An Immunomodulating Fatty Acid Analogue Targeting Mitochondria Exerts Anti-Atherosclerotic Effect beyond Plasma Cholesterol-Lowering Activity in apoE-/- Mice

Rita Vik,Cesare R Sirtori,Ottar K Nygård,Federica Dellera,Pål Aukrust,Trond Brattelid,Bodil Bjørndal,Giulia S Ganzetti,Cinzia Parolini,Rolf K Berge,Stefano Manzini,Pavol Bohov,Sverre Holm,Bente Halvorsen,Marco Busnelli,Giulia Chiesa,Andrej A Romanovsky

doi:10.1371/journal.pone.0081963

Abstract

Tetradecylthioacetic acid (TTA) is a hypolipidemic antioxidant with immunomodulating properties involving activation of peroxisome proliferator-activated receptors (PPARs) and proliferation of mitochondria. This study aimed to penetrate the effect of TTA on the development of atherosclerotic lesions in apolipoprotein (apo)-E-/- mice fed a high-fat diet containing 0.3% TTA for 12 weeks. These mice displayed a significantly less atherosclerotic development vs control. Plasma cholesterol was increased by TTA administration and triacylglycerol (TAG) levels in plasma and liver were decreased by TTA supplementation, the latter, probably due to increased mitochondrial fatty acid oxidation and reduced lipogenesis. TTA administration also changed the fatty acid composition in the heart, and the amount of arachidonic acid (ARA) and eicosapentaenoic acid (EPA) was reduced and increased, respectively. The heart mRNA expression of inducible nitric oxidase (NOS)-2 was decreased in TTA-treated mice, whereas the mRNA level of catalase was increased. Finally, reduced plasma levels of inflammatory mediators as IL-1α, IL-6, IL-17, TNF-α and IFN-γ were detected in TTA-treated mice. These data show that TTA reduces atherosclerosis in apoE-/- mice and modulates risk factors related to atherosclerotic disorders. TTA probably acts at both systemic and vascular levels in a manner independent of changes in plasma cholesterol, and triggers TAG catabolism through improved mitochondrial function.

Highlights

Atherosclerosis is a complex vascular disease with a bidirectional interaction between lipids and inflammation as a major feature
TTA is reported to be an important regulator of lipids through peroxisome proliferator-activated receptors (PPARs) [12,16,31] and to have positive effects on plasma lipid risk factors related to cardiovascular diseases [32] and most probably to atherosclerosis [33]
The plasma cholesterol, free cholesterol, HDL- and LDLcholesterol levels were increased by TTA treatment, suggesting that effect of TTA on plaque reduction is not related to its cholesterol lowering properties

Summary

Introduction

Atherosclerosis is a complex vascular disease with a bidirectional interaction between lipids and inflammation as a major feature. These interactions involve monocytes/ macrophages, T cells, vascular smooth muscle cell (SMC) and endothelial cells, and in addition to inflammation and lipid deposition, matrix remodelling is an important characteristic of the atherosclerotic lesion [1]. The growing epidemic of obesity and diabetes associated with a metabolic phenotype characterized by dyslipidemia may further contribute to an increased risk of cardiovascular disease. These factors force us to consider new strategies for prevention and treatment of atherosclerotic disorders. Statins have been shown to possess anti-inflammatory properties, modulation of the nonresolving inflammation that characterizes the atherosclerotic process is still a therapeutic challenge

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