The Influence of Polyphenols on Atherosclerosis Development

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1		Kamila Kasprzak-Drozd	--	6770	2023-04-27 14:37:46	\|
2	format correct	Jessie Wu	-1 word(s)	6769	2023-04-28 05:32:06	\| \|
3	format correct	Jessie Wu	+ 8 word(s)	6777	2023-04-28 05:34:11	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms24087146

Polyphenols have attracted tremendous attention due to their pro-health properties, including their antioxidant, anti-inflammatory, antibacterial and neuroprotective activities. Atherosclerosis is a vascular disorder underlying several cardiovascular diseases (CVDs). One of the main risk factors causing atherosclerosis is the type and quality of food consumed. Therefore, polyphenols represent promising agents in the prevention and treatment of atherosclerosis, as demonstrated by in vitro, animal, preclinical and clinical studies. However, most polyphenols cannot be absorbed directly by the small intestine. Gut microbiota play a crucial role in converting dietary polyphenols into absorbable bioactive substances. An increasing understanding of the field has confirmed that specific gut microbiota (GM) taxa strains mediate the gut microbiota–atherosclerosis axis.

atherosclerosis cardiovascular diseases polyphenols inflammatory diseases oxidative stress gut phenolic acids gut microbiota flavonoids cacao green tea resveratrol curcumin quercetin protocatechuic acid Trimethoxycinnamic Acid Gallic Acid equol Medite

1. Introduction

A process mainly observed in developed or developing countries ^[1], atherosclerosis is considered a major cause of morbidity. Population growth, an aging population and epidemiological changes are increasing the number of deaths from cardiovascular disease (CVD) ^[2]. Atherosclerosis is a chronic inflammatory disease characterised by damage and hardening of the inner layer of the arterial wall and the accumulation of plaques, which can result in thrombosis. The multifactorial disease is primarily due to lipid accumulation and the development of chronic inflammation in the vessels ^[1].

The pathogenesis of atherosclerosis is related to the migration of monocytes, their transformation into macrophages and endothelial activation. The accumulation of oxidised low-density lipids, becoming foam cells, results in the formation of atherosclerotic plaque and obstruction of normal blood flow ^[3]. Activation of macrophages and smooth muscle cells leads to a release of hydrolytic enzymes, cytokines, chemokines and growth factors that induce focal apoptosis ^[4]. The atherosclerotic process is accompanied by an immune response to low-density lipoprotein low-density lipoprotein (LDL) and other antigens, alleviating or exacerbating the course of the disease ^[5]. The resulting atherosclerotic plaques are divided into those with a predominantly lipid component or fibrous tissue ^[4]. The aforementioned processes lead to cardiovascular disease ^[3].

With lifestyle changes that include smoking cessation, increased daily physical activity, and reduced consumption of fatty foods, there has been a decline in cardiovascular disease CVD mortality in the United States in the 21st century. Despite this, it is estimated that almost 50% of the adult population will be burdened with some form of CVD by 2023 ^[6]. Many studies have been conducted to date showing the impact of quality of life and diet on the incidence of various chronic diseases, including diabetes, hypertension and cardiovascular disease. According to the 2015–2020 guidelines, the recommended daily intake of fruit is two cups, yet Americans continue to consume more than the recommended amount of meat compared to fruit and vegetables.

The different phases in the pathogenesis of atherosclerosis are all promising therapeutic targets. Statins that lower LDL cholesterol and have additional pleiotropic effects are widely used. However, there is a considerable risk in patients on statin therapy, with some individuals unable to achieve target LDL cholesterol goals or cannot tolerate the medicine. Moreover, high statin dose may cause side effects such as rhabdomyolysis, non-allergic rhinitis and hyperglycemia ^[7]. Clinical trials using orally active HDL-raising agents was disappointing, just like trials on inhibitors of cholesteryl ester transfer protein ^[8]. Due to atherosclerosis being an inflammatory disorder, approaches that dampen inflammation are also being pursued ^[9]. However, such approaches will have to be restricted to high-risk patients, because of the risks associated with manipulating systemic inflammation. For this reason, scientists are constantly looking for alternative ways to prevent atherosclerosis. A link between antioxidant consumption and the inhibition of atherosclerosis was recently discovered. Accordingly, nutrient-containing polyphenols, especially anthocyanins and flavonoids, have potential in countering cardiovascular disease. Furthermore, phenylalanines, consisting of aromatic carbon and hydroxyl rings, are known to have an important function in scavenging reactive oxygen species. Organic-rich fruits, vegetables, teas or traditional medicinal herbs should therefore form an indispensable part of everybody’s diet ^[10]. Of note, extra virgin olive oil is particularly rich in polyphenols and has shown strong antioxidant properties.

A poor diet causes many negative effects, contributing to the development of many diseases. Numerous studies have shown the positive effects of the Mediterranean diet on cardiovascular health. It has been found to reduce plasma lipid, glucose and blood pressure concentrations, as well as the plasma concentrations of inflammatory biomarkers (interleukin IL-6, vascular cell adhesion protein 1(VCAM 1) and Intercellular Adhesion Molecule 1 (ICAM-1). The Mediterranean diet is characterised by a high content of cereals, vegetables (rich in fibre), fruits, and seafood (sources of omega-3 polyunsaturated fatty acids). Consumers of this diet limit red wine, meat, dairy, eggs and sweets. Until the 1960s, the Mediterranean style of eating resulted in the lowest rates of chronic disease and the highest life expectancy in the region ^[4].

In recent years, there has been a surge of interest in the interaction of polyphenols and gut microbiota. They have become the subject of numerous scientific studies due to their potential beneficial effects on the body’s health, in particular, the prevention of cancer and cardiovascular disease ^[11]. Polyphenols act selectively on microorganisms, inhibiting the growth of pathogens and showing prebiotic effects. The colonic microbiome converts polyphenols into bioactive compounds, resulting in better absorption of them ^[12]. A relationship between the microbiome and atherosclerosis is observed in the presence of inflammation occurring with intestinal dysbiosis. There is then an increased permeability of the mucosal barrier, thus increasing permeability to bacteria ^[13].

2. Effect of Polyphenols on the Composition of Gut Microbiota

More than 10,000 polyphenolic compounds ^[14] have been identified in plant products that increase the abundance of beneficial microorganisms. Because phenolic compounds can exert a prebiotic effect, it is crucial to understand their inhibitory or stimulating effect on beneficial or pathogenic bacteria.

Polyphenolic compounds affect gut microbiota (GM) by influencing the growth and metabolism of bacteria and by interfering with the cellular function of the cell membrane. Moreover, a significant proportion of polyphenols act on GM by hindering biofilm formation and, notably, bacterial quorum sensing. For example, some classes of flavonoid polyphenols may affect Staphylococcus bacteria by decreasing bacterial helicase activity and increasing cytoplasm membrane permeability. In addition, a citrus extract containing flavanones and other isolated compounds from this group of secondary metabolites was found to contribute to hindering the formation of biofilm by inhibiting the quorum signal in which the lactone acyl-homoserine is mediated (these compounds inhibit its synthesis) ^[15]. Cranberry proanthocyanidins limited the motility and reduced the biofilm formation of Pseudomonas aeruginosa ^[16]. These compounds can also reduce the number of other pathogenic bacteria, such as Helicobacter pylori, Escherichia coli and Clostridium perfringens ^[17]^[18]. However, due to the structural diversity of polyphenol classes, the mechanisms of their antimicrobial activities have not yet been fully resolved.

Gut microbiota integrity is key to the maintenance of gastrointestinal and overall body homeostasis. Growth as a biofilm promotes homeostasis at various mucosal surfaces, and disruptions of this mode of growth in such settings are detrimental to health. Microbial biofilms naturally colonise various surfaces of the body, including the gastrointestinal tract, the lungs, the vagina and the skin. Homeostatic maintenance of these complex microbial ecosystems is critical to health, and how their disruptions are a direct cause of pathophysiology. In the gut, the microbiome is made up of mixed communities of viruses, bacteria, fungi, and Eukarya that co-habit with mucus layers. Microbial colonization, diversity, and density vary along the length of the gastrointestinal tract, with the lowest numbers of microbes only forming scattered biofilm fragments in the stomach and upper gut, whereas a rich and dense microbial biofilm lines the large intestinal mucosa. Polyphenols contribute to maintaining the integrity of the gut microbiota biofilm. In general, polyphenolic compounds contribute to the growth and settlement of families of probiotic bacteria beneficial for human health (Lactobacillaceae, Bifidobacteriaceae) ^[19].

It is known that quercetin has a positive effect on the balance of bacteria in the Firmicutes/Bacteroidetes clusters ratio, restricting the growth of bacteria associated with obesity, such as Erysipelotrichaceae, Bacillus spp. and Eubacterium cylindroides. In addition, anthocyanins have been found to significantly stimulate the growth of Bifidobacterium spp., Lactobacillus and Enterococcus spp., suggesting that anthocyanins may positively select beneficial members of the intestinal microbial community ^[20]. For example, the polyphenolic compounds contained in tea (especially hydrolyzing tannins) are characterised by the ability to inhibit the development of numerous pathogens, including Staphylococcus aureus and Esherichia coli ^[21]. Green tea polyphenols also have a stimulating effect on the population growth of the Firmicutes and Bacteroidetes communities, as found in vitro and in animal studies. This brings about pro-health effects—reduction in Firmicutes/Bacteroidetes bacteria population and improvement in the ratio of Prevotella/Bacteroides ^[22]. Animal studies have shown that the administration of tea polyphenols restored the richness and diversity of the gut microbial population after previous administration of the antibiotic (cefixime), regulated gut microbial dysbiosis, and also increased the number of beneficial microbes such as Lactobacillus, Akkermansia, Blautia, Roseburia and Eubacterium ^[23]. According to research by Jaquet et al. ^[24], the consumption of a coffee preparation resulting from aqueous co-extraction of green and roasted coffee beans promotes metabolic activity and enhances the number of Bifidobacterium spp. population. Overall, coffee and tea consumption are considered to have a beneficial effect on the human body ^[24].

A crossover, controlled intervention study on the effects of moderate consumption of red wine has shown that this engenders improvement of blood pressure and lipid blood profiles and the composition of the gut microbiota. Compared to baseline, daily intake of red wine polyphenols for 4 weeks was found to significantly increase the number of groups of Enterococcus, Prevotella, Bacteroides, Bifidobacterium, Bacteroides uniformis, Eggerthella lenta and Blautia coccoides-Eubacterium rectale. The obtained results suggest possible probiotic benefits of wine ^[25]. Beyond the aforementioned, according to a randomised controlled trial by Vetrani et al. ^[26], a polyphenol-rich diet had an impact on the composition of the intestinal microflora wherein these modifications were associated with changes in glucose/lipid metabolism ^[26]. In related work, a proportional increase in Akkermansia spp. caused by dietary supplementation with cranberry extract, was found to be associated with an improvement in the characteristics of metabolic syndrome (induced by a diet high in fat and sucrose in an animal study) ^[27]. According to a clinical study, ingestion of bioactive compounds such as hesperidin and naringin (found in citrus fruits and orange juice) can improve intestinal microflora homeostasis (while enhancing blood biochemical parameters) by increasing the population of fecal Bifidobacterium spp. and Lactobacillus spp. ^[28]. The in vitro anti-Helicobacter pylori activity of citrus polyphenols such as hesperetin, naringenin, poncirin and diosmetin has also been demonstrated ^[29].

There are data from human studies that show changes in the diversity and composition of dominant bacterial communities in response to dietary supplementation with hormonal compounds in combination with functional foods. Isoflavones alone were noted to stimulate dominant microorganisms of the Clostridium coccoides–Eubacterium rectale cluster, Lactobacillus-Enterococcus group, Faecalibacterium prausnitzii subgroup and Bifidobacterium genus ^[30].

3. The Impact of Polyphenols and Their Metabolites on the Mechanisms and Factors Causing Atherosclerosis

Atherosclerosis is a chronic inflammatory disorder of medium and large arteries and an underlying cause of cardiovascular disease. As previously stated, one of the main risk factors causing atherosclerosis is the type and quality of food that the population eats. According to the dietary guidelines presented by the US Health and Human Services, only about 30% of the American population meets the dietary recommendations for fruit consumption and less than 20% for vegetables ^[31]. Moreover, almost 90% of Americans overuse salt, and 70% consume excessive amounts of saturated fats and sugars. Consumption of fruits and vegetables is very important due to the presence of polyphenols with a wide range of health-promoting properties, especially in inflammatory diseases like atherosclerosis ^[32].

The poor dietary choices made by many individuals have profound pathological effects and therefore contribute to the development of cardiovascular diseases. Current treatments for CVD, such as optimised statin therapy, are associated with considerable residual risk and several side effects in some patients.

The outcomes of research on the identification of alternative pharmaceutical agents for the treatment of atherosclerosis are mostly disappointing, with many promising leads failing at the clinical level. Reach in polyphenols food products with health benefits beyond their nutritional value represent promising agents in the prevention of CVD or as an additional therapy with current treatments. Polyphenols play a role in reducing ROS, inflammatory processes such as monocyte adhesion and vascular smooth muscle cell proliferation and migration, all of which are key events in atherosclerosis. This section will highlight the potential of several plant polyphenols and polyphenol reach products, including fruits, vegetables, teas and oils, as anti-CVD therapies based on clinical and pre-clinical mechanism-based studies.

3.1. Cacao and Green Tea Flavonols

Catechins are a class of flavanols mainly present in cocoa and green tea. This group of phytochemicals attracts interest because of their antioxidant properties and their ability to inhibit the secretion of pro-inflammatory compounds from activated endothelial cells ^[33]. In evaluating their effectiveness in reducing cardiovascular diseases, e.g., atherosclerosis, a trial involving 27 healthy people receiving a cacao flavanol-rich diet for 5 days revealed an increase in NO production and improved vasodilation ^[34]. In addition, as end-stage renal disease (ESRD) sufferers have an increased risk of CVD due to impairment of their vascular function, a trial involving 57 ESRD participants found improved vascular function (increased flow-mediated dilation (FMD), and reduced blood pressure ^[35]) after 30 days of cocoa flavanol-rich dietary supplementation.

A high risk of CVD occurs in individuals with obesity. However, an intake of 814 mg/day of catechins for 4 weeks increased vasodilation in 30 overweight patients. This came without changes in HDL, LDL-C and total cholesterol (TC) levels between those patients and the control group ^[36]. Other studies have shown that a cocoa-enriched calorie-restricted diet in 50 healthy people reduced their oxidised LDL (oxLDL) levels after one month when compared to calorie restriction only ^[37]. In addition, in human intervention trials in normo- and hypercholesterolemic subjects, the intake of 13 g/day cocoa powder for 4 weeks had beneficial effects on LDL and HDL cholesterol and oxidised LDL concentrations in plasma, especially in subjects with high LDL level ^[38].

In individuals at high risk of CVD, the intake of cocoa flavonols has shown to modulate levels of inflammatory mediators and serum levels of the leukocyte-endothelial cell adhesion molecules P-selectin and soluble intercellular adhesion molecule (sICAM-1). Other human, 7-month consuming studies conducted on hemodialysis patients have shown that the catechins administration (455 mg per day in the first group), as well as four cups of green tea (second group), decreased atherosclerotic pro-inflammatory factors such as monocyte chemoattractant protein 1 (MCP-1), TNF-α, sICAM-1 and CRP with respect to a control group. These anti-inflammatory effects may contribute to the overall benefits of cocoa and decaffeinated green tea extracts consumption against atherosclerosis ^[39]. Catechins also have antioxidant and anti-inflammatory effects on the endothelium. A reduction in the concentration of CRP protein and monocyte chemotactic protein was shown in people who consumed 5–6 cups of green tea per day for 14 days. Taking 580 mg of green tea catechins a day contributed to a decrease in the blood concentration of pro-inflammatory cytokines—TNF-α and IL-6—as well as the concentration of 8-hydroxy-2-deoxyguanosine, one of the markers of damage to the DNA structure by reactive oxygen species produced in the inflammatory reaction ^[40].

In the past decade, three large-scale studies have been conducted to investigate the potential cardioprotective effects of flavanols—PREDIMED ^[41], Cocoa, Cognition and Aging study (CoCoA) ^[42] and Flaviola Health study ^[43]. A test population of 7172 people participated in the largest of these, PREDIMED—a 4-year observational study. The patients were administered various doses of flavanol, from 90 mg to 263 mg per day. The findings confirmed a significant association between increased flavanol intake and reduced CVD risk, even after consideration of other risk factors (e.g., lipid-lowering therapies, other nutrients etc.) ^[41]. In the second study—CoCoA (Cocoa, Cognition and Aging), 90 elderly patients consumed either a low (48 mg per day), intermediate (520 mg per day) or high (993 mg per day) flavanol dose for 8 weeks ^[42]. The results of the study showed that individuals who had received either the high or intermediate daily dose of flavanols had significantly reduced insulin resistance, better blood pressure parameters, as well as a reduction in the amount of lipid peroxidation ^[42]. In the (Flaviola Health study, similar observations were found. During this research, 100 healthy women and men without a history of CVD received, for 1 month, 900 mg of cocoa flavanol per day ^[43]. Accordingly, flavanol supplementation significantly increased FMD and HDL levels, and simultaneously reduced blood pressure, arterial stiffness, as well as total and LDL-C levels ^[43].

Animal studies also confirm the beneficial effects of cacao flavonols. Kurosawa et al. ^[44] administered these compounds in the form of a cacao liquor polyphenols (CLP), in the spontaneous familial hypercholesterolemic model, to Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. After 1 month of dietary administration of CLP at 1% to the KHC rabbits, the authors observed that the plasma concentration of thiobarbituric acid reactive substances (a lipid-peroxidation index) was significantly decreased. Moreover, the antioxidative effect of CLP on LDL was observed from 2 to 4 months after the start of administration. In addition, the area of atherosclerotic lesions in the aorta in the CLP group was significantly smaller than that in the control group, and the tissue cholesterol and thiobarbituric acid reactive substances concentrations were lower in the CLP group than in the control group. Hence, the anti-atherosclerotic effect of CLP was demonstrated both rheologically and histopathologically. Finally, the authors confirmed that the antioxidative effect of CLP was superior to those of the well-known antioxidative substances (probucol, vitamin E and vitamin C). Therefore, CLP suppressed the generation of atherosclerosis, and its antioxidative effect appeared to have an important role in its anti-atherosclerotic activity. Overall, it can be said that cacao flavonols have an activity that causes the maintenance of healthy blood vessels, e.g., inhibition of vasodilative activity through controlling the levels of NO and eicosanoids ^[43], regulation of cytokine production, and an antioxidative effect on LDL. These effects might contribute to the anti-atherosclerotic effect ^[44].

3.2. Resveratrol

Resveratrol is a natural polyphenol derived from wine that has powerful antioxidant, anti-inflammatory and anti-aging effects. Numerous studies have shown that this compound has protective effects against cardiovascular diseases. Timmers et al. ^[45] found that resveratrol in obese people had a metabolic effect similar to that of caloric restriction after 30 days of supplementation. In particular, blood pressure, sleep and resting metabolic rates, triglycerides, glucose and markers of inflammation were all lowered. There was a reduction in systolic and diastolic blood pressure and an improvement in lipid metabolism indices in people with type 2 diabetes after three months of daily administration of 250 mg of resveratrol. In further studies ^[46], a similar set was used, with the addition of resveratrol in the diet of obese patients. This time, however, the resveratrol treatment was longer and combined with epigallocatechin-3-gallate (EGCG). The intention was to seek synergies between polyphenolic compounds. However, the effects were modest: supplementation improved only several biochemical indicators, e.g., the blood lipid profile and skeletal muscle capacity. However, changing these biochemical markers did not translate into clinically significant improvements in insulin sensitivity, which is very much expected in patients with obesity. Another study of dietary resveratrol in humans was conducted within one year ^[47]. The findings confirmed that resveratrol downregulated the expression of several pro-inflammatory cytokines. The levels of TNF-α, C-C motif chemokine ligand 3 (CCL3), interleukin- 1-beta (IL-1-β), interleukin-8 (IL-8), and chemokine (C-X-C motif) ligand 2 (CXCL2) were diminished. The treatment also modulated the expression of inflammation-related micro-RNAs. However, the effects were not very impressive—typically, less than two-fold changes were detected ^[48].

Recent studies have shown that resveratrol has the ability to inhibit mTORC1 activation [i]. mTOR (the mammalian target of rapamycin) belongs to the PIKK family (phosphatidylinositol kinase-related kinase), and is a serine/threonine-specific protein kinase that plays a key role in many physiological processes. mTOR inhibition has been suggested to have a helpful effect on atherosclerosis, heart failure and myocardial hypertrophy. In this context, mTOR inhibition is profitable in the treatment of many cardiovascular diseases, including atherosclerosis ^[49].

Substances focused on mTORC1 inhibition reduce the atherosclerotic process mainly by correcting the function of the endothelial layer and by inducing autophagy. This process diminishes the content of macrophages in plaques and causes the efflux of cholesterol from plaques. mTORC1 inhibition also reduces the formation of foam cells, which are fat-filled macrophages that engulf cholesterol esters and LDL ^[50]. In addition to the effective treatment of CVD, mTOR inhibitors have proven to be effective therapies for hypertensive heart diseases, such as hypertension, heart failure and cardiac hypertrophy.

Other studies have confirmed that resveratrol inhibits mTOR ^[51] in the vascular system, including smooth muscle cells and endothelial cells. Moreover, it contributes an inhibitory effect on oxLDL-induced smooth muscle cell proliferation and age-related endothelial dysfunction, as well as to endothelial damage caused by oxidative stress. The oxLDL-induced proliferation of smooth muscle cells is believed to be one of the major factors contributing to atherosclerosis. It develops fibroatherosclerotic plaques, mainly through the activation of PI3K/Akt signaling. In addition, resveratrol was found to significantly reduce palmitic acid (PA)-induced reactive oxygen species (ROS) generation and improve endothelial dysfunction by inducing autophagy via the AMP-activated protein kinase AMPK-mTOR pathway in human aortic endothelial cells. The effects exerted by mTOR inhibition can contribute to its therapeutic effects in ameliorating atherosclerosis in animal models of atherosclerosis ^[52]. Due to its outstanding ability to activate SIRT1 (NAD-dependent protein deacetylase sirtuin-1) and AMPK, the protective effects of resveratrol on the cardiovascular system may also involve both targets.

3.3. Curcumin

Studies have shown that curcumin prevents atherosclerosis in several animal models, doing so through multiple mechanisms, e.g., antioxidant, anti-aging and anti-inflammatory effects ^[49]. For example, a human study supplementing with 1g of curcuminoids daily for 8 weeks increased patient superoxide dismutase levels while lowering plasma malondialdehyde concentrations, indicating reduced oxidative stress. In addition, those receiving curcuminoids had decreased plasma CRP levels ^[53]. Moreover, a meta-analysis of clinical trials also found reduced CRP levels with curcumin, although no effect was seen on plasma TC, HDL, and LDL-C ^[54]. Curcumin also inhibits mTOR activation in the vascular system. This compound has been reported to protect endothelial cells from oxidative stress-induced damage and apoptosis by promoting autophagy by inhibiting mTOR ^[49]. Recent results confirm that the nicotinate-curcumin hybrid impedes the formation of macrophage-derived foam cells by enhancing autophagy. This effect may be due to its mTOR inhibitory effects ^[55]. Similarly, hydroxyacetylated curcumin has a beneficial effect in delaying the formation of foam cells.

3.4. Quercetin

Quercetin is a flavonoid common in fruits and vegetables. In randomised clinical trials, quercetin supplementation with 150 mg daily for 6 weeks reduced blood oxidised LDL in adults at high risk of cardiovascular disease. Interesting results were obtained in adult smokers who supplemented with 100 mg of quercetin daily for 10 weeks. In these people, quercetin significantly improved the plasma lipid profile by lowering total and LDL cholesterol levels and increasing the HDL fraction levels in the blood ^[56].

Quercetin’s mTOR inhibitory activity may partly contribute to its anti-atherosclerotic effect, which has been observed in animal models and cultured cells of atherosclerosis ^[49]. A recent study has shown that this flavonoid delays angiogenesis via inhibiting the vascular endothelial growth factor receptor 2 (VEGFR-2)-dependent protein kinase AKT/mTOR pathway ^[57]. In addition, research conducted by Liu et al. ^[58] confirmed that quercetin attenuates the rise of lipid levels in the liver by inhibiting mTOR (large lipid amounts in the liver and macrophages initiate atherosclerosis).

Quercetin also activates the AMPK pathway in vascular smooth muscle cells and contributes to the inhibition of induced contraction of the rat aorta. Taking into account this mechanism, it is likely that quercetin restricts mTOR generation via the AMPK-dependent pathway. This flavonoid also increases the activation of the SIRT1 in oxLDL-stimulated endothelial cells, which may also induce an mTOR-inhibiting effect ^[59].

A study by Shen et al. ^[60] showed that in ApoE-/- mice treated with quercetin at a dose of 1.5 mg per day, TC and TG levels were significantly decreased after 14 weeks. The atherosclerotic-protective action of quercetin put forward by Loke et al. ^[61] resulted from observations of improvements in NO availability by increased nitric oxide synthase (eNOS) activity and heme-oxygenase-1 (HO-1), as well as by a reduction in leukotriene B4 and LDL oxidation ^[61]. Leukotriene B4 is an agonist of inflammatory responses connecting with TNF-α and interleukins and the recruitment of neutrophils and monocytes ^[32]. Shen et al. ^[60] also reported an increase in eNOS and HO-1 action as the main mechanism connected with atherosclerosis reduction via quercetin. Of note, HO-1 mediates the rate-limiting phase of heme degradation. Moreover, HO-1 prevents atherosclerosis by affecting bilirubin, which reduces lipid peroxidation. Heme-oxygenase-1 also inhibits the development of the disease in mice in a lipid-independent way ^[32].

Quercetin-3-glucuronide has been reported to decrease the formation of macrophage foam cells by restricting the expression of CD36 macrophages and scavenger receptor A1 (SR-A1) in RAW 264.7 cells. This flavonoid is known to accumulate in atherosclerotic lesions in the human aorta (in particular, in the macrophage-derived foam cells). In addition, metabolites of quercetin might exhibit anti-atherosclerotic effects in injured/inflamed arteries with activated macrophages ^[62].

3.5. Protocatechuic Acid

Protocatechuic acid (PCA) is a bioactive compound present in medicinal herbs, vegetables, fruits and spices. It is the main metabolite of anthocyanins produced by the intestinal microflora ^[63]. PCAs have been shown to have promising anti-atherosclerotic effects at physiologically achievable concentrations. The protocatechuic acid derivative can accelerate cholesterol efflux in MPM loaded with AcLDL or THP-1 macrophages. Furthermore, PCA can inhibit intercellular adhesion molecule 1-dependent (ICAM1-dependent) monocyte adhesion and vascular cell adhesion molecule 1 (VCAM-1), activated human umbilical vein endothelial cells (HUVEC), as well as CCL2-mediated monocyte transmigration, thereby reducing the development of atherosclerosis in ApoE-/- mice. PCA has also been demonstrated to have an inhibitory effect on VSMC proliferation (induced by oleic acid) by activating AMPK and arresting the cell cycle in the G0/G1 phase in the A7r5 smooth muscle cell line ^[63]. Therefore, it can also be explored as a potential new molecule for the prevention and treatment of atherosclerosis.

3.6. Trimethoxycinnamic Acid

α-Asarone is a biologically active compound from the class of phenylpropanoids. It shows hypocholesterolemic action. 2,4,5-trimethoxycinnamic acid, the non-toxic metabolite of asarone, has been found to represent its main pharmacological properties, e.g., lowering total blood cholesterol, high- and low-density lipoprotein cholesterol in hypercholesterolaemic rats ^[62]. Therefore, α-asarone is a subject of further research as a hypocholesterolemic and cardiovascular protective agent.

3.7. Gallic Acid

Gallic acid (GA) is an anthocyanin metabolite that has been found to improve atherosclerosis through antihypertensive and vasopressor action. This phenolic acid can increase nitric oxide levels by increasing endothelial eNOS phosphorylation in RAW264.7 macrophages. In addition, its administration inhibited angiotensin-I converting enzyme (ACE), causing blood pressure reduction in spontaneously hypertensive rats that were comparable to captopril ^[64]. These results indicate that gallic acid exhibits multiple therapeutic properties and has the potential to prevent atherosclerosis.

3.8. Equol

Equol is an isoflavone. This compound is formed as a result of the processing of daidzein by the intestinal flora. It has been suggested that equol may slow down the development of atherosclerosis by attenuating endoplasmic reticulum stress and, in part, by activating the Nrf2 signaling pathway ^[62]. A clinical study in Japanese men showed that equol might have high atherosclerotic-protective properties ^[65]. Evidence from other studies and short-term randomised controlled trials show equol has an antiatherosclerotic effect, improves arterial stiffness and can prevent ischemic heart disease ^[66]. Therefore, the use of equol has developed promise in the field of cardiovascular disease prevention.

3.9. Mediterranean Diet

The Mediterranean diet is the gold standard for polyphenol dietary intake; therefore, it has been subjected to much research ^[33]. The PREDIMED study was the largest trial investigating the potential cardiovascular protective effects of this diet ^[41]. Initial analysis of the study, conducted on over 7000 Spanish people, found that after approximately 5 years, those with the highest polyphenol intake had a 37% lower relative risk of all-cause mortality when compared to those with the lowest polyphenol intake ^[67]. Moreover, further research on 200 high-risk patients found that those on the Mediterranean diet had reduced blood pressure after 1 year compared to those on a control diet ^[68]. In this work, a positive association between total polyphenol intake and plasma NO level was noted, suggesting a possible mechanism by which polyphenols induced vasodilation and reduced the risk of CVD ^[69]. Improvement in blood pressure and reduction in plasma TG were also found in a subset of 573 elderly participants of the project after a 5-year follow-up ^[69]. The PREDIMED study indicated an association between the Mediterranean diet and the cardiovascular protective effects of polyphenols through vascular function improvement and blood pressure reduction. Of note, all of the participants of the PREDIMED study were recruited from a single country (Spain), and therefore, differences in lifestyle between countries may alter the outcome of the study.

A study on the components of the Mediterranean diet conducted by Jungeström et al. ^[70] included 1139 high-risk participants and revealed reduced plasma levels of several inflammatory biomarkers related to atherosclerosis with polyphenol intake ^[70]. Another study on 78 obese patients who were randomised to receive one of the following diets for 8 weeks; low omega-3 polyunsaturated fatty acids (PUFAs), low polyphenol, high omega-3 PUFAs, low polyphenol, low omega-3 PUFAs, high polyphenol, or high omega-3 PUFAs high polyphenol, but found no changes in their blood pressure or total and LDL cholesterol levels. Those on the high polyphenol diets did have reduced TG levels, and their HDL plasma concentrations were also lowered ^[71]. Upon further analysis of this research, an inverse correlation between LDL-C levels and the intake of gallic acid was suggested.

The Effect of Olive Oils on Oxidative Damage in European Populations (EUROLIVE) randomised clinical trial found a high positive correlation between the intake of polyphenols in the form of olive oil and serum HDL levels in 200 healthy men after three weeks of a rich-olive oil diet. Furthermore, oxidative stress markers decreased with increased polyphenol concentrations, while TG levels were reduced in all patients ^[72]. This decrease in oxidative stress markers was confirmed in a later study on 117 individuals with metabolic syndrome ^[33].

The consumption of extra virgin olive oil is associated with a reduction in inflammatory biomarkers and molecules implicated in atherosclerosis as well as CVD incidence and mortality as well as other complications such as heart failure and atrial fibrillation. These anti-inflammatory and cardioprotective effects of extra virgin olive oil are mostly attributable to its high content of antioxidants, e.g., monounsaturated fatty acids, tocopherols and polyphenols. The cardioprotective properties of the Mediterranean Diet were demonstrated for the first time in the Seven Country Study ^[32]. Rosenblat et al. found that extra virgin olive oil with green tea polyphenols had significant effects on plaque reduction throughout the entire aorta of about 20%, compared to extra virgin olive oil alone (11%) ^[73]. Eilertsen discovered that extra virgin olive oil with and without green tea polyphenols can reduce oxLDL and lipid peroxidation ^[74]. Overall, supplementing oils into the diet, especially olive oil, reduces atherosclerotic plaque; the primary mechanism of interest for this result is the improvement of antioxidant capacity. However, there is a limited amount of available randomised controlled trials.

3.10. Other Polyphenol-Rich Foods

Grapes and pomegranates have been studied for their potential beneficial effects in ApoE-/- mouse models of atherosclerosis and CVD. The most abundant polyphenols in grapes are anthocyanins, flavanals, flavanols and resveratrol ^[32]. Pomegranates are also rich in anthocyanins, flavanols and ellagitannins, but additionally contain punicalagin, which is specific for pomegranates ^[32]. The pomegranate juice, flowers and byproducts caused significant changes in plaque after their supplementation. Aviram et al. ^[75] noted a 44% reduction of plaque through juice consumption, while Kaplan et al. reported a 17% reduction ^[76]. Aviram et al. additionally confirmed a 39% reduction with byproduct powder, a 38% reduction with byproduct liquid, and an amazing 70% reduction of atherosclerotic plaque with pomegranate flower intake ^[75]. Pomegranate flower preparations were additionally able to reduce serum glucose levels ^[32]. Rosenblat et al. ^[77] reported that pomegranate byproduct reduced 57% of plaque. In studies involving red wine grape pomace, a significant reduction in lesion size was seen ^[32]. Herein, grape powder polyphenols reduced the lesion size by 41%. A reduction in plaque in the thoracic aorta was also observed with both white (30%) and red (62%) dealcoholised wine. Additionally, the red wine reduced plaque by 16% in the aortic root. Overall, it can be concluded that pomegranate flowers and grape extract can reduce TC and TG.

In many studies conducted on ApoE-/- mouse models, the attributed cause of plaque reduction was due to decreases in macrophage oxidative stress, oxLDL uptake, and reduced lipid peroxide concentration ^[75]. Here, the peroxide concentration is low can be attributed to the high free radical scavenging ability of the grape and pomegranate polyphenols. In addition, polyphenols interfere with oxLDL binding to macrophage scavenger receptors and, in this way, reduce cholesterol uptake ^[75]. Rosenblat et al. ^[77] also found that pomegranate polyphenols significantly increased glutathione levels. This action contributes to a reduction in the potential of cells to oxidise LDL cholesterol.

Peluzio et al. ^[78] discovered that grape extract (enriched with vitamin E) increases the expression of LDL receptors in the liver. This activity leads to increased cholesterol uptake by the liver, thereby reducing circulating cholesterol levels. The authors also noted increased fecal excretion of cholesterol and triacylglycerols, hence supporting their conviction that higher cholesterol removal is one of the main benefits of treatment using pomegranate phenolic compounds ^[78]. In related studies, dealcoholised wine was found to reduce atherosclerotic plaque by inhibiting VCAM-1 and ICAM-1 adhesion molecule pathways, including NF-κB, MAPK, interferon type 1 (IFN-1), and IL-1β. Thus, grapes and pomegranate show promising results in ameliorating atherosclerosis by reducing oxidative stress by decreasing oxLDL uptake by macrophages and lipid peroxidation ^[32].

Shema-Didi et al. ^[79] found a reduction in blood pressure in 101 hemodialysis patients with a high risk for CVD who were treated with pomegranate juice three times a week for 1 year. During this research, there a correlation was also noted between the length of juice intake and time and improvements in HDL and TG levels. Furthermore, the subset of participants who had pathologically high TG and HDL levels at the start of the research showed significant improvements in these factors ^[79].

Many other fruits, for example, apples, lychee and plums, also have positive effects on atherosclerosis prevention. Their polyphenols probably act through the reduction of oxidative stress by reduction in adhesion molecules, as well as through inhibition of inflammatory pathways and enhancement of antioxidant capacity. Apples contain quercetin, flavonols, procyanidins, and phenolic acids. Lychee is a source of many polyphenols, e.g., catechins, anthocyanins, and procyanidins. Plums have a slightly varied polyphenol profile, and contain neochlorogenic and chlorogenic acids, which improve antioxidant capacity and reduce LDL ^[32]. The apple studies conducted on ApoE-/- mice showed that these fruits could reduce atherosclerosis through a large variety of metabolic actions, including increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity ^[80], peroxisome proliferator-activated receptor α (PPARα) and Nrf2, reduced plasma uric acid concentration and decreased circulating cholesterol in serum ^[81]. Additionally, Xu et al. ^[80] showed reduced VCAM-1 level by apple polyphenols, similar to dealcoholised wines. The lychee study proposed that increased NO production attenuated atherosclerosis, while the plum study suggested that its intake increased serum amyloid P-component (SAP) levels that reduce inflammation ^[32].

Research on vegetable polyphenols using ApoE-/- mice was conducted by Lin et al. These authors studied chicory ^[82], while Joo et al. ^[83] studied anthocyanins from red Chinese cabbage. A lipid profile analysis showed that red Chinese cabbage had beneficial effects, specifically by reducing the TC and LDL/VLDL levels ^[83], while the chicory study showed reduced cholesterol in the aorta ^[82]. Chicory was reported to decrease plaque by lowering TC and activating ATP-binding cassette transporter 1 (ABCA-1) and ATP-binding cassette sub-family G member 1, which are pivotal players in HDL-dependent cholesterol efflux ^[82]. Anthocyanins from red Chinese cabbage were also noted to reduce VCAM-1 and improve antioxidant capacity and lipid metabolism ^[83].

It seems that these effects result from the action of the primary polyphenols in cruciferous vegetables (kaempferol, isorhamnetin, quercetin and caffeic acid derivatives). These polyphenols can promote eNOS activity and HO-1 expression to reduce oxidative stress and plaque accumulation.

4. The Anti-Atherosclerosis Therapeutic Potential of Polyphenol by Gut Microbiota Modulation

Polyphenols are thought to prevent the development of chronic diet-related diseases; however, most of them can not be absorbed directly by the small intestine. Therefore, their bioavailability and impact on the host mostly depend on their conversion [w]. Gut microbiota (GM) plays a crucial role in converting dietary polyphenols into absorbable bioactive substances. Indeed, some intestinal metabolites derived from natural polyphenol products have more biological activities than the chemical compounds from which they originate.

Several studies have shown that the antiatherosclerotic effect of flavonoids is the result of the activity of metabolites formed under the influence of gut microbiota. For example, protocatechuic acid is a metabolite of anthocyanins that causes an anti-atherogenic effect through miRNA-10b-ABCA1/ABCG1-cholesterol efflux signaling cascade ^[84]. Food intake is a two-way street, however, and studies have indicated that the intake of anthocyanins remarkably remodeled the “pro-atherogenic” GM community to the desired state through increasing relative taxa Lactobacillus, Akkermansia, Bifidobacterium, and Roseburia. In contrast, the content of Prevotellaceae members has decreased. Alongside the GM modulation, protocatechuic acid regulated the NF-κB arterial inflammatory pathway and hepatic lipid metabolism. Consistently, aberrant morphological changes in the aorta, intestine, and liver, as well as deregulated endothelial function biomarkers (VCAM-1, TNFα), were also found to be mitigated due to flavonoid intake ^[85]. Thus, the administration of anthocyanins significantly reduced atherosclerosis in rats. Still, how these results can be translated into the ‘real life’ with the ever-changing gut microbiome has not been fully understood. Chen et al. ^[86] noted that polymethoxyflavones (PMFs) from citrus peels exhibit comprehensive biochemical functions, including antioxidant, anti-inflammatory, etc. Moreover, PMF intake modulated the GM composition to a healthier phenotype, basically increasing Lactobacillus, Bacteroides, Akkermansia, and Bifidobacterium presence. In this activity, butyrate-producing microbes and TMA-producing microbes were specifically increased and decreased, respectively, under PMFs action. PMFs also inhibited the biosynthetic pathway of trimethylamine N-oxide (TMAO) generation by lessening the transformation of L-carnitine to TMAO.

In related work, nobiletin, a compound belonging to polymethoxyflavones was found to suppress NF-κB and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathways to avoid TMAO-induced vascular inflammation ^[87]. Moreover, other PMFs blocked L-carnitine-induced vascular inflammation via decreasing VCAM-1, TNFα, and E-selectin. In addition, macrophage foam cell formation was suppressed by PMFs ^[86]. Another study involving humans looked at quercetin, and the use of this flavonoid was found to inhibit platelet aggregation and thrombus formation. Similarly, in animal models, its use drastically improved lipid metabolism and inflammation.

Quercetin has also been found to influence the composition of the gut microbiome. This led to the association of the genera Anaerovibrio and Phascolarctobacterium as specific microflora characteristics of its therapy ^[88]. In researching quercetin, 32 metabolic signatures were identified as participating in quercetin actions, among them, the primary bile acid biosynthesis pathway. Thus, quercetin might be acting directly or indirectly to encourage GM metabolite bile acid. As previously highlighted, bile acids act to maintain host metabolic activities such as adipose tissue browning, insulin sensitivity, intestinal barrier integrity, etc. ^[89]. In other work, tryptophan and sucrose metabolic pathways were identified during in vivo studies as quercitin’s area of action.

Ferulic acid is a polyphenol with antioxidant and anti-inflammatory activities. This phytonutrient can modulate GM composition by decreasing the ratio of Firmicutes/Bacteroidetes. In research involving ferulic acid, it was found to decrease tryptophan plasma concentration that was elevated in high-fat diet-fed ApoE-/- mice ^[90]. Other research has indicated that pomegranate juice intake can abolish acrolein-induced GM dysbiosis by rebalancing Firmicutes/Bacteroidetes ratio and reducing the concentration of the order Clostridiales and the genera Coprococcus and Dehalobacteria. This polyphenol-rich drink was discovered to inhibit acrolein-induced lipid accumulation, peroxidation, and oxidative stress by suppressing essential lipid biosynthetic pathways of 3-hydroxy-3-methylglutaryl-COA reductase, diacylglycerol acyltransferase 1, and Sterol-regulatory element-binding protein maturation in in vivo and in vitro atherosclerotic models ^[91]. Moreover, Chitin-glucan plus polyphenol-rich pomegranate peel extract was seen to modulate Alistipes and Lactobacillu’s relative abundance and also improve hepatic lipids, decrease inflammation, and ameliorate endothelial dysfunction through eNOS activation in high fat diet-fed ApoE-/- mice ^[92]. In addition, resveratrol was found to be able to promote the beneficial microbes, e.g., Bacteroides, Bifidobacterium, Lactobacillus, and Akkermansia. In research, this action elevated bile salt hydrolase activity through cytochrome P450 27A1 and hepatic bile acid neosynthesis. In this way, bile acid deconjugation and fecal excretion are promoted to contribute to cholesterol homeostasis ^[93].

In related work, tea polyphenols reduced plaque/lumen area and enhanced the relative abundance of Bifidobacterium population in the gut of high-fat diet-fed ApoE-/- mice. Moreover, Bifidobacterium increased count inversely correlated with plaque/lumen area. This implies that tea polyphenols specifically target Bifidobacterium to decrease atherosclerotic plaque ^[94]. Lastly, tea polyphenols were found to promote short-chain fatty acids production in high-fat diet-fed mice ^[95], while 2, 3, 5, 4′-Tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG) on the GM–atherosclerotic disease axis, modulated gut microbiome composition (Proteobacteria, Bacteroidetes, Firmicutes, Tenericutes, and the species Helicobacter pylori and Akkermasia muciniphila). Furthermore, TSG remarkably inhibited atherosclerotic plaque formation, improved lipid dysregulation, and suppressed inflammation to combat atherosclerotic in ApoE-/- mice ^[95]. However, further studies are required to establish whether gut microbiota modulation is the main mechanism by which TSG attenuates atherosclerosis.

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