**15. HDL-based diet**

Melatonin also counteracts the cell oxidative burden indirectly by stimulating the produc‐ tion of cell ROS detoxifying enzymes, specially glutathione peroxidase, glutathione reduc‐ tase and superoxide desmutase. Melatonin besides being a more effective anti-oxidant than resveratrol can reverse the pro-oxidant DNA damage induced in low concentration of re‐

Moreover, 6-hydroxymelatonin, the main *in vivo* metabolite of melatonin, and its precursor, *N*-acetyl-5-hydroxytryptamine, were potent in reducing *in vitro* LDL peroxidation. The abili‐ ty of the parent molecule melatonin as well as its metabolites to function in radical detoxifi‐ cation greatly increases its ability to limit oxidative abuse at many levels within cells [9]. Therefore it can be suggested that although melatonin *per se* would have physiologically or pharmacologically effects to inhibit *in vivo* LDL oxidation, its action sinergically with its main catabolite would be more active [75]. Melatonin may exert protective and benefical ef‐

It is important to underline that the recent discovery of melatonin in grapes [74] opens new

Vitamin C is a water-soluble vitamin and is believed to regenerate vitamin E from its oxi‐ dized state back to its activated state. The principal sources of vitamin C are citrus fruits, tomatoes and potatoes. Natural vitamin E is a mixture of tocopherols and tocotrienols syn‐ thesized only by plants and the natural sources are vegetal oils. In fact, olive oil contains vi‐

Vitamin E acts as a chain-breaking anti-oxidant for LDL lipids [27]. *In vitro* enrichment of LDL in vitamin E drastically increases their resistance to oxidative stress and it has also been reported to inhibit the cytotoxicity of ox-LDL toward cultured endothelial cells. Vitamin E has been reported to retard atherosclerosis progression in certain arteries of primates fed an atherosclerosis diet. In humans, both women and men, exhibited reduced vascular disease parameters [75], beneficial effects in the reduction of risk of onset and progression of athero‐ sclerosis, due to its inhibition of LDL oxidation and association with molecular modulation of the interaction of immune and endothelial cells. A long term supplementation with vita‐ min E in hypercholesterolemic patients and/or chronic smokers increase levels of autoanti‐ bodies against ox-LDL. There is also a quite convincing evidence from *in vitro* studies that

It is important to underline that there are no definite recommendations on the dose and du‐ ration of supplementation with vitamins in human. Although, high dietary intake of fruit and vegetables is associated with a reduction in the incidence of atherosclerosis, stroke and cardiovascular mortality in general [27]. Moreover, epidemiologic studies have reported that high dietary intake of foods rich in vitamin E, vitamin C and *β*-carotene have been in‐

fects against CVDs reducing the risk of atherosclerosis and hypertension [9].

pespectives in the field of natural anti-oxidative atheroprotective strategies.

tamin E and many of its beneficial effects are attributed to this constituent.

vitamin C strongly inhibits LDL oxidation [27].

versely associated with the incidence of CVDs [35].

sveratrol, when added in combination [74].

18 Current Trends in Atherogenesis

**14. Vitamins**

It is well known that LDL are crucial to the development of atherosclerotic lesions, whereas HDL are inhibitors of the process, so the primary focus of pharmaceutical lipid modulation is reduced LDL; this strategy has reduced cardiovascular morbidity and mortality by up to 25% [76].

Recent studies also suggest that HDL inhibits oxidation, prevents the expression of inflam‐ matory mediators and the expansion of pro-atherogenic myeloid cells and reduces the ex‐ pression of pro-coagulant enzymes, each of which may contribute in smaller ways to atheroprotective effects [77].

The synthesis and release of HDL into the peripheral vasculature is the first step in reverse cholesterol transport that is proposed to be a major mechanism by which HDL mediates its atheroprotective effects [78]. However, HDL possesses multiple anti-atherosclerotic proper‐ ties in addition to reverse cholesterol transport. HDL acts as a transporter of a variety of fatsoluble vitamins, including vitamin E, and also as a natural anti-oxidant protecting for LDL in a multifactorial manner. Moreover, HDL are associated with enzymes with anti-oxidant capacity, like paraoxonase that is a major contributor to the anti-oxidant activity of HDL [78]. Paraoxonase is synthesized in the liver and released into the circulation, where it be‐ comes closely associated with HDL.

HDL has also been demonstrated to improve endothelial function, maintain the integrity of vascular endothelium and may induce the production of vasodilators, such as prostacyclin, by the endothelium. HDL has also been demonstrated to exhibit anti-thrombotic and antiinflammatory activities.

The combination of a low saturated fat diet and increased exercise raises HDL levels by 5– 14% and lowers triglyceride, LDL and total cholesterol levels by 4–18%, 7–15% and 7-18%, respectively. Thus, simple lifestyle measures including a correct diet and increased activity represent a cost-effective and low-risk intervention that is associated with a range of health benefits [76].

There is considerable interest at present in the possible therapeutic effects of elevating HDL levels to capitalize on their vasculoprotective effects. Although, clinical evidence to date has provided inconsistent results and suggests that raising HDL levels may not be the straight‐ forward answer to atheroprotection [79,80]; HDL-based therapies, also combined with other atheroprotective strategies, may be a valide future atheroprotective approach.
