**6. Polyphenol**

**4. Physical exercise**

6 Current Trends in Atherogenesis

breast, prostate and endometrium [28].

physical inactivity accelerates it [3,29].

adipose tissue [3].

**5. Diet**

been forgotten by modern societies.

condition for human and most animal species [3].

Physical activity is currently recognized as a potent tool for the prevention of chronic degen‐ erative diseases, including CVDs and common tumors, such as those affecting the colon,

There is a body of clinical and experimental evidence showing that voluntary and imposed physical exercise prevents the progression of CVDs and reduces cardiovascular morbidity and mortality. Therefore a physically active state is an appropriate and natural biological

It has been demonstrated that exercise slows the progression of atherosclerosis, promoting its stabilization and preventing plaque rupture in a variety of hypercholesterolaemic animal models, such as apolipoproteinE-deficient mice and LDL receptor-deficient mice, whereas

Exercise increases blood anti-oxidant capacity through elevating hydrophilic anti-oxi‐ dants (uric acid, bilirubin and vitamin C) and decreases lipophilic anti-oxidants (carote‐ noids and vitamin E) [28]. It is noteworthy that exercise prevents plaque vulnerability and atherosclerosis progression without necessarily correcting classic risk factors, such as hypercholesterolaemia, endothelial dysfunction and high blood pressure, suggesting that exercise can directly affect plaque composition and phenotype, thus preventing the ap‐ pearance of fatal lesions. Besides the effect of diet and drugs, the protective role of regu‐ lar exercise against atherosclerosis is well established and its beneficial atheroprotective effects are not limited to one particular cell, but to a variety of cells and tissues involved in the pathogenesis of atherosclerosis and metabolic disorders, such as macrophages and

Regular exercise and a correct diet would be natural atheroprotective approaches which has

Several epidemiological studies suggest that a correct diet is significantly associated with reduced risks of CVDs. Phytochemicals including polyphenols like flavonoids, resveratrol and ellagitannins have been shown to be associated with lower risks of CVDs [30,31]. In fact, they are potent anti-oxidants and anti-inflammatory agents, thereby counteracting oxidative damage and inflammation. Actually, dietary anti-oxidants have attracted con‐ siderable attention as preventive and therapeutic agents. There is adequate evidence from observational *in vitro*, *ex vivo* and *in vivo* studies that consumption of certain foods results to a reduction in oxidative stress [27]. Evidence linking dietary anti-oxidants to atherosclerosis in humans is still circumstantial and although in some studies the associa‐ tion of anti-oxidant intake and low risk for atherosclerosis is perceptible, in others this Polyphenols are the most abundant anti-oxidants in human diet and are common constitu‐ ents of foods of plant origin and are widespread constituents of fruits, vegetables, cereals, olive, legumes, chocolate and beverages, such as tea, coffee and wine [32,33].

They are defined according to the nature of their backbone structures: phenolic acids, flavo‐ noids and the less common stilbenes and lignans. Among these, flavonoids are the most abundant polyphenols in the diet [34]. Despite their wide distribution, the health effects of dietary polyphenols have been attentively studied only in recent years [32] and several stud‐ ies, although not all, have found an inverse association between polyphenol consumption and CVDs motality [35].

Polyphenols exert anti-atherosclerotic effects in the early stages of atherosclerosis devel‐ opment, they decrease LDL oxidation, improve endothelial function, increase vasorelaxa‐ tion, modulate inflammation and lipid metabolism, improve anti-oxidant status and protect against atherothrombotic events including myocardial ischemia and platelet ag‐ gregation [35].

Many polyphenols have direct anti-oxidant properties, acting as reducing agents, and may react with reactive chemical species forming products with much lower reactivity. Polyphenols may also affect indirectly the redox status by increasing the capacity of en‐ dogenous anti-oxidants or by inhibiting enzymatic systems involved in ROS formation [36]. The free-radical scavenging activity of many polyphenols has been reported to be much stronger than that of vitamin C, vitamin E or glutathione, the major anti-oxidants present in the body.

In spite of their potent protective effects in the development of atherosclerosis, little is known about aortic distribution of polyphenols [34].

Resveratrol so has been demonstrated to exert a variety of health benefits including antiatherogenic, anti-inflammatory and anti-tumor effects. These positive effects are attributed

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**Figure 6.** Main atheroprotective mechanisms exert by resveratrol. LDL: low density lipoprotein; HDL: high density lipo‐

Resveratrol reduced not only vascular lipid levels, including LDL and triglycerides, but also the myocardial complications by influencing infarct size, apoptosis and angiogenesis. In ad‐ dition, resveratrol feeding prevented steatohepatitis induced by atherogenic diets through modulation of expression of genes involved in lipogenesis and lipolysis, reduced total and

Several investigations with human and various animal model have demonstrated an ab‐ sence of toxic effects after supplementation with resveratrol across a wide range of dos‐

Promising findings by several groups have demonstrated the potential cardioprotection of

mainly to its anti-oxidant and anti-coagulative properties.

protein; ROS: reactive oxygen species.

ages [38].

LDL levels, while increasing HDL levels in plasma.

resveratrol by reducing atherosclerotic plaque onset and formation.

**Figure 5.** Main atheroprotective mechanisms exert by polyphenols. VSMC: vascular smooth muscle cell; LDL: low den‐ sity lipoprotein; ROS: reactive oxygen species.

#### **6.1. Resveratrol**

Resveratrol naturally occurs as a polyphenol found in grapes and grape products, including wine, as well as other sources, like nuts [37]. In grapes, resveratrol is present in the skin as both free resveratrol and piceid.

Initially characterized as a phytoalexin, a toxic compound produced by higher plants in re‐ sponse to infection or other stresses, such as nutrient deprivation, resveratrol attracted little interest until 1992 when it was postulated to explain some of the cardioprotective effects of red wine [36].

Treatment with resveratrol has been found to reduce oxidative stress and increase the activi‐ ties of several anti-oxidant enzymes including superoxide dismutase, catalase, glutathione, glutathione reductase, glutathione peroxidase and glutathione-5-transferase [38]. Resvera‐ trol also prevents the oxidation of polyunsaturated fatty acids found in LDL and inhibits the ox-LDL uptake in the vascular wall in a concentration-dependent manner, as well as pre‐ vents damage caused to lipids through peroxidation [38]. These effects were found to be stronger respect the well known anti-oxidant vitamin E. Moreover, resveratrol has been pro‐ posed to influence and maintain a balance between production of vasodilatators and vaso‐ costrictors respectively [38,39], thereby preventing platelet aggregation and oxidative stress, which leads to reduction in CVD risk [40].

Resveratrol so has been demonstrated to exert a variety of health benefits including antiatherogenic, anti-inflammatory and anti-tumor effects. These positive effects are attributed mainly to its anti-oxidant and anti-coagulative properties.

**Figure 5.** Main atheroprotective mechanisms exert by polyphenols. VSMC: vascular smooth muscle cell; LDL: low den‐

Resveratrol naturally occurs as a polyphenol found in grapes and grape products, including wine, as well as other sources, like nuts [37]. In grapes, resveratrol is present in the skin as

Initially characterized as a phytoalexin, a toxic compound produced by higher plants in re‐ sponse to infection or other stresses, such as nutrient deprivation, resveratrol attracted little interest until 1992 when it was postulated to explain some of the cardioprotective effects of

Treatment with resveratrol has been found to reduce oxidative stress and increase the activi‐ ties of several anti-oxidant enzymes including superoxide dismutase, catalase, glutathione, glutathione reductase, glutathione peroxidase and glutathione-5-transferase [38]. Resvera‐ trol also prevents the oxidation of polyunsaturated fatty acids found in LDL and inhibits the ox-LDL uptake in the vascular wall in a concentration-dependent manner, as well as pre‐ vents damage caused to lipids through peroxidation [38]. These effects were found to be stronger respect the well known anti-oxidant vitamin E. Moreover, resveratrol has been pro‐ posed to influence and maintain a balance between production of vasodilatators and vaso‐ costrictors respectively [38,39], thereby preventing platelet aggregation and oxidative stress,

sity lipoprotein; ROS: reactive oxygen species.

both free resveratrol and piceid.

which leads to reduction in CVD risk [40].

**6.1. Resveratrol**

8 Current Trends in Atherogenesis

red wine [36].

**Figure 6.** Main atheroprotective mechanisms exert by resveratrol. LDL: low density lipoprotein; HDL: high density lipo‐ protein; ROS: reactive oxygen species.

Resveratrol reduced not only vascular lipid levels, including LDL and triglycerides, but also the myocardial complications by influencing infarct size, apoptosis and angiogenesis. In ad‐ dition, resveratrol feeding prevented steatohepatitis induced by atherogenic diets through modulation of expression of genes involved in lipogenesis and lipolysis, reduced total and LDL levels, while increasing HDL levels in plasma.

Several investigations with human and various animal model have demonstrated an ab‐ sence of toxic effects after supplementation with resveratrol across a wide range of dos‐ ages [38].

Promising findings by several groups have demonstrated the potential cardioprotection of resveratrol by reducing atherosclerotic plaque onset and formation.

#### **6.2. Flavinoid**

Flavonoids, many of which are polyphenolic compounds, are believed to be beneficial for the prevention and treatment of atherosclerosis and CVDs mainly by decreasing oxidative stress and increasing vasorelaxation [32,40,41]. More than 8.000 different flavonoids have been described and since they are prerogative of the kingdom of plants, they are part of human diet with a daily total intake amounting to 1 g, which is higher than all other classes of phytochemicals and known dietary anti-oxidants. In fact, the daily intake of vita‐ min C, vitamin E and β-carotene from food is estimated minor of 100 mg. A number of dif‐ ferent factors, such as harvesting, environmental factors and storage, may affect the polyphenol content of plants. Additional variability in flavonoid content could be expected in finished food products because its availability is largely dependent on the cultivar type, geographical origin, agricultural practices, post-harvest handling and processing of the fla‐ vonoid containing ingredients [32].

Since the evidence of therapeutic effects of dietary flavinoids continues to accumulate, flavi‐ noids could be considered as anti-oxidant nutrients available in everyday life as a protective

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**Figure 7.** Main atheroprotective mechanisms exert by flavinoids. LDL: low density lipoprotein.

anti-diabetic and anti-mutagenic properties [42].

Tea, a beverage consumed worldwide, is a source of both pleasure and healthful benefits. Originally recommended in traditional Chinese medicine, green tea (*Camellia sinensis*) has gained considerable attention due to its anti-oxidant, anti-inflammatory, anti-hypertensive,

Green tea constitutes 20%-22% of tea production and is principally consumed in China, Ja‐ pan, Korea and Morocco. Green tea, or non-fermented tea, contains the highest amount of flavonoids, in comparison to its partially fermented (oolong tea) and fermented (black tea) counterparts and, due to its high content of polyphenolic flavonoids, has shown unique car‐ diovascular health benefits. In green tea, catechins comprise 80% to 90% of total flavonoids, with epigallocatechin gallate, being the most abundant catechin (48–55%), followed by epi‐

tool for prevention of atherosclerosis.

**7. Green tea**

Flavonoids are widely distributed in the plant and are categorized as flavonol, flavanol, fla‐ vanone, flavone, anthocyanidin and isoflavone. Quercetin is one of the most widely distrib‐ uted flavonoids, which are abundant in red wine, tea and onions. Quercetin intake is therefore suggested to be beneficial for human health and its anti-oxidant activity should yield a variety of biological effects.

The major flavanols in the diet are catechins. They are abundant in green tea (about 150mg/ 100ml) and lesser extent in black tea (13.9 mg/100 ml) where parent catechins are oxidized into complex polyphenols during fermentation. Red wine (270 mg/L) and chocolate (black chocolate: 53.5 mg/100 g; milk chocolate: 15.9 mg/100 g) are also sources of catechins [34].

Polyphenols and/or flavonoids exhibit a variety of beneficial biological effects, including an‐ ti-oxidant, anti-hypertensive, anti-viral, anti-inflammatory and anti-tumor activities; more‐ over some flavonoids have also been reported to modulate insulin resistance, endothelial function and apoptosis [32,41].

Many studies have shown that flavonoids demonstrate protective effects against the initia‐ tion and progression of atherosclerosis. The bioactivity of flavonoids and related polyphe‐ nols appears to be mediated through a variety of mechanisms, though particular attention has been focused on their direct and indirect anti-oxidant actions. In particular, it has been shown that the consumption of flavinoids limits the development of atheromatous lesions, inhibiting the oxidation of LDL, which is considered a key mechanism in the endothelial le‐ sions occurring in atherosclerosis.

Mechanisms of anti-oxidant effects include also: suppression of ROS formation either by in‐ hibition of enzymes or chelating trace elements involved in free radical production, scaveng ROS and upregulation or protection of anti-oxidant defences [32]. The phenolic hydroxyl groups of flavonoids, which act as electron donors, are responsible for free radical scaveng‐ ing activity [27,40].

Since the evidence of therapeutic effects of dietary flavinoids continues to accumulate, flavi‐ noids could be considered as anti-oxidant nutrients available in everyday life as a protective tool for prevention of atherosclerosis.

**Figure 7.** Main atheroprotective mechanisms exert by flavinoids. LDL: low density lipoprotein.
