Dihomo-γ-linolenic acid inhibits several key cellular processes associated with atherosclerosis

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1865

Article

Gallagher, Hayley¹  Williams, Jessica O.¹  Ferekidis, Nele¹  Ismail, Alaa¹  Chan, Yee-Hung¹  Michael, Daryn R.¹  Guschina, Irina A.¹  Tyrrell, Victoria J.²  O'Donnell, Valerie B.²  Harwood, John L.¹  Khozin-Goldberg, Inna³  Boussiba, Sammy³  Ramji, Dipak P.¹ 

[1] Cardiff Univ, Cardiff Sch Biosci, Sir Martin Evans Bldg,Museum Ave, Cardiff CF10 3AX, S Glam, Wales

[2] Cardiff Univ, Syst Immun Res Inst, Cardiff CF14 4XN, S Glam, Wales

[3] Ben Gurion Univ Negev, J Blaustein Inst Desert Res, French Associates Inst Agr & Biotechnol Drylands, Microalgal Biotechnol Lab, Sede Boger Campus, IL-84990 Sede Boqer, Israel

关键词: Atherosclerosis;    Dihomo-gamma-linolenic acid;    Foam cells;    Inflammation;    Macrophages;    Smooth muscle cells;    Gene expression;   

DOI  :  10.1016/j.bbadis.2019.06.011

来源: Elsevier

【 摘 要 】

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-gamma-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-gamma 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 El, 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.

【 授权许可】

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