Novel insights into the molecular mechanisms of the antiatherosclerotic properties of antioxidants: the alternatives to radical scavenging.

Since the oxidation hypothesis of atherogenesis was first proposed, mechanisms of low density lipoprotein (LDL) oxidation and the biological properties of oxidized LDL have been investigated in depth. The major mechanism for the antiatherogenic effects of antioxidants, especially radical scavenging antioxidants, has been thought to be direct inhibition of LDL oxidation. The recently developed genomic technology has allowed this hypothesis to be addressed more rigorously than relying on the simple chemical properties of these therapeutic agents. Oxidized LDL, which is known to be proatherogenic, induces many categories of genes that have a potential involvement in the development of atherosclerotic lesions. The genes involved in cell growth, survival, adhesion, and inflammatory responses were upregulated through some nuclear receptor-depending pathways in cells exposed to stimulants such as shear stress, TNF-alpha, and oxidized LDL. On the other hand, these transcriptome analyses have shown a novel mechanism underlying phenolic antioxidants contribute to antiatherogenicity by regulating the expression of genes involved in protein degradation and transcriptional pathways. These studies reveal the often-suspected complexity of the atherogenic process and have the potential for novel therapeutic intervention.