Hydroxyoctadecadienoic
acids (HODEs) are stable oxidation products of
linoleic acid, the generation of which is increased where oxidative stress is increased, such as in diabetes. In early
atherosclerosis,
13-HODE is generated in macrophages by 15-lipoxygenase-1. This enhances protective mechanisms through
peroxisome proliferator-activated receptor (
PPAR)-g activation leading to increased clearance of
lipid and
lipid-laden cells from the arterial wall. In later
atherosclerosis, both
9-HODE and
13-HODE are generated nonenzymatically. At this stage, early protective mechanisms are overwhelmed and pro-inflammatory effects of
9-HODE, acting through the receptor GPR132, and increased apoptosis predominate leading to a fragile, acellular plaque. Increased HODE levels thus contribute to
atherosclerosis progression and the risk of clinical events such as
myocardial infarction or
stroke. Better understanding of the role of HODEs may lead to new pharmacologic approaches to modulate their production or action, and therefore lessen the burden of atherosclerotic disease in high-risk patients.