Inflammation, lipids, and free radicals: lessons learned from the atherogenic process.
This review focuses on the question of how oxidative stress in cells populating atherosclerotic lesions stimulates gene expression, cell proliferation, and cell death, and how these events contribute to the initiation, progression, and destablization of the lesions. It is hypothesized that oxidative stress in endothelial cells, macrophages, and smooth muscle cells occurs as a result of the depletion of the cellular content of reduced glutathione. Glutathione becomes oxidized in response to the accumulation of oxidized lipids, the formation of reactive oxygen species released from the mitochondria and generated as part of the activation-induced respiratory burst, and the generation of nitric oxide, peroxynitrite, and thiol radicals. Both in vitro and in vivo evidence suggests that these cells can take up modified lipoproteins that become trapped within the artery wall leading to the overaccumulation of oxidized fatty acids and oxidized forms of cholesterol. The cells also generate oxidized lipids via the activity of lipoxygenases, cyclooxygenases, and myeloperoxidase. A sublethal oxidative stress can activate redox-sensitive kinase cascades and transcription factors such as NFB and AP-1, with resulting increases in the expression of factors associated with an inflammatory response and cellular proliferation. There is also accumulating evidence that suggests that oxidative stress may be associated with the induction of cell death either via stimulation of apoptosis and/or necrosis and that increased cell death contributes to the formation of a necrotic core, the hallmark of an advanced, unstable lesion.
Rosenfeld
M E
ME
Department of Pathobiology, University of Washington, Seattle 98195, USA.
D017209:Apoptosis; D001161:Arteriosclerosis / Q000235:genetics / Q000503:physiopathology*; D002455:Cell Division; D018450:Disease Progression; D004727:Endothelium / Q000166:cytology; D005609:Free Radicals / Q000009:adverse effects; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D050356:Lipid Metabolism; D018384:Oxidative Stress
D005609:Free Radicals; D005978:Glutathione