Is there a role for 15-lipoxygenase in atherogenesis?

Area of Science:

• Cardiovascular Biology
• Lipid Metabolism
• Enzymology

Background:

• 15-Lipoxygenase (15-LO) is implicated in atherogenesis.
• It is proposed to oxidize low-density lipoprotein (LDL) making it a ligand for macrophage scavenger receptors.
• 15-LO and oxidized LDL are found together in atherosclerotic lesions, and inhibitors block LDL oxidation and atherosclerosis progression.

Purpose of the Study:

• To clarify the unclear mechanism of 15-lipoxygenase action in atherogenesis.
• To address discrepancies in the stereochemistry of 15-LO-oxidized linoleate products found in lesions.
• To investigate alternative roles for 15-LO metabolites, such as modulating gene expression.

Main Methods:

• Review of existing biochemical and molecular biological data on 15-LO in atherogenesis.
• Analysis of studies on the co-localization of 15-LO and oxidized LDL in atherosclerotic lesions.
• Consideration of findings from antioxidant drug studies blocking lipoxygenase activity.

Main Results:

• Induction of 15-LO alone is insufficient for lesion formation.
• Observed levels of racemic 13-hydroxyoctadecadienoic acid (13-HODE) in lesions conflict with expected stereochemistry from purified enzyme.
• The precise cellular location and timing of 15-LO product generation may be critical.

Conclusions:

• The exact role of 15-lipoxygenase in atherogenesis remains uncertain.
• Alternative functions, including modulation of gene expression and mitogenesis, are possible.
• Transgenic models offer future opportunities to elucidate the function of 15-LO in atherosclerosis.