– A very recent study (“Effect of a combination of citrus flavones and flavanones and olive polyphenols for the reduction of cardiovascular disease risk: an exploratory randomized, double-blind, placebo-controlled study in healthy subjects”; Maravillas Sánchez Macarro et al.; Nutrients 2020) showed that supplementation with a combination of two citrus fruit extracts, grapefruit (Citrus paradisi Macfad) and bitter orange (Citrus aurantium L.), and one olive leaf extract (Olea europaea L.) during eight weeks improved endothelial function measured by FMD, reduced blood pressure and lipid metabolism-related parameters, and improved antioxidant and inflammatory status.
This clinical study included 96 subjects, 51 subjects in the active supplement group (27 men, 24 women; mean age 47.3 _ 11.2 years) and 45 in the placebo group (26 men, 19 women; mean age 51.3 _ 10.8 years): an improvement of FMD. Both systolic and diastolic blood pressure decreased significantly in the active product group significant improvement in serum levels of total cholesterol, LDL-C, and oxidized-LDL (ox-LDL), with statistically significant differences for within-group comparisons in subjects assigned to the active product group, as well as between group-differences versus placebo.
– Regarding variables related to oxidative stress, the GHS/GSSH ratio increased significantly in the active product treatment product.
Levels of IL-6 decreased from 1.49 _ 0.96 pg/mL at baseline to 0.91 _ 0.56 pg/mL after eight weeks of treatment with the active product.
A previous study (“Endothelium-dependent vascular relaxing effects of different citrus and olive extracts in aorta rings from spontaneously Hypertensive rats”. Noemi López-Carreras et al.; Food Research International 2015) also showed that citrus extracts containing hesperidin and naringin exerted beneficial vascular relaxing effects and antioxidant effect of the extracts assayed to elucidate their possible protective to prevent NO destruction by oxygen free radicals.
Researchers demonstrated the involvement of the endotelial relaxing factor NO in the aorta relaxing effects. Endothelial NO release is a mechanism that has been implicated in the vascular relaxing effect of all the different assayed plant extracts, and we can propose the participation of prostacyclin release in the vascular relaxing effect of the lemon and olive extracts. The main flavonoids used in this study were hesperidin and naringin.
– The consumption of some classes of flavonoids is known to potentiate NO endothelium-dependent relaxation (Duffy, S. J. et al.; “Short- and Long-Term Black Tea Consumption Reverses Endothelial Dysfunction in Patients With Coronary Artery Disease”. Circulation 2001. Stein, J. et al.; “Purple Grape Juice Improves Endothelial Function and Reduces the Susceptibility of LDL Cholesterol to Oxidation in Patients With Coronary Artery Disease”. Circulation 1999).
Flavonoids have been proven to improve endothelian function by causing vasodilation in the peripheral vasculature (Eilat-Adar, S. et al. “Nutritional Recommendations for Cardiovascular Disease Prevention”. Nutrients 2013)
Several flavonoids increase the bioavailability of endothelial vasodilator factors, mainly NO and also endothelium-derived hyperpolarizing factor (EDHF) and inhibit the production of pro-inflammatory substances which considerably improves the function of vascular endothelium (Paredes, M.D. et al.; “Beneficial effects of different flavonoids on vascular and renal function in L-name hypertensive rats”. Nutrients 2018).
Merola, N.; “The effect of consumption of citrus fruit and olive leaf extract on lipid metabolism. Nutrients 2017
Guerrero, J.A. et al.; “Flavonoids inhibit platelet function through binding to the thromboxane A2 receptor”. J. Thromb. Haemost. 2005
– In patients with metabolic syndrome, supplementation with olive fruit extract (9–10 mg/day of hydroxytyrosol) combined with red yeast rice (10–11 mg/day of monacolins, including 5–6 mg/day of lovastatin) for eight weeks resulted in a 20% reduction of ox-LDL vs. an increase of 5% in the placebo group (Verhoeven, V. et al. “Can red yeast rice and olive extract improve lipid profile and cardiovascular risk in metabolic syndrome?- A double blind, placebo controlled randomized trial”). BMC Complement Altern. Med. 2015).
– A remarkable finding of the study was a significant reduction of the cytokine IL-6, a marker of inflammation High IL-6 concentrations have been associated with increased risk of myocardial infarction (MI) in healthy men. Moreover, IL-6 and its receptor levels have an early peak at the acute phase of MI, likely related to plaque instability (Bacchiega, B.C. et al.; “Interleukin 6 Inhibition and Coronary Artery Disease in a High-Risk Population: A Prospective Community-Based Clinical Study”. J. Am. Heart Assoc. 2017).
– In the Health, Aging, and Body Composition study of 2225 participants 70 to 79 years old without baseline cardiovascular disease, IL-6 was significantly associated with all outcomes, including coronary heart disease, stroke, and congestive heart failure (Cesari, M. Inflammatory Markers and Onset of Cardiovascular Events: Results from the Health ABC Study. Circulation 2003).
– Functional virgin olive oil intake improved postprandial endothelial function (determined by IRH) in a linear trend from baseline to 5 h compared with virgin olive oil. Of note, hydroxytyrosol was the main biological metabolite and it increased in a dose-dependent manner with the polyphenol content of the extra virgin olive oil (Valls, R.-M. et al; Effects of functional olive oil enriched with its own phenolic compounds on endothelial function in hypertensive patients. A randomised controlled trial. Food Chem. 2015, 167, 30–35).
– Oral supplementation with hydroxytyrosol in middle-aged healthy adults exerted anti-atherosclerotic effects by improving endothelial function (Quirós-Fernández, R. et al. “Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial”. Nutrients 2019, 11, 640).
– Individuals with variations in the NO synthase gene (Glu298Asp polymorphism) had a worse postprandial endothelial function; this was improved with a meal based on extra virgin olive oil with a high content of phenols (Jimenez-Morales, A.I. et al, “Glu298Asp polymorphism interacts with virgin olive oil phenols to determine the postprandial endothelial function in patients with the metabolic síndrome”. J. Clin. Endocrinol. Metab. 2011, 96, E1694–E1702).
– Overall, evidence shows that virgin olive oil phenols may improve endothelial function in large, medium and small size vessels, indicating the involvement of various mechanisms, including a higher NO bioavailability, upregulation of antioxidant pathways and a decrease in pro-oxidant substances production (“The Fluid Aspect of the Mediterranean Diet in the Prevention and Management of Cardiovascular Disease and Diabetes: The Role of Polyphenol Content in Moderate Consumption of Wine and Olive Oil” Paola Ditano-Vázquez et al.; Nutrients 2019).
– The results provide biological evidences of the protective effects of the HT metabolite on endothelium against an inflammatory stimulus, suggesting that consumption of an appropriate diet with EVOO could be useful to prevent endothelial dysfunction (“Targeting endothelial-to-mesenchymal transition: the protective role of hydroxytyrosol sulfate metabolite” (Erika Terzuoli et al.; European Journal of Nutrition 2018).
– Thus, our results suggest a protective effect of olive oil polyphenols on endothelial dysfunction induced by hyperglycemia and free fatty acids (“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”;Carolina Emilia Storniolo et al; Redox Biol. 2014).
– This effect involved a decrease in platelet thromboxane synthesis and an increase in leucocyte nitric oxide production (“Virgin Olive Oil Polyphenol Hydroxytyrosol Acetate Inhibits in Vitro Platelet Aggregation in Human Whole Blood: Comparison With Hydroxytyrosol and Acetylsalicylic”; Acid José Antonio González Correa et al. Br J. Nutr 2009).
– HT enhanced nitric oxide (NO) production in a dose-dependent manner (“Hydroxytyrosol Induces Vascular Smooth Muscle Cells Apoptosis Through NO Production and PP2A Activation With Subsequent Inactivation of Akt”; Houda Zrelli et al.; Plant Med 2011).
– Taken together, our data suggest that, during endotoxin challenge, oleuropein potentiates the macrophage-mediated response, resulting in higher NO production, currently believed to be beneficial for cellular and organismal protection (“Oleuropein, the Bitter Principle of Olives, Enhances Nitric Oxide Production by Mouse Macrophages; F Visioli et al; Life Sci 1998).
– Selected mixtures of oleuropein and catechin with low nitrite (1 microM) were shown to induce muscle relaxation of stomach strips in a structure-dependent way. Data presented here brings strong support to the concept that polyphenols consumed in a variety of dietary products, under gastric conditions, reduce nitrite to *NO that, in turn, may exert a biological impact as a local relaxant (“Dietary Polyphenols Generate Nitric Oxide From Nitrite in the Stomach and Induce Smooth Muscle Relaxation”; Bárbara S Rocha et al; Toxicology 2009).
– The findings indicate that antihypertensive effects of oleuropein might be partly mediated by improving the release of nitric oxide, and antioxidant and sympathoplegic activities (“Effects of Oleuropein in Rats With Simultaneous Type 2 Diabetes and Renal Hypertension: A Study of Antihypertensive Mechanisms”; Ali Akbar Nekooeian et al.; J Asian Nat Prod Res 2014).
– The combined use of polyphenols, as in PEOP (polyphenol phenol extract from olive pomace) could represent a powerful tool for the treatment and chemoprevention of endothelial dysfunction-associated vascular diseases (“Effects of Polyphenol Extract From Olive Pomace on Anoxia-Induced Endothelial Dysfunction”; Daniela Palmieri et al.; Microvasc 2012).
– FVOO (tunctional virgin olive oil enriched with its onw phenols) provided more benefits on endothelial function than a standard natural virgin olive oil in pre- and hypertensive patients. In the present study, improvement in endothelial function, reflected in an increase in IRH after FVOO, was inversely related to LDL oxidative damage. Thus, a reduction in both oxidative stress (decreased oxidative damage to LDL) and resulting inflammation could account for the improvement in the endothelial function observed after FVOO ingestion. Our results point to a key role for polyphenols in the improvement of the endothelial function in the pre- and hypertensive patients (“Effects of Functional Olive Oil Enriched With Its Own Phenolic Compounds on Endothelial Function in Hypertensive Patients. A Randomised Controlled Trial” Rosa-M Valls et al.; Food Chem 2015).
– We report the first evidence that monophenols tyrosol and p-coumaric acid are selectively protective only in homocysteine-activated cells, while they are ineffective in reducing ICAM-1 expression induced by TNFalpha. Finally, we report the synergistic effect of o-diphenolic and monophenolic compounds. Olive oil phenolic compounds approaching potential in vivo concentrations are able to modulate the Hcy-induced expression of adhesion molecules, and likely delay plaque formation, confirm the beneficial role of extra virgin olive oil and the Mediterranean diet on human health, suggesting a possible therapeutic role of these compounds in Hcy-induced CVDs. (“Olive Oil Phenolic Compounds Inhibit Homocysteine-Induced Endothelial Cell Adhesion Regardless of Their Different Antioxidant Activity”; Caterina Manna et al.; J Agric Food Chem 2009)