approaches to inhibit lipid accumulation in macrophage foam cells and reduce inflammatory responses may be of therapeutic value in preventing coronary artery disease.

Liver X receptors (LXRs) are sterol-responsive transcription factors that regulate expression of genes involved in cholesterol metabolism and homeostasis. Maintenance of normal cholesterol levels has implicated the involvement of LXR-induced genes in the pathophysiology of atherosclerosis. The modulation of LXRs or their downstream targets may provide alternative therapeutic strategies for the management of this disease.

In atherosclerosis, the vascular smooth muscle cell (VSMC) contributes to vessel wall inflammation and lipoprotein retention, as well as to the formation of the fibrous cap that provides stability to the plaque. The VSMC can undergo a proliferative response that underlies the development of in-stent restenosis, bypass graft occlusion and transplant vasculopathy. Although the benefit/risk of therapeutic inhibition of VSMC proliferation in atherosclerosis is unclear, experimental and human evidence strongly suggests the therapeutic potential of antiproliferative therapy for in-stent restenosis, bypass graft failure and other vascular proliferative disorders.

Traditional risk factors like hypercholesterolemia are important for atherogenesis, but it is now apparent that the immune system also plays an important role. Uncovering the mechanisms by which specific components of the immune system impact atherogenesis will not only provide new insights into the pathogenesis of lesion formation, but could also lead to novel therapeutic approaches that involve immune modulation.

Research points to pivotal roles for lipids in the development of atherosclerotic plaques. Lipid-lowering statins substantially reduce acute coronary events resulting from plaque development, but only modestly reduce arterial stenosis. This apparent paradox has shifted the goal of therapy towards plaque stabilization rather than enlargement of the lumen. More thorough understanding of the biology of atherosclerosis should enable us to manipulate plaque stability, and reduce further the acute complications of atherosclerosis.