Hydroxyoctadecadienoic acids: novel regulators of macrophage differentiation and atherogenesis

Abstract

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)-γ 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.