Oxidized LDL Signal Transduction Pathways and Protection of Vascular Cells

It is becoming increasing clear that cells can respond to oxidative stress in a variety of ways. While most of our attention has focused on responses to high levels of oxidative stress, especially of oxidized LDL, and its promotion of a proinflammatory response, recruitment of macrophages, and the development of atherosclerotic lesions,96 oxidative stress may also have a protective effect. Vascular cells have the capacity to adapt to oxidative stress and this has been shown at low levels of oxidative stress. Low levels of oxidized LDLs (oxLDLs) were cytoprotective in early studies. The protective effect occurred through mechanisms involving an increase in levels of glutathione (GSH), an intracellular antioxidant.97-99 Regulation occurs through cell signaling mechanisms. Recent studies have found that the protective response was mediated by the transcriptional control of genes regulated by the electrophile response element, such as hemeoxygenase-1.100

Many of the activities of oxidized LDL may be mediated through specific elec-trophilic lipid products of lipid peroxidation. The following observations support this hypothesis: (1) electrophilic lipids regulate GSH levels, and polymorphisms in proteins involved in GSH synthesis are associated with inflammatory disease in human populations;101102 (2) depletion of GSH or loss of hemeoxygenase in animal models enhances susceptibility to the cardiovascular disease process;103 104 (3) elec-trophilic lipids derived from both enzymatic and nonenzymatic lipid peroxidation are found in the vasculature of both humans and animal models.

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