Abstract
Atherosclerosis and its complications are responsible for one in three global deaths. Nutraceuticals show promise in the prevention and treatment of atherosclerosis but require an indepth understanding of the mechanisms underlying their actions. A previous study showed that the omega-6 fatty acid, dihomo-γ-linolenic acid (DGLA), attenuated atherosclerosis in the apolipoprotein E deficient mouse model system. However, the mechanisms underlying such protective effects of DGLA are poorly understood and were therefore investigated. We show that DGLA attenuates chemokine-driven monocytic migration together with foam cell formation and the expression of key pro-atherogenic genes induced by three pro-inflammatory cytokines in human macrophages. The effect of DGLA on interferon-γ signaling was mediated via inhibition of signal transducer and activator of transcription-1 phosphorylation on serine 727. In relation to anti-foam cell action, DGLA inhibits modified LDL uptake by both macropinocytosis and receptor-mediated endocytosis, the latter by reduction in expression of two key scavenger receptors (SR-A and CD36), and stimulates cholesterol efflux from foam cells. DGLA also improves macrophage mitochondrial bioenergetic profile by decreasing proton leak. Gamma-linolenic acid and prostaglandin E1, upstream precursor and key metabolite respectively of DGLA, also acted in an anti-atherogenic manner. The actions of DGLA extended to other key atherosclerosis-associated cell types with attenuation of endothelial cell proliferation and migration of smooth muscle cells in response to platelet-derived growth factor. This study provides novel insights into the molecular mechanisms underlying the anti-atherogenic actions of DGLA and supports further assessments on its protective effects on plaque regression in vivo and in human trials.
Highlights
Atherosclerosis, an inflammatory disease of the vasculature and the underlying cause of cardiovascular disease (CVD), is responsible for about 31.5% of all global deaths [1,2,3]
Previous studies showed that dihomo-γ-linolenic acid (DGLA) at concentrations of 50–200 μM inhibited lipopolysaccharide (LPS) induced tumour necrosis factor-α (TNF-α) production in peripheral blood mononuclear cells (PBMC) [31]
To investigate whether such anti-inflammatory action extends to macrophages and other proinflammatory/atherogenic mediators, the effect of several concentrations of DGLA on IFN-γ induced expression of monocyte chemotactic protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) mRNA, which are both expressed at high levels during inflammation and atherosclerosis [5,23], was first investigated in human THP-1 macrophages
Summary
Atherosclerosis, an inflammatory disease of the vasculature and the underlying cause of cardiovascular disease (CVD), is responsible for about 31.5% of all global deaths [1,2,3]. Atherosclerosis is initiated in response to various risk factors, the accumulation of LDL in the intima of arteries and its subsequent oxidation to oxidized LDL (oxLDL) [1,2,3] This triggers arterial endothelial cell activation and/or dysfunction leading to secretion of chemokines by these cells and increased expression of Abbreviations: ABC, ATP-binding cassette transporter; AcLDL, acetylated LDL; Apo, apolipoprotein; CE, cholesteryl esters; CVD, cardiovascular disease; DGLA, dihomo-γ-linolenic acid; ECM, extracellular matrix; FC, free cholesterol; FCCP, carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; HASMC, human aortic smooth muscle cells; GLA, gamma-linolenic acid; HMDM, human monocyte-derived macrophages; HUVEC, human umbilical cord endothelial cells; ICAM-1, intercellular adhesion molecule-1; IFN-γ, interferon-γ; IL, interleukin; LA, linoleic acid; LPS, lipopolysaccharide; LXR, liver X receptors; LY, lucifer yellow; MCP-1, monocyte chemotactic protein-1; NEFA, non esterified fatty acids; oxLDL, oxidized LDL; PBMC, peripheral blood mononuclear cells; PDGF, platelet-derived growth factor; PGE1, prostaglandin E1; PUFA, polyunsaturated fatty acid; RT-qPCR, real-time quantitative polymerase chain reaction; SR, scavenger receptor; STAT-1, signal transducer and activator of transcription-1; TBHP, tert-butyl hydroperoxide; TNF-α, tumour necrosis factor-α; VCAM-1, vascular cell adhesion molecule-1; VSMC, vascular smooth muscle cells. Excessive degradation by a range of proteases produced under inflammatory conditions causes plaque destabilization and rupture and subsequent thrombosis [2,3,4,5]
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