Eicosapentaenoic Acid Prevents Saturated Fatty Acid-Induced Vascular Endothelial Dysfunction: Involvement of Long-Chain Acyl-CoA Synthetase

Ishida, Takayuki; Naoe, Satoko; Nakakuki, Masanori; Kawano, Hiroyuki; Imada, Kazunori

doi:10.5551/jat.28167

Cited by 26 publications

(21 citation statements)

References 33 publications

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“…Taking into account the effects of FFA on inflammation, oxidative stress, and expression of adhesion molecules (51–53), our results may support a role for FFA as a link between the (altered) gut microbiota, host metabolism, and disease status. It is interesting to note that differences among FFA in their ability to promote endothelial activation in vivo or in vitro have been demonstrated (54–56), which is in line with the associations found in our study. Importantly, these biomarkers are considered as early preclinical indicators of CVD development in the long term (57–60).…”

Section: Discussionsupporting

confidence: 92%

Intestinal Dysbiosis Is Associated with Altered Short-Chain Fatty Acids and Serum-Free Fatty Acids in Systemic Lupus Erythematosus

et al. 2017

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Metabolic impairments are a frequent hallmark of systemic lupus erythematosus (SLE). Increased serum levels of free fatty acids (FFA) are commonly found in these patients, although the underlying causes remain elusive. Recently, it has been suggested that factors other than inflammation or clinical features may be involved. The gut microbiota is known to influence the host metabolism, the production of short-chain fatty acids (SCFA) playing a potential role. Taking into account that lupus patients exhibit an intestinal dysbiosis, we wondered whether altered FFA levels may be associated with the intestinal microbial composition in lupus patients. To this aim, total and specific serum FFA levels, fecal SCFA levels, and gut microbiota composition were determined in 21 SLE patients and 25 healthy individuals. The Firmicutes to Bacteroidetes (F/B) ratio was strongly associated with serum FFA levels in healthy controls (HC), even after controlling for confounders. However, this association was not found in lupus patients, where a decreased F/B ratio and increased FFA serum levels were noted. An altered production of SCFA was related to the intestinal dysbiosis in lupus, while SCFA levels paralleled those of serum FFA in HC. Although a different serum FFA profile was not found in SLE, specific FFA showed distinct patterns on a principal component analysis. Immunomodulatory omega-3 FFA were positively correlated to the F/B ratio in HC, but not in SLE. Furthermore, divergent associations were observed for pro- and anti-inflammatory FFA with endothelial activation biomarkers in lupus patients. Overall, these findings support a link between the gut microbial ecology and the host metabolism in the pathological framework of SLE. A potential link between intestinal dysbiosis and surrogate markers of endothelial activation in lupus patients is supported, FFA species having a pivotal role.

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Section: Discussionsupporting

confidence: 92%

Intestinal Dysbiosis Is Associated with Altered Short-Chain Fatty Acids and Serum-Free Fatty Acids in Systemic Lupus Erythematosus

et al. 2017

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“…Our study revealed that EPA suppresses Wnt signaling in smooth muscle cells. EPA is also known to affect macrophages and endothelial cells [ 49 , 50 , 51 ]. Additionally, Wnt signaling is associated with inflammation and aging [ 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Suppression of Wnt Signaling and Osteogenic Changes in Vascular Smooth Muscle Cells by Eicosapentaenoic Acid

et al. 2017

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Vascular medial calcification is often observed in patients with arteriosclerosis. It is also associated with systolic hypertension, wide pulse pressure, and fluctuation of blood pressure, which results in cardiovascular events. Eicosapentaenoic acid (EPA) has been shown to suppress vascular calcification in previous animal experiments. We investigated the inhibitory effects of EPA on Wnt signaling, which is one of the important signaling pathways involved in vascular calcification. Intake of food containing 5% EPA resulted in upregulation of the mRNA expression of Klotho, an intrinsic inhibitor of Wnt signaling, in the kidneys of wild-type mice. Expression levels of β-catenin, an intracellular signal transducer in the Wnt signaling pathway, were increased in the aortas of Klotho mutant (kl/kl) mice compared to the levels in the aortas of wild-type mice. Wnt3a or BIO, a GSK-3 inhibitor that activates β-catenin signaling, upregulated mRNA levels of AXIN2 and LEF1, Wnt signaling marker genes, and RUNX2 and BMP4, early osteogenic genes, in human aorta smooth muscle cells. EPA suppressed the upregulation of AXIN2 and BMP4. The effect of EPA was cancelled by T0070907, a PPARγ inhibitor. The results suggested that EPA could suppress vascular calcification via the inhibition of Wnt signaling in osteogenic vascular smooth muscle cells via PPARγ activation.

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“…In human umbilical vein endothelial cells (HUVECs) that were exposed to ox-LDL, EPA improved the balance between NO and ONOO À1 , acting synergistically with statins [41]. EPA attenuated palmitic acideinduced generation of reactive oxygen species, expression of adhesion molecules and cytokines, activation of apoptosis-related proteins, and apoptosis in HUVECs [42,43]. EPA also inhibited lipid peroxidation in membrane vesicles with normal or elevated cholesterol levels; this effect was also augmented by the presence of a statin [44].…”

Section: Effects Of Epa On Endothelial Function/dysfunctionmentioning

confidence: 99%

Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis

Borow¹,

2015

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Residual cardiovascular (CV) risk remains in dyslipidemic patients despite intensive statin therapy, underscoring the need for additional intervention. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, is incorporated into membrane phospholipids and atherosclerotic plaques and exerts beneficial effects on the pathophysiologic cascade from onset of plaque formation through rupture. Specific salutary actions have been reported relating to endothelial function, oxidative stress, foam cell formation, inflammation, plaque formation/progression, platelet aggregation, thrombus formation, and plaque rupture. EPA also improves atherogenic dyslipidemia characterized by reduction of triglycerides without raising low-density lipoprotein cholesterol. Other beneficial effects of EPA include vasodilation, resulting in blood pressure reductions, as well as improved membrane fluidity. EPA's effects are at least additive to those of statins when given as adjunctive therapy. In this review, we present data supporting the biologic plausibility of EPA as an anti-atherosclerotic agent with potential clinical benefit for prevention of CV events, as well as its cellular effects and molecular mechanisms of action. REDUCE-IT is an ongoing, randomized, controlled study evaluating whether the high-purity ethyl ester of EPA (icosapent ethyl) at 4 g/day combined with statin therapy is superior to statin therapy alone for reducing CV events in high-risk patients with mixed dyslipidemia. The results from this study are expected to clarify the role of EPA as adjunctive therapy to a statin for reduction of residual CV risk.

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Eicosapentaenoic Acid Prevents Saturated Fatty Acid-Induced Vascular Endothelial Dysfunction: Involvement of Long-Chain Acyl-CoA Synthetase

Cited by 26 publications

References 33 publications

Intestinal Dysbiosis Is Associated with Altered Short-Chain Fatty Acids and Serum-Free Fatty Acids in Systemic Lupus Erythematosus

Intestinal Dysbiosis Is Associated with Altered Short-Chain Fatty Acids and Serum-Free Fatty Acids in Systemic Lupus Erythematosus

Suppression of Wnt Signaling and Osteogenic Changes in Vascular Smooth Muscle Cells by Eicosapentaenoic Acid

Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis

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