XII^th International Symposium on Atherosclerosis, Stockholm, Sweden. (June 25-29, 2000)
Inflammation is a key feature of plaque disruption in the acute syndrome. Lipoproteins or their derivatives can promote local inflammation and thrombogenicity in the arterial wall and lipid lowering actually constitutes a form of antiinflammatory and antithrombotic therapy.

Stockholm, Sweden -- In his plenary lecture at the XIIth International Symposium on Atherosclerosis, Dr P. Libby (Harvard Medical School, Boston, USA) suggested that the therapeutic approaches for prevention of atherosclerotic disease to be used in the next millenium would be based on the knowledge of the pathogenetic processes involved in the different phases of the progression of atherosclerosis. According to Dr Libby, the understanding of the pathogenesis of atherosclerosis has now radically changed with the knowledge that inflammation is a key feature of plaque disruption in the acute syndrome, and contributes to its thrombogenicity.

Lipid lowering and inflammation
Lipid lowering by diet reduces macrophage accumulation, proteinase expression and activity, and increases in collagen content of atheroma of hypercholesterolemic rabbits, all features that should reinforce the resistance of the fibrous cap to rupture. Atheroma disruption by itself would have little clinical consequence were it not for inciting thrombus formation. In his presentation, Dr Libby reported a reduction in tissue factor (TF) at the level of the arterial wall during lipid lowering treatment, which in part reflects diminished macrophage accumulation. This may have several molecular and cellular bases, analogous to those that regulate TF expression itself. For example, lipid lowering reduces the local production of inflammatory cytokines, which in turn augment the expression of leukocyte adhesion molecules on endothelial cells, as well as the expression of certain chemokines, such as MCP-1, involved in monocyte migration. These findings support the view that lipoproteins or their derivatives can promote local inflammation and thrombogenicity in the arterial wall and that lipid lowering actually constitutes a form of anti-inflammatory and antithrombotic therapy.

The role of CD40 and its ligand CD40L
Cells in human atherosclerotic lesions express the immune mediator CD40 and its ligand CD40L. The interaction of CD40 with CD40L induces both humoral and cell-mediated immune responses. CD40L-positive T cells accumulate in atheroma, and, by virtue of their early appearance, may coordinate important aspects of atherogenesis. Interruption of CD40L-CD40 signaling by administration of an anti-CD40L antibody limits experimental autoimmune diseases such as collagen-induced arthritis, lupus nephritis, acute or chronic graft-versus-host disease, multiple sclerosis and thyroiditis. Ligation of CD40 on atheroma-associated cells in vitro activates functions related to atherogenesis, including induction of proinflammatory cytokines, matrix degrading metalloproteinases, adhesion molecules, and tissue factor. Treatment with an antibody against mouse CD40L limits atherosclerosis in mice lacking the receptor for low density lipoprotein that had been fed a high cholesterol diet for 12 weeks. This antibody reduces the size of aortic atherosclerotic lesions by 59% and their lipid content by 79%. Furthermore, atheromas of mice treated with anti-CD40L antibody contain significantly fewer macrophages (64%) and T lymphocytes (70%), and exhibit decreased expression of vascular cell adhesion molecule-1 (VCAM-1). These data support the involvement of inflammatory pathways in atherosclerosis and indicate a role for CD40 signalling during atherogenesis in hyperlipidaemic mice.

Leukocyte adhesion to endothelial cells
Adhesion of circulating leukocytes to the endothelium is a critical step in atherogenesis. This process depends on the interaction between adhesion molecules on the endothelial cell surface and their cognate ligands on leukocytes. These endothelial cell adhesion molecules include VCAM-1 and intercellular adhesion molecule (ICAM, E-selectin, and P-selectin). Inhibition of VCAM-1 expression in human endothelial cells by peroxisome proliferator-activated receptor-a (PPARa), a nuclear receptor expressed in endothelial cells, with a consequent decrease in monocyte adherence, has important implications regarding atherogenic mechanisms as well as the treatment of atherosclerosis. These findings suggest PPARa as a potential mediator of critical inflammatory processes in the vessel wall.