Fig 1.

Molecular mechanisms of inflammation and oxidative stress in atherosclerotic plaques. Endothelial dysfunction in relation to hypercholesterolemia, hypertension, type 2 diabetes, and smoking is associated with induction of adhesion molecules for inflammatory cells, ICAM-1, VCAM-1, E-selectin and fibronectin. The infiltration and activation of inflammatory cells are associated with the activation of the oxidant enzymes MPO and NOX-1, resulting in the production of ROS and the oxidation of phospholipids and protein in LDL, resulting in the accumulation of ox-LDL. It stimulates the endothelium to secrete MCP-1 and IL-8, which induce transmigration of leucocytes into the endothelial space. Macrophages secrete M-CSF, thereby stimulating macrophage proliferation and inducing the expression of scavenger receptors CD36, LOX-1 and SR-A. The scavenger receptor mediated uptake of ox-LDL by macrophages leads to massive cholesterol and lipid accumulation and formation of foam cells, finally resulting in apoptotic macrophages and exposure of thrombogenic lipids. Deficient TSP-1 expression is associated with a decreased phagocytosis of dead cells. Foam cells secrete MMPs and SMS resulting in the production of ceramide that induces smooth SMC apoptosis (black cells). Activation of SMS also blunts the action of ABCA-1 and ABCG-1 resulting in impaired cholesterol and lipid efflux from foam cells. Ox-LDL induces TLRs of which the ligands enhance the expression of inflammatory mediators IL-6 and TNF-α. Ox-LDL induces migration inhibitory factor that stimulates SMC migration. The uptake of ox-LDL by SMCs leads to the production of SMC foam cells and secretion of MMPs that degrade the extracellular matrix proteins rendering the plaque more prone to rupture. Ox-LDL stimulates platelet adhesion and aggregation by decreasing endothelial production of nitric oxide, and enhances the pro-coagulant activity of endothelium by inducing the release of tissue factor. Ox-LDL reduces the fibrinolytic activity of endothelium by increasing the release of plasminogen activator inhibitor-1. Finally, ox-LDL induces apoptosis in endothelial cells (black) contributing to plaque erosion and rupture.