Polyphenol fraction of extra virgin olive oil protects against endothelial dysfunction induced by high glucose and free fatty acids through modulation of nitric oxide and endothelin-1

Abstract

Epidemiological and clinical studies have reported that olive oil reduces the incidence of cardiovascular disease. However, the mechanisms involved in this beneficial effect have not been delineated. The endothelium plays an important role in blood pressure regulation through the release of potent vasodilator and vasoconstrictor agents such as nitric oxide (NO) and endothelin-1 (ET-1), respectively, events that are disrupted in type 2 diabetes. Extra virgin olive oil contains polyphenols, compounds that exert a biological action on endothelial function. This study analyzes the effects of olive oil polyphenols on endothelial dysfunction using an in vitro model that simulates the conditions of type 2 diabetes. Our findings show that high glucose and linoleic and oleic acids decrease endothelial NO synthase phosphorylation, and consequently intracellular NO levels, and increase ET-1 synthesis by ECV304 cells. These effects may be related to the stimulation of reactive oxygen species production in these experimental conditions. Hydroxytyrosol and the polyphenol extract from extra virgin olive oil partially reversed the above events. Moreover, we observed that high glucose and free fatty acids reduced NO and increased ET-1 levels induced by acetylcholine through the modulation of intracellular calcium concentrations and endothelial NO synthase phosphorylation, events also reverted by hydroxytyrosol and polyphenol extract. Thus, our results suggest a protective effect of olive oil polyphenols on endothelial dysfunction induced by hyperglycemia and free fatty acids.

A Mediterranean diet supplemented with extra virgin olive oil or nuts improves endothelial markers involved in blood pressure control in hypertensive women

“…All of these events may be related to the effects of specific fatty acids, polyphenols, phytoestrogens or other minor components present in EVOO and/or nuts. In this way, Moreno-Luna et al [42] reported that olive oil polyphenols decrease BP in young women with mild hypertension and we also observed that olive oil polyphenols have a protective effect on the imbalance of NO/ET-1 induced by hyperglycemia and free fatty acids [43].…”

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...…”

Hydroxytyrosol in the Prevention of the Metabolic Syndrome and Related Disorders

“…Lopez-Villodres et al [84] found that HT supplementation (10 mg/kg/day × 2 months) increased in diabetic rats the levels of nitrites and nitrates, potent donors of NO acting as vasorelaxing agent. In addition, Storniolo et al [85] demonstrated that HT (10 µM) counteracted hyperglycemia-induced endothelin-1 expression, a well-known hypertensive agent, in a more extend than oleic acid.…”

“…HT was reported to be ineffective on eNOS expression and activity (i.e., phosphorylation on its Ser1177) in absence of oxidative stress in HUVECs (0.1 to 100 µM) [134]. In an endothelial cell culture model of hyperglycemia, Storniolo et al [85] showed that HT (10 µM) increases NO • production, which is correlated to an increase of endothelial nitric oxide synthase phosphorylation (P-eNOS)/endothelial nitric oxide synthase (eNOS) ratio. When stimulated by acetylcholine, an activator of eNOS/NO • signaling pathway, HT increased NO • production, more than oleic acid; this increase was linked to higher intracellular calcium concentration.…”