The vicious circle between oxidative stress and inflammation in atherosclerosis

Abstract

The initial event in atherogenesis is the increased transcytosis of low density lipoprotein, and its subsequent deposition, retention and modification in the subendothelium. It is followed by the infiltration of activated inflammatory cells from the coronary circulation into the arterial wall. There they secrete reactive oxygen species (ROS) and produce oxidized lipoproteins capable of inducing endothelial cell apoptosis, and thereby plaque erosion. Activated T lymphocytes, macrophages and mast cells, accumulate in the eroded plaque where they secrete a variety of proteases capable of inducing degradation of extracellular proteins, thereby rendering the plaques more prone to rupture. This review summarizes the recent advancements in the understanding of the roles of ROS and oxidized lipoproteins in the activation of inflammatory cells and inducing signalling pathways related to cell death and apoptosis. In addition, it presents evidence that this vicious circle between oxidative stress and inflammation does not only occur in the diseased arterial wall, but also in adipose tissues. There, oxidative stress and inflammation impair adipocyte maturation resulting in defective insulin action and adipocytokine signalling. The latter is associated with increased infiltration of inflammatory cells, loss of anti-oxidant protection and cell death in the arterial wall.

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.

Fig 2

Regulatory mechanisms of interactions between oxidative stress and inflammation. PPAR-γ reduces the expressions of ICAM-1, VCAM-1 and MCP-1, resulting in reduced macrophage accumulation, ROS production and ox-LDL deposit. In addition, PPAR-γ increases expressions of CD36 and anti-oxidant enzymes SOD and GPX, resulting in a further reduction of ox-LDL. Higher PPAR-γ is also associated with increased LXR-α and ABCA-1 expression, resulting in a decrease of cholesterol and lipids. The reduction in ox-LDL is associated with a decrease of TLR-mediated inflammation, and thereby reduced ROS production. In addition this reduction is associated with higher NOS production resulting in improved endothelial vasoreactivity, blood pressure regulation and left ventricle function. Reduction of ox-LDL results in restoring PPAR-γ expression that is associated with increased IRS-2 and glucose transporter-4 expressions, which are important regulators of insulin sensitivity and glucose uptake. Improved insulin action results in decreased mitochondrial oxidative stress, increased SOD-2 expression and reduced ROS production.

Fig 3

Macrophage infiltration in adipose tissues, oxidative stress and IR. Circulating monocytes adhere to activated endothelial cells. Activated CD8⁺ T cells and chemokines induce monocyte migration into adipose tissues where they differentiate into macrophages. Interaction of saturated fatty acids with TLRs leads to secretion of inflammatory cytokines/chemokines (IL-6 and TNF-α). Together with the adipocytokines leptin and resistin, they impair c-jun N-terminal kinase and NF-κB signalling, resulting in IR and reduced adiponectin (Acrp-30) secretion, and thereby loss of adipocyte maturation. Together they also induce adipocyte proliferation. Infiltration of inflammatory cells is associated with ROS and ox-LDL production, endothelial cell apoptosis, impaired LXR and VEGF signalling, and decreased blood flow leading to hypoxia and increased oxidative stress. Ox-LDL can further induce adipose tissue hyperplasia, and by inducing lipoprotein lipase it enhances lipid accumulation resulting in adipose tissue hypertrophy. The latter is also facilitated by MMPs secreted by macrophages. Hypoxia and increased oxidative stress induces apoptosis of adipocytes. Increased apoptosis also results from reduced Acrp-30 secretion and growth arrest specific 6 mediated survival pathway. Apoptotic adipocytes attract macrophages which normally remove apoptotic adipocytes. However, ox-LDL impairs phagocytosis of dead adipocytes by inhibiting resolvin E1 and protectin D1 production.