Role of Polyphenols and Carotenoids in Endothelial Dysfunction: An Overview from Classic to Innovative Biomarkers

Abstract

Nowadays, the dramatically increased prevalence of metabolic diseases, such as obesity and diabetes mellitus and their related complications, including endothelial dysfunction and cardiovascular disease, represents one of the leading causes of death worldwide. Dietary nutrients together with healthy lifestyles have a crucial role in the endothelium health-promoting effects. From a growing body of evidence, active natural compounds from food, including polyphenols and carotenoids, have attracted particular attention as a complementary therapy on atherosclerosis and cardiovascular disease, as well as preventive approaches through the attenuation of inflammation and oxidative stress. They mainly act as radical scavengers by promoting a variety of biological mechanisms, such as improvements in endothelial function, blood pressure, platelet activity, and insulin sensitivity, and by modulating various known biomarkers. The present review highlights the role of polyphenols and carotenoids in early endothelial dysfunction with attention to their beneficial effect in modulating both classical and recent technologically generated emerging biomarkers. These, alone or in combination, can play an important role in the prediction, diagnosis, and evolution of cardiovascular disease. However, a main challenge is to speed up early and prompt new interventions in order to prevent or slow down disease progression, even with an adequate intake of bioactive compounds. Hence, there is an urgent need of new more validated, appropriate, and reliable diagnostic and therapeutic biomarkers useful to diagnose endothelial dysfunction at an earlier stage.

Figure 1

Endothelial dysfunction. Figure adapted from Di Pietro N. et al. JSM Atherosclerosis, 2016 [12]. Under oxidative condition, NO may react with O₂⁻ to form ONOO⁻; this leads to the decrease of NO bioavailability leading to endothelial dysfunction, enhanced LDL peroxidation, and chronic vascular inflammation. This is associated with lipid accumulation in the arterial wall, an NF-κB activation that in turn triggers the upregulation of VCAM-1 and ICAM-1. The increased VCAM-1 and ICAM-1 membrane exposure leads to increased adhesion and infiltration of monocytes. eNOS: endothelial nitric oxide synthase; NO: nitric oxide; O₂⁻: superoxide anion; ONOO⁻: peroxynitrite; cGMP: cyclic guanosine monophosphate; LDL: low-density lipoprotein; ox-LDL: oxidized low-density lipoprotein; TNF-α: tumor necrosis factor alpha; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; ICAM-1: intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule 1.

Figure 2

Classical and innovative biomarkers modulated by polyphenols and carotenoids in early endothelial dysfunction. Part of the figure is adapted from Di Pietro N et al. JSM Atherosclerosis, 2016 [12]. Both polyphenols and carotenoids have been shown to significantly reduce all the key events of early endothelial dysfunction through their antioxidant and anti-inflammatory actions, as described in detail in the figure text. This is proven by their ability in modulating several classic and some innovative biomarkers here summarized. Among the future innovative perspectives, integrated personal omics profiling (iPOP) will potentially allow to obtain personalized prevention and nutritional food intervention through the intricate and mutual interaction of omics technology (genome, epigenome, transcriptome, proteome, cytokines, metabolome, autoantibody-ome, and microbiome). eNOS: endothelial nitric oxide synthase; NO: nitric oxide; O₂⁻: superoxide anion; ONOO⁻: peroxynitrite; cGMP: cyclic guanosine monophosphate; LDL: low-density lipoprotein; ox-LDL: oxidized low-density lipoprotein; TNF-α: tumor necrosis factor alpha; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; ICAM-1: intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule 1; ROS: reactive oxygen species; NOX4: NADPH oxidase 4; AGEs: advanced glycation end-products; MMP9: matrix metallopeptidase 9; PECAM-1: platelet endothelial cell adhesion molecule; clusters of differentiation: CD31, CD31+/41-, CD144+, CD41+, and CD14; interleukins: IL1beta, IL6, IL8, and IL12; PI3K/Akt: phosphoinositide 3-kinases/protein kinase B; MAPK: mitogen-activated protein kinase; FMD: flow-mediated dilation; RHI: reactive hyperemia index; BP: blood pressure; RH-PAT: reactive hyperemia peripheral arterial tonometry; PWV: pulse wave velocity; NOx: nitrogen oxides; sICAM-1: soluble ICAM-1; sVCAM-1: soluble VCAM1; sE-selectin: soluble E-selectin; hsCRP: high-sensitivity C-reactive protein; EPCs: endothelial progenitor cells; EVs: extracellular vesicles; SOD: superoxide dismutase; CAT: catalase; ET-1: endothelin-1; MCP-1: monocyte chemoattractant protein 1; TLR4: Toll-like receptor 4.