**13. Melatonin supplementation**

the phenolic compounds. The phenolic content in virgin olive oil could reduce the lipid oxi‐

Moreover, olive oil minor components have also been involved in the anti-oxidant activity of olive oil. Some components of the unsaponifiable fraction, such as squalene, β-sitosterol or triterpenes, have been shown to display anti-oxidant and chemopreventive activities and capacity to improve endothelial function decreasing the expression of cell adhesion mole‐

Olive oil phenolic compounds are able to bind the LDL lipoprotein and to protect other phe‐ nolic compounds bound to LDL from oxidation. The role of phenolic compounds from olive oil on DNA oxidative damage remains controversial and perhaps more sensitive methods would be required to detect differences among the types of olive oil consumed. Further studies are required to establish the potential benefits of olive oil and those of its minor com‐

One of the most well known and important characteristic of the Mediterranean diet is the presence of virgin olive oil as the principal source of energy from fat. In contrast to other edible oils with a similar fatty composition, like sunflower, soybean and rapeseed canola oils, virgin olive oil is a natural juice, while the seed oils must be refined before consump‐ tion, thus changing its original composition during this process. Virgin olive oils are those obtained from the olives solely by mechanical or other physical means under conditions that do not lead alteration in the oil. The olives have not undergone any treatment other than

Virgin olive oil is a source of healthy unsaturated fatty acids and hundreds of micronu‐

Results of the randomized cross-over clinical trials performed in humans on the anti-oxidant effects of olive oil phenolic compounds are controversial. The protective effects on lipid oxi‐ dation in these trials have been better displayed in oxidative stress conditions, i.e. males, submitted to a very strict anti-oxidant diet, hyperlipidaemic or peripheral vascular disease patients. Carefully controlled studies in appropriate populations, or with a large sample size, are urgently required to definitively establish the *in vivo* anti-oxidant properties of the

Epidemiological studies have revealed both a higher incidence of CVDs and cerebrovascular mortality in soft water areas and a negative correlation between water hardness and cardio‐ vascular mortality [56,57]. Actually, there is not enough evidence to determine whether hard water contains protective substances not present in soft water or if there are detrimental

Water contains oligominerals, such as calcium, magnesium, cobalt, lithium, vanadium, sili‐ con, copper, iron, zinc and manganese, that are some important factors in reducing the risk

trients, especially anti-oxidants, as phenol compounds, vitamin E and carotenes.

dation and inhibit platelet-induced aggregation [53].

washing, decantation, centrifugation or filtration [53].

active components of virgin olive oil [55].

**12. Oligoelements in water**

substances in soft water*.*

cules and increasing vasorelaxation [54].

16 Current Trends in Atherogenesis

ponents on DNA oxidative damage.

Melatonin, an endogenously produced indoleamine, is a remarkably functionally pleiotropic molecule [66] which functions as a highly effective anti-oxidant and free radical scavenger [67,68]. Endogenously produced and exogenously administered melatonin has beneficial ac‐ tions on the cardiovascular system [69,70,71].

Exogenously administered melatonin is quickly distributed throughout the organism; it may cross all morphophysiological barriers and it enters cardiac and vascular cells easily. High‐ est intracellular concentration of melatonin seem to be in the mitochondria; this is especially important as the mitochondria are a major site of free radicals and oxidative stress genera‐ tion. Moreover, melatonin administration in a broad range of concentration, both by the oral and intravenous routes, has proven to be safe for human studies [72,73].

Melatonin itself appears to have an atheroprotective activity during LDL oxidation and also melatonin's precursors and breakdown products inhibit LDL oxidation, comparable to vita‐ min E. Because of its lipophilic and nonionized nature, melatonin should enter the lipid phase of the LDL particles and prevent lipid peroxidation [9] and may also augments en‐ dogenous cholesterol clearance.

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‐ sveratrol, when added in combination [74].

Actually, it is difficult to conclude that a clinical benefit of anti-oxidants in CVD is estab‐ lished. Thus, it is necessary to clarify why anti-oxidants showed their beneficial effects *in vitro*, whereas less satisfactory results were observed in some, although not all, clinical

Atherosclerosis and Current Anti-Oxidant Strategies for Atheroprotection

http://dx.doi.org/10.5772/53035

19

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

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

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‐

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 anti-

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

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.

conditions [40].

25% [76].

**15. HDL-based diet**

atheroprotective effects [77].

comes closely associated with HDL.

inflammatory activities.

benefits [76].

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

It is important to underline that the recent discovery of melatonin in grapes [74] opens new pespectives in the field of natural anti-oxidative atheroprotective strategies.
