Anthocyanins and Vascular Health: Comparison
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Anthocyanins are a subgroup of flavonoid polyphenols previously investigated for improving cardiovascular health and preventing the development of endothelial dysfunction. Phenolic metabolites can reach higher plasma concentrations and can persist in the circulation for periods much longer than their original anthocyanin form; therefore, the biological activity and health promoting effects of anthocyanins may differ from their metabolites.

  • anthocyanins
  • metabolites
  • oxidative stress

1. Introduction

The increased occurrence of cardiovascular disease (CVD) over the last 25 years, with one in four deaths in Europe, has presented CVD as a public health priority, particularly in the prevention through lifestyle interventions. Although daily recommendations for healthier lifestyle choices are of high importance for patients with CVD comorbidities, there are many implications and aspects to consider. Endothelial dysfunction (ED) is an independent prognosticator of cardiovascular events playing a vital role in the initiation of atherosclerosis and the progression of clinical complications consistently associated with diabetes, obesity, and hypertension [1].
Recently, the consumption of anthocyanins, which are a subgroup of flavonoid polyphenols, has been associated with reduced CVD mortality [2]. More than two-thirds of trials have reported beneficial effects of anthocyanins derived from fruits on the markers of CVD risk, including endothelial function [3][4]. Despite their overall health promoting effects, anthocyanins have very low bioavailability, less than 1% detected in vivo, which is translated to plasma concentrations of less than 100 nM [5][6]. This could be related to the instability of anthocyanins at physiological pH, which are usually present in plasma for 1–4 h before degradation [5][6]. On the contrary, the degradation products of anthocyanins, known as phenolic metabolites, can be found in the circulation at concentrations higher than their original forms (<42-fold) and can be detected up to 48 h after consumption of many fruits and vegetables [7][8]. In healthy men, the consumption of 240 g of blueberries increased flow-mediated dilation (FMD) at 1–2 and 6 h post-consumption [8]. This was strongly linked to the increase in phenolic metabolites found in plasma, including ferulic acid, isoferulic acid, vanillic acid, 2-hydroxybenzoic acid, benzoic acid, and caffeic acid (sum of conjugated and non-conjugated compounds), that reached a total plasma concentration of 0.4 µM [8]. Studies now reveal that phenolic metabolites’ presence in plasma correlates with improved markers of endothelial function, suggesting that the metabolites are at the forefront of the observed biological activity. Considering these findings, studies are currently establishing better identification of the benefits of anthocyanins, through investigating the mechanism of action of phenolic metabolites, leading to a clearer understanding of application in vivo. Thereby, the focus of the presearchnt review is to highlight the recent research on specific anthocyanins’ phenolic metabolites for improving vascular function (Figure 1), in addition to showing how the biological activity may differ between the precursor and metabolite products at physiologically relevant concentrations.
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Figure 1. A diagram of the chemical structures of metabolites.

2. Metabolism of Anthocyanins

Anthocyanins are water-soluble, glycosylated, and non-acetylated polyphenolic compounds that form the red, blue, and purple pigments of fruits [9]. There are over 700 different types of anthocyanin found in nature but only six anthocyanidins: cyanidin, delphinidin, pelargonidin, peonidin, malvidin, and petunidin, are widely distributed in the human diet [10]. The anthocyanidin types differ in the number of hydroxyl groups attached to their ring structure, degree of methylation, type, and the number of sugar molecules (mono-, di-, or tri-glycosides), and number of aliphatic or aromatic acids, which enable them to scavenge reactive oxygen species (ROS) directly [11]. The structure of anthocyanins plays a critical role in determining the extent of degradation caused by saliva in the mouth. This is largely governed by oral microbiota glycosides in the form of mono, di, and tri that are susceptible to this first-line degradation phase [12]. After ingestion, anthocyanins are absorbed by the stomach lining and are rapidly present in the bloodstream, reaching maximum concentrations of around 0.1 μM within the first 1–3 h [13]. At 4 h following consumption, 60–90% of the original anthocyanins may disappear from the gastrointestinal tract where they are transformed into metabolites [14][15]. The gastrointestinal conditions are influential in the stability of anthocyanin degradation products, as pH and temperature can cause significant degradation depending on the structure of the anthocyanin, such as the methoxy group on the B ring has been shown to improve stability whereas the hydroxyl group and acylation reduce stability [16]. When anthocyanins reach the small intestine, they degrade to glucuronic, methylated, and sulfate metabolites in the liver which are known as phase-2 metabolites and peak in plasma (<1 μM) at 3–5 h [7][17]. The above degradation products are catalyzed by the following enzymes: uridine diphosphate-glucuronosyltransferases, sulfotransferases, and catechol-O-methyltransferases [18]. Nevertheless, it is still possible for a low percentage of anthocyanins such as cyanidin-3-glucoside (C3G) and pelargonidin-3-glucoside to be absorbed into the gastrointestinal wall in their original unmetabolized form [16].
Unabsorbed anthocyanins are then extensively metabolized by the intestinal microbiota in the colon, giving rise to phenolic acids, including protocatechuic acid (PCA) and phloroglucinaldehyde, which are derived from the A and B rings of the parental compound [19]. Phenolic acids can also go through methylation, which alters the number of hydroxyl and methoxyl groups in ring B compared to the precursor compound [17]. Phenolic acids that have been methylated, such as vanillic acid (VA) or ferulic acid, can reach peak plasma concentration (1–2 µM) within 15 h, in addition to being detected in plasma up to 48 h after ingestion [7]. Following berry ingestion, metabolites can reach substantial concentrations in some participants (1–40 µM) with a diverse mixture of glucuronide and sulfate isomers ranging between 0.01 and 0.35 µM [20]. Moreover, the gut microbiota plays an important role in the metabolism and bioavailability of phenolic metabolites. When not absorbed by the small intestine they can reach the large intestine through being subjected to fermentation by gut microbiota. The fermentation can result in various metabolites: short chains fatty acid, phenolic acid, and urolithins. The gut microbiota can also affect the bioavailability of anthocyanins by modifying their chemical structure through enzymatic transformations. For example, some bacteria in the gut can convert flavonoids into more bioavailable forms, such as aglycones, which are more easily absorbed in the gut and transported to the bloodstream. Aglycons can enter epithelial cells by passive diffusion, or a sodium-dependent glucose transporter can be involved in the transport of the glycosides.

3. Anthocyanin Metabolites and Endothelial Function In Vivo

In recent years, there has been a growing interest in establishing a correlation of metabolite detection in plasma after the consumption of anthocyanins with improved endothelial function/CVD markers. A recent observational study found that up to 80% of the total dietary anthocyanins are derived from the consumption of berries, wines, and non-alcoholic drinks [21]. In a randomized control clinical trial, adults with moderate hypercholesterolemia who consumed an anthocyanin-rich strawberry drink daily for 4 weeks were associated with an increased FMD at week 0, 1 h post strawberry drink consumption [22]. The improved FMD was linked to an increase in plasma metabolites and, more specifically, selected metabolites were observed to be associated with pre-occlusion diameters which could partly explain the FMD responses [22]. Two additional studies have reported similar findings, demonstrating an increase in FMD responses after the consumption of berry extracts, which were associated with elevated plasma levels of metabolites [23][24]. It is important to note that none of these studies measured nitric oxide (NO) production, despite observing an increase in FMD and plasma levels of metabolites following the consumption of berry extracts. Nitric oxide is a potent vasodilator that plays a crucial role in regulating blood flow and blood pressure, and therefore, its absence in these studies leaves the open question of whether the observed improvements in FMD were directly linked to NO production or due to other mechanisms. However, in a 6-month study, after the consumption of blueberry powder daily, an increase of 1.45% in FMD was seen in middle-aged/older men and women with metabolic syndrome and increases in cyclic guanosine monophosphate [25]. Moreover, after the daily consumption of blueberry powder for 12 weeks improved endothelial function and reduced oxidative stress in postmenopausal women aged 45–65 years with elevated blood pressure, was directly linked to the increase in polyphenol metabolites at 4, 8, and 12 weeks compared to the placebo group [26]. Despite having no change in phosphorylated endothelial nitric oxide synthase (eNOS) expression over the 12 weeks, the blueberry group FMD was inversely associated with NADPH oxidase protein expression and positively associated with phosphorylated eNOS expression [26]. There have been studies in which the plasma metabolites were not associated with improved vascular responses following the intake of energy-dense high-fat/high-sugar meals [27]. However, within this study, the test meal included 65.1 g of fat (including 25.8 g of saturated fat). It has been previously observed that meal consumption per se reduces FMD responses and that postprandial vascular function is significantly impaired following previous high fat intake [27]. Moreover, in a study that included 102 prehypertensive participants, no change in endothelial function was seen following the daily consumption of encapsulated Aronia berry extract [28]. Despite no change in endothelial function following the intervention, improvements in augmentation index (Aix) and pulse wave velocity (PWV) were found in the Aronia group vs the control group. A total of 23 urinary and 43 plasma phenolic metabolites, mainly cinnamic and benzoic acid derivatives, benzene diols, and triols, were significantly correlated with the decreases in PWV and Aix found in the study [28]. A recent systematic and meta-analysis review has demonstrated that Hibiscus sabdariffa can improve CVD markers, including improved blood pressure [29]. This has been directly linked to increases in NO production via eNOS as well as a reduction in proinflammatory markers and oxidative stress [30]. It is now considered likely that the phenolic metabolites derived from hibiscus play a predominant role. Metabolites such as hippuric and gallic acid (GA) have been detected in plasma following the acute intake of hibiscus extract and could explain the previous findings [31]. It is possible that the mechanisms underlying the changes in vascular function are related to alterations at the epigenetics level over time. However, it is also likely that the initial changes are related to the modulation of signaling pathways directly linked to FMD responses during the close temporal position. Nevertheless, it should be noted that this finding is not conclusive, and further research is necessary to determine the exact mechanisms underlying these changes. It is important to note that the bioavailability of phenolic metabolites can be influenced by many factors, including their chemical structure, solubility, and interaction with other food components. Therefore, understanding the mechanisms in mouse models or in vitro could help with further clarification for application in vivo.

4. Anthocyanin Metabolites and the Adhesion of Monocytes

During the initial stages of atherosclerosis, monocytes accumulate within the vasculature and adhere onto ECs, before differentiating into macrophages. These macrophages remain on the vessel wall, and due to the existence of oxidized lipids, trigger the development of foam cells. However, foam cells cannot leave the vessel wall, leading to chronic inflammation in the local area, promoting the formation of plaques, and raising the likelihood of thrombosis. One type of co-culture model previously used for identifying nutritional components that can mitigate these parameters during the initial stages of atherosclerosis includes the EC–monocyte adhesion assay [32]. In this method, monocyte suspension cells, usually THP-1 or U937 cells, are fluorescently labeled and incubated on top of ECs with anthocyanin or metabolite treatments in the presence of inflammatory cytokines such as TNF-α [32]. The ability of anthocyanins to attenuate monocyte adhesion to ECs has been previously reported in studies, using anthocyanin-rich extracts of glycosides and aglycones but at supra-physiological concentrations (10–200 μM) [33][34][35]. However, more recent studies have shown that the exposure of ECs to individual anthocyanins and their phenolic metabolites, at physiologically relevant concentrations (0.1–2 μM), reduced monocyte adhesion to TNF-α-activated ECs (Figure 2) [36]. Both anthocyanins and gut metabolites have been able to decrease the adhesion of monocytes with a magnitude ranging from 18.1 to 47% compared to TNF-α stimulation [36]. In some cases, where the parent anthocyanin C3G decreased the adhesion by 41.8% at 10 μM, its metabolites reduced the adhesion by 18–59.3% when used at lower concentrations [37].
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Figure 2. The mechanisms of action by which anthocyanin metabolites prevent the adhesion of monocytes to endothelial cells. Phenolic metabolites can modulate the monocyte adhesion process through activation of Nrf2 transcription factor that increases the antioxidant defence system via the upregulation of antioxidant element (ARE) genes involved in reducing oxidative stress. Phenolic metabolites may also modulate the expression and activity of the NF-κB pathway which is directly linked to the induction of inflammation. NF-κB is known to upregulate the expression of adhesion molecules (vascular cell adhesion molecule (VCAM-1) and intracellular adhesion molecule (ICAM-1)) on the surface of endothelial cells as well as the production of inflammatory cytokines including IL-6, IL-1β, and TNF-α all of which is suppressed by metabolites and contribute to the reduced adhesion of leukocytes including monocytes. Phenolic metabolites also scavenge free radicals by suppressing the expression of NOX2/4 in the mitochondria of endothelial cells.
The mechanisms by which phenolic metabolites reduce the adhesion of monocytes to ECs could be combined with suppressed expression of adhesion molecules (vascular cell adhesion molecule (VCAM-1), intracellular cell adhesion molecule (ICAM-1), or E-selectin), chemokines (MCP-1 or CD40), and a reduction in proinflammatory cytokines (IL-6 or TNF-α) [38][39]. This possibly implicates a prime pharmacological target for controlling inflammatory disease, as the dialogue between ECs and monocytes/macrophages through these key components is a critical event in atherosclerosis [37][38]. Previously, anthocyanin malvidin inhibited TNF-α-induced MCP-1, ICAM-1, VCAM-1, and E-selectin production [39][40]. Moreover, soluble VCAM-1 was suppressed by PCA at 1 μM, and this effect is achievable at relevant concentrations in vivo [41][42]. Reductions in VCAM-1 mRNA have been induced by metabolites only at supra-physiological concentrations (<20 μM), while mixtures of metabolites and flavonoids at physiological concentrations showed no activity [42]. According to the contradictory findings, the method of measuring VCAM-1 or ICAM-1 either via its mRNA expression or in its soluble form may occur as a limitation [42][43]. Membrane-bound VCAM-1 and ICAM-1 do, however, directly bind to leukocytes in the progression of the atherosclerosis process; this is yet to be explored and could be a better marker to verify the association and find out if metabolites interfere with proteolytic cleavage [44][45]. Interestingly, phenolic metabolites seem to not have an active effect on mRNA transcription at physiologically relevant concentrations, and possibly act post-translationally, as suggested by others [42]. Moreover, studies have also used supra-physiological concentrations of TNF-α which may not replicate plasma concentration in vivo and may also explain the contradictory findings [42].

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