Reactive oxygen species and thiol redox signaling in the macrophage biology of atherosclerosis - PubMed (original) (raw)

FIG. 1.

An overview of the roles of monocytes and macrophages in atherogenesis. (A) The early atherosclerotic lesion. Oxidative modification of the low-density lipoproteins (LDLs) in the subendothelial space results in production of cytotoxic oxidatively modified LDL (OxLDL), which promotes endothelial dysfunction and the expression of adhesion molecules. Specific interactions of selectins and other adhesion molecules expressed by endothelial cells (e.g., vascular cell adhesion molecule-1 and intercellular adhesion molecule-1) with their counterparts on inflammatory cells (e.g., very late antigen-4 and lymphocyte function-associated antigen 1) result in the rolling, adhesion, and transmigration of circulating inflammatory cells, primarily monocytes, into the intima. Infiltrated monocytes differentiate into macrophages and express a number of scavenger receptors, for example, scavenger receptor A, scavenger receptor BI, CD36, and CD68. Scavenger receptor-mediated internalization of OxLDL and other LDL modifications result in the formation of lipid-laden foam cells. Monocyte cellularity in these early lesions is regulated by monocyte egress and apoptosis. (B) The advanced atherosclerotic plaques. The persistent production of inflammatory mediators, including chemokines (e.g., monocyte chemoattractant protein-1 [MCP-1] and RANTES), cytokines (e.g., interleukin [IL]-1, IL-6, tumor necrosis factor α, and interferon-γ), proteases (e.g., matrix metalloproteinases and cathepsins), and reactive oxygen species (ROS) formation by infiltrated immune cells, generates an inflammatory milieu, which promotes the recruitment, accumulation, and activation of additional inflammatory cells and smooth muscle cells, resulting in plaque expansion. In complex lesions, macrophage foam cells undergo cell death through apoptotic or nonapoptotic pathways (e.g., oncosis). Foam cell lysis and impaired clearance of apoptotic cells (efferocytosis) and subsequent secondary necrosis promote the formation of necrotic cores and further fuel inflammatory responses within advanced atherosclerotic plaques. In vulnerable plaques, these inflammatory mechanisms lead to the thinning of the protective fibrous cap and expansion of the necrotic core, predisposing these lesions to mechanical destabilization and plaque rupture. Exposure of the thrombogenic contents of the plaques to the coagulation cascade results in thrombus formation.