Anti-atherogenic actions of dihomo-gamma-linolenic acid and its key metabolites

Abstract

Atherosclerosis, an inflammatory disease of medium and large arteries, is the underlying cause of cardiovascular diseases. Current pharmaceutical therapies against atherosclerosis are not fully effective. Nutraceuticals, such as polyunsaturated fatty acids(PUFA), represent promising alternatives but require detailed understanding of their mechanisms of action. Dihomo-gamma-linolenic acid (DGLA), an omega-6 PUFA, attenuates atherosclerosis in the apolipoprotein-E-deficient mouse model of the disease. Previous research in the laboratory showed that DGLA inhibited several key macrophage processes associated with atherosclerosis in vitroand increased the levels of prostaglandin E1(PGE1) and 15-S-hydroxyeicosatriaenoic acid (15-S-HETrE) in human macrophages, thereby suggesting that these metabolites are potentially responsible for the anti-atherogenic actions of DGLA. Unfortunately, the effects of PGE1and 15-S-HETrE on key atherosclerosis-associated processes are poorly understood and formed the focus of studies in this project.Similar to DGLA, PGE1and 15-S-HETrE attenuated chemokine-driven monocytic migration together with macropinocytosis, oxidised low-density lipoprotein (oxLDL) uptake and the expression of key scavenger receptors in human macrophages in vitro. The use of Atherosclerosis RT2Profiler PCR Arrays showed that DGLA, PGE1and 15-S-HETrE inhibited the expression of 16, 12 and 21 genes respectively in human macrophages in vitrowith 3 common regulated genes. These genes included those that play key roles in stress response and apoptosis, lipid transport and metabolism, and regulation of inflammation. The use of pharmacological inhibitors against cyclooxygenases and lipoxygenases together with bone marrow-derived macrophages from wildtype and 12/15-lipooxygenase deficient mice showed the key roles of these enzymes in the actions of DGLA in vitro. In addition, DGLA supplementation produced changes in signalling lymphocyte activation molecule and cell lineage populations within the bone marrow of LDL receptor deficient mice fed a high fat diet. Overall, these studies provide novel insights into the anti-atherogenic actions of DGLA and its metabolites and inform on its therapeutic potential.