Eicosapentaenoic Acid Protects against Palmitic Acid-Induced Endothelial Dysfunction via Activation of the AMPK/eNOS Pathway

Abstract

Recent studies have shown that free fatty acids are associated with chronic inflammation, which may be involved in vascular injury. The intake of eicosapentaenoic acid (EPA) can decrease cardiovascular disease risks, but the protective mechanisms of EPA on endothelial cells remain unclear. In this study, primary human umbilical vein endothelial cells (HUVECs) treated with palmitic acid (PA) were used to explore the protective effects of EPA. The results revealed that EPA attenuated PA-induced cell death and activation of apoptosis-related proteins, such as caspase-3, p53 and Bax. Additionally, EPA reduced the PA-induced increase in the generation of reactive oxygen species, the activation of NADPH oxidase, and the upregulation of inducible nitric oxide synthase (iNOS). EPA also restored the PA-mediated reduction of endothelial nitric oxide synthase (eNOS) and AMP-activated protein kinase (AMPK) phosphorylation. Using AMPK siRNA and the specific inhibitor compound C, we found that EPA restored the PA-mediated inhibitions of eNOS and AKT activities via activation of AMPK. Furthermore, the NF-κB signals that are mediated by p38 mitogen-activated protein kinase (MAPK) were involved in protective effects of EPA. In summary, these results provide new insight into the possible molecular mechanisms by which EPA protects against atherogenesis via the AMPK/eNOS-related pathway.

A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling

“…Palmitic acid stimulates the production of superoxide radicals through activating NADPH oxidases and downregulation of eNOS [12,13]. Superoxide reacts with NO, forming the potent and versatile oxidant peroxynitrite (ONOO•−) which may oxidize the eNOS cofactor tetrahydrobiopterin or destabilize the eNOS dimer, causing uncoupling of eNOS [29].…”

“…It has been reported that chronic elevations in plasma free fatty acids (FFAs) contribute to the development of endothelial damage, diminished endothelium-dependent vasodilation, and hypertension [9,10] by triggering overproduction of reactive oxygen species (ROS), leading to uncoupling of eNOS [11]. Palmitic acid, the most prominent FFA in the bloodstream, stimulates the production of ROS, at least in part, through activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and down-regulation of eNOS and associated protective pathways, including nuclear factor-erythroid 2-related factor 2 (Nrf2) [12,13]. Decreasing lipotoxicity and its associated oxidative stress, as well as promoting up-regulation of anti-oxidant enzymes and cytoprotective proteins, may be key components to prevent and treat cardiovascular diseases.…”

Role of free fatty acids in endothelial dysfunction

“…This table shows the reported dietary nutrients/drugs that have been shown to be effective against FFAs-induced ED, and the potential mechanisms highlighted in these studies. Two differently-colored texts in the table have been used to highlight different studies on the same drug or the use of more than one study model used within the same articleDrug/dietary constituentEffects/relevant mechanismsNature of the studyω-3 PUFAs (EPA)AMPK/eNOS pathway ↑In vitro study on primary HUVECs [18]iNOS ↓EC apoptosis, Caspase-3,p53/MAPK, Bax ↓NADPH oxidase/ROS ↓NF-κB activation ↓ Astragalus membranaceus NO ↑Ex vivo study on rat aortic rings [134, 141]Endothelium-dependentvasodilation ↑NF-κB ↓Cyanidin-3-O-glucosideOxidative stress ↓In vitro study on primary HUVECs [131]NF-κB activation and adhesionmolecules ↓Nrf2/EpRE pathway ↑Dihydropyridine calcium channel blockers (Nifedipine and amlodipine)Forearm blood flow responses toClinical trial [128]ACh ↑Leucocyte activation ↓Oxidative stress ↓In vitro monocytic cells [128]NF-κB ↓TNF-α, IL-6 ↓In vitro study on HUVECs [131]IKKβ/NF-κβ phosphorylation ↓IRS-1 phosphorylation ↓NO production ↑L-carnitineEndothelium-dependent leg blood flow ↑Clinical trial [107]LosartanVasodilation ↑Clinical study [139]eNOS activity ↑IRS-1 phosphorylation ↓Study on rats [139]Olive oil polyphenolseNOS activity ↑In vitro study on ECV304 cells [102]ET-1 ↓PerindoprilVasodilation ↑Clinical study [141]SalidrosideeNOS activation, NO production ↑In vivo study on HFD-fed ApoE −/− mice [106]AMPK/PI3K/Akt/eNOS pathway,Cellular AMP/ATP ratio ↑Atherosclerotic lesion ↓Withaferin AROS, TNF-α, IL-6 ↓In vitro stu...…”

Palmitate-induced inflammatory pathways in human adipose microvascular endothelial cells promote monocyte adhesion and impair insulin transcytosis

“…Long-term exposure to high concentrations of saturated fatty acids have previously been found to trigger apoptosis in cells in culture. In endothelial cells, most studies on viability and lipotoxic effects of palmitate used exposure of more than 24 h and doses more than 0.3 mM often with a high palmitate/BSA ratio (24,30,44,53). Moreover, the apoptosis induced by high concentrations of PA in aortic cells is independent of NF-B activation, dissociating the proinflammatory effects of saturated fatty acids from their toxicity at high concentrations (12).…”