Abstract
Nitric oxide (NO) is an important signaling molecule involved in many pathophysiological processes. NO mediates vasodilation and blood flow in the arteries, and its action contributes to maintaining vascular homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. Dietary antioxidants and their metabolites have been found to be directly and/or indirectly involved in the modulation of the intracellular signals that lead to the production of NO. The purpose of this study was to investigate the contribution of conjugated metabolites of hydroxytyrosol (HT) and tyrosol (TYR) to the release of NO at the vascular level, and the related mechanism of action, in comparison to their parental forms. Experiments were performed in human aortic endothelial cells (HAEC) to evaluate the superoxide production, the release of NO and production of cyclic guanosine monophosphate (cGMP), the activation of serine/threonine-protein kinase 1 (Akt1), and the activation state of endothelial nitric oxide synthase (eNOS). It was observed that the tested phenolic compounds enhanced NO and cGMP concentration, inhibiting its depletion caused by superoxide overproduction. Moreover, some of them enhanced the activation of Akt (TYR, HT metabolites) and eNOS (HT, HVA, TYR-S, HT-3S). Overall, the obtained data showed that these compounds promote NO production and availability, suggesting that HT and TYR conjugated metabolites may contribute to the effects of parental extra virgin olive oil (EVOO) phenolics in the prevention of cardiovascular diseases.
Highlights
Nitric oxide (NO) is a key modulator of vascular function, and an imbalance in endothelium-derived NO can underlie the pathogenesis of vascular impairments, inducing the progression to hypertension, atherosclerosis, and vasospasm, affecting blood flow in the vessels [1]
Endothelial nitric oxide synthase uncoupling can lead to endothelial dysfunction, and the upregulation of endothelial nitric oxide synthase (eNOS) activity through the activation of serine/threonine-protein kinase 1 (Akt1) contributes to maintaining or restoring a healthy vascular function [8]
Hydroxytyrosol (HT) and tyrosol (TYR) are two bioactive phenolic acids abundant in extra virgin olive oil (EVOO) and have been the subject of a range of investigations elucidating their role on the health benefits associated with the regular consumption of EVOO [10,11,12], including the prevention of cardiovascular diseases and the maintenance of healthy vascular function [3,9,13]
Summary
Nitric oxide (NO) is a key modulator of vascular function, and an imbalance in endothelium-derived NO can underlie the pathogenesis of vascular impairments, inducing the progression to hypertension, atherosclerosis, and vasospasm, affecting blood flow in the vessels [1]. The available literature shows that HT, TYR, and metabolic derivatives (methylated, sulfated, glucuronidated forms) are bioavailable forms present in the circulation after EVOO consumption [16,17]. Recent studies have started to take into great consideration the bioactivity and contribution to the beneficial health effects of the methylated, sulfated, and glucuronidated forms of HT and TYR [21,25,26,27,28] Within this context, the aim of this study was to evaluate the potential modulation of NO balance by the bioavailable conjugated metabolites of HT and TYR in endothelial cells, in comparison to their parental forms.
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