Mediterranean Diet and Its Protective Mechanisms against Cardiovascular Disease: An Insight into Platelet Activating Factor (PAF) and Diet Interplay

Review Article

Ann Nutr Disord & Ther. 2015;2(1): 1016.

Mediterranean Diet and Its Protective Mechanisms against Cardiovascular Disease: An Insight into Platelet Activating Factor (PAF) and Diet Interplay

Detopoulou P1, Demopoulos CA2, Karantonis HC3 and Antonopoulou S4*

1Department of Nutrition, General Hospital Korgialenio Benakio, Greece

2Department of Chemistry, National and Kapodistrian University of Athens, Greece

3Department of Food Science and Nutrition, University of the Aegean, Greece

4Department of Nutrition-Dietetics, Harokopio University, Greece

*Corresponding author: Antonopoulou S, Department of Nutrition -Dietetics, Harokopio University, 70 El.Venizelou Street, Athens, 17671, Greece

Received: September 01, 2015; Accepted: January 05, 2015; Published: January 08, 2015

Abstract

Several prospective studies and clinical trials have shown a protective effect of the Mediterranean Diet (MD) against cardiovascular disease, even after assessing for hard clinical end-points. However, the exact mechanisms through which MD exerts its actions have not been fully elucidated. The aim of the present review is to clarify the potential bio-protective mechanisms of MD against cardiovascular disease, i.e. the role of macro- and micro- nutrients, antioxidants, polyphenols, the effects of MD on postprandial metabolism and endothelial function and nutrient- gene interactions. A special emphasis is given on Platelet Activating Factor (PAF), which plays a key role in atherosclerosis. Its inhibitors are abundant in Mediterranean foods and have an anti-inflammatory and anti-thrombotic action.

Keywords: Mediterranean diet; Cardiovascular disease; Platelet activating factor; Postprandial state

Abbreviations

MD: Mediterranean Diet; PAF: Platelet Activating Factor; TNF-a: Tumor Necrosis Factor-alpha; Ox-LDL: Oxidized LDL; NFkB: Nuclear Factor kappaB; Ox-PAPC: 1-palmitoyl-2-arachidonoylsn- glycero-3-phosphorylcholine; LTA: Lipoteichoic Acid, LPS: Lipopolysaccharides; TLR: Toll Like Receptor; Lyso-PAF-AT: acetyl- CoA:lyso-PAF acetyltransferase; DHA: Docosahexaenoic Acid; PAFCPT: DTT-insensitive CDP-choline:1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase; PAF-AH: PAF-acetylhydrolase; Lp- PLA2: Lipoprotein-associated phospholipase-A2 ; PAMPS: Pathogen- Associated Molecular Patterns

Introduction

The Mediterranean basin is a cross roads between East and West mixing elements of the two cultures. Apart from its geographical position, it is distinguished by its unique climate and the warmth of residents. The available food, historical events, wars, customs, religious traditions, along with novel foods formed a particular diet of the inhabitants of the Mediterranean, the Mediterranean Diet (MD). The first systematic attempt to investigate the diet of Mediterranean countries was done after the Second World War by the Rockefeller Foundation [1]. The findings of the study were published in the institution's monograph in 1953 [2]. This document described the Cretan diet as a diet containing olives, olive oil, cereals, bread, legumes, wild greens, herbs and fruits along with small quantities of goat meat, milk and fish [2]. The Cretans themselves, however, did not seem happy with their diet as only one in six said that it considers the standard diet as satisfactory [2] while members of one family felt "hungry most of the time of day" [2] probably due to the hard manual work.

Then, the Seven Countries study (Netherlands, USA, Japan, Finland, Italy, Former Yugoslavia, Greece), launched in 1960 and coordinated by Ancel Keys, Professor of the University of Minnesota (USA), demonstrated the protective effects of the traditional Cretan diet on mortality and cardiovascular disease [3,4]. The scientific community began to believe that the Cretans rather do or eat something right [5]. Ancel Keys also supported the motto "eat well and stay well" [6].

Then, the Seven Countries study (Netherlands, USA, Japan, Finland, Italy, Former Yugoslavia, Greece), launched in 1960 and coordinated by Ancel Keys, Professor of the University of Minnesota (USA), demonstrated the protective effects of the traditional Cretan diet on mortality and cardiovascular disease [3,4]. The scientific community began to believe that the Cretans rather do or eat something right [5]. Ancel Keys also supported the motto "eat well and stay well" [6].

In general, the term MD describes the traditional Cretan diet which has the following characteristics [7]:

However, it should be noted that there are marked differences in the diets of Mediterranean countries. Wine consumption is a central component of the diet of French and constitutes a possible interpretation of the "French paradox" [8] and the Spanish diet is rich in fish. Another notable difference is observed between Greece and Italy. In Greece whole grains are consumed, especially in Crete, while in Italy the most important source of carbohydrates is pasta [7]. In some cases, differences in food habits are observed within the same country. For example, in southern Italy, the consumption of cereals, fruits and vegetables is higher than in the north, where higher consumption of dairy products is observed [7]. Despite the differences in the various countries of the Mediterranean, the basic aspects of nutrition with the temperament of the people seem to make a "right recipe" confirming the words Umberto Echo that unity can found through diversity. Evaluating the benefits of MD in health as well as the importance of social development of the Mediterranean countries at the 5th Session of the Intergovernmental Committee for Intangible Cultural Heritage of UNESCO in November 2010, the UNESCO anointed the Mediterranean Diet as a cultural monument of Greece, Italy, Spain and Morocco (decision 5.COM 6.41) [9].

MD and Cardiovascular disease

Several prospective studies and clinical trials have shown a protective effect of MD against cardiovascular events after assessing for hard clinical end-points. According to results of a meta-analysis an increased attachment to the MD by 2 units led to a reduction in cardiovascular mortality and the incidence of cardiovascular disease by 10% (RR = 0.90; 95% CI: 0.87- 0.93) [10]. Most recent prospective studies also point to a cardio-protective effect of this dietary pattern in Mediterranean and non-Mediterranean populations as well [11- 19]. Moreover, the results of clinical trials for primary and secondary prevention of cardiovascular disease enable the confirmation of potential causal relationships. Recently, the PREDIMED Study (The Prevention con Diet Mediterranean) in 7447 high risk individuals from Spain revealed a protective effect of Mediterranean diet supplemented with extra virgin olive oil or nuts compared to a control diet (primary prevention) [20]. More particularly the Mediterranean diet groups had a ~30% reduction in the primary end point (composite end point of stroke, myocardial infarction, and cardiovascular deaths) [20]. A key study revealing the importance of adopting a Mediterraneantype diet in secondary prevention was the Lyon Heart Study [21- 23], which involved 605 patients followed for 3.5 years. In this study patients with myocardial infarction were medically treated and were advised to follow the MD or the diet recommended by the American Heart Association. The group following the MD experienced had 70% fewer heart disease deaths. The studies of Singh et al [24,25] and the THIS study (The Heart Institute of Spokane Diet Intervention and Evaluation Trial) followed [26] with positive effects.

Atherosclerosis and cardio protective mechanisms of the MD

Despite the strong evidence supporting the beneficial role of the MD in cardiovascular disease the exact mechanisms through which it exerts its actions have not been fully elucidated and some biochemical aspects of the diet-disease interplay have been neglected. In the present review several protective properties of the MD will be presented pertaining to its macronutrient, micronutrient, polyphenol and antioxidant content, its beneficial effects on postprandiallipemia and glycemia and endothelial function, the presence of Platelet- Activating Factor (PAF) inhibitors with antithrombotic and antiinflammatory activities and several gene-diet interactions.

Before analyzing the bioactive components of the MD one-by-one it is appropriate to briefly recall some key points of atherosclerosis and to enlighten the pathophysiological role of PAF and its analogs in this process. In the mid-1970s, the "lipid hypothesis" existed for atherosclerosis development was replaced by the "response to injury hypothesis" developed by Russel Ross, which supported that atherosclerotic lesions develop as a result of local injury to the arterial endothelium followed by platelet adhesion and accumulation [27]. Later, it was found that endothelium activation was sufficient for the activation of immune inflammatory responses related to atherogenic process. Moreover, cholesterol administration in rabbits was found to trigger monocyte adhesion onto the endothelium, followed by their migration through the morphologically intact endothelium in the sub-endothelial space [28]. This observation led Michael Gimbrone to propose that during atherosclerosis a modification of the normal endothelium takes place, resulting to a dysfunctional endothelium that loses its barrier function [29]. Today it is accepted that atherosclerosis is a chronic inflammatory disease, in the onset of which adhesion of monocytes/ lymphocytes to activated endothelium takes place [30].

A number of lipid bioactive mediators have been identified as primary initiators of atherogenesis. Among these, PAF (1-O-alkyl- 2-acetyl-sn-glycero-3-phosphocholine) is the strongest lipid inflammatory mediator [31], while many structure analogs known as oxidized phospholipids, such as the oxidized form of 1-palmitoyl-2- arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC), mimics its activity [32]. It is evidenced that PAF mediates the production of tumor necrosis factor-alpha (TNF-a) through monocyte activation with the same mechanism as oxidized LDLs (Ox-LDLs) [33] (Figure 1). The detection of PAF molecules on Ox-LDL particles [34] may suggest that Ox-LDL's lead to TNF-a production in part through PAF induced monocyte activation [35]. One of the most important atherogenetic actions of PAF is that it mediates the adhesion of monocytes to endothelium in synergy with P-select in [36]. Moreover, the adhesion of monocytes onto endothelium allows PAF to signal the transport of nuclear factor kappaB (NF-kB) in the nucleus of those monocytes, leading to the transcription of various genes and the biosynthesis of their related protein products such as MCP-1, IL-8, TNF-a, associated with chronic inflammation [37]. Modified lipoproteins are able to cause oxidative stress resulting in the production of both free radicals and PAF or its analogs (Figure 1) [34,38]. Once produced, PAF and its analogs bind to PAF-receptors or Toll like receptors (TLRs) (see below) signaling in this way the inflammatory mechanisms in an uncontrolled and prolonged way that play a central role in triggering atherosclerosis [38-40]. Moreover, PAF orchestrates and reinforces these initial reactions since it causes the production of new free radicals and the biosynthesis and production of new PAF or its analogs [40,41]. In vivo studies in our laboratory on high-cholesterol fed rabbits show increased blood levels of PAF, as reflected by PAF attached on lipoprotein particles or blood albumin (free PAF) and PAF on blood cells (bound PAF) [42,43]. Similar studies on the activity of PAF metabolic enzymes in blood show an increase of circulating PAF in rabbits with diet-induced hyperlipidemia and point to leucocytes as the cells that provide the main newly biosynthesized PAF in blood in this case [44].

Figure 1: Simplified schematic representation for the role of PAF in the crosstalk of dyslipidemia, inflammation and atherogenesis. Chronic inflammation that may cause atherosclerosis may be the result of prolonged states of dyslipidemia, oxidative stress and acute inflammation mediated by various proinflammatory factors. Atherosclerosis prevention may be accomplished through down regulation of oxidative stress by antioxidants, regulation of physiological blood lipid profile, inhibition of inflammatory signal transduction systems at the level either of proinflammatory mediator biosynthesis or of their receptor signaling. These protective effects may be may exerted either by medication or by appropriate diet using appropriate combination of foods.
TC: Total Cholesterol; LDL-C: LDL-Cholesterol; HDL-C: HDL-Cholesterol; PAF-R: PAF-Receptor; TAG: Triacylglycerols; LPS: Lipopolysaccharides; LTA: Lipoteichoic Acid; HSP: Heat Shock Proteins

    

    
    

    

    Figure 1:  Simplified schematic representation for the role of PAF in the crosstalk of dyslipidemia, inflammation and atherogenesis. Chronic inflammation that may cause atherosclerosis may be the result of prolonged states of dyslipidemia, oxidative stress and acute inflammation mediated by various proinflammatory factors. Atherosclerosis prevention may be accomplished through down regulation of oxidative stress by antioxidants, regulation of physiological blood lipid profile, inhibition of inflammatory signal transduction systems at the level either of proinflammatory mediator biosynthesis or of their receptor signaling. These protective effects may be may exerted either by medication or by appropriate diet using appropriate combination of foods. 
TC: Total Cholesterol; LDL-C: LDL-Cholesterol; HDL-C: HDL-Cholesterol; PAF-R: PAF-Receptor; TAG: Triacylglycerols; LPS: Lipopolysaccharides; LTA: Lipoteichoic Acid; HSP: Heat Shock Proteins

Interestingly, PAF receptor appears to have a particular role in controlling inflammation since it may mediate signaling in the pathogenesis of inflammatory diseases through other molecules outside of PAF and its analogs. Such molecules constitute Lipoteichoic Acid (LTA), and various lipopolysaccharides (LPS) as components of contaminant microorganisms. These molecules when recognized by PAF receptor cause the initiation of the inflammatory process, which if uncontrolled may result to chronic inflammation and initiation of atherosclerosis (Figure 1).

Apart from PAF-receptors, PAF and its analogs also bind to Toll like receptors (TLRs), who's signaling is associated with signaling of new PAF production and atherogenesis promotion [45]. TLRs are type I transmembrane glycoproteins with extracellular transmembrane and intracellular part and belong to the pattern recognition receptors of the innate immune system. They are expressed in cells of the immune system and other tissues, such as those of the cardiovascular system. The activation of TLRs activates the NF-kB pathway leading to production of cytokines that in turn evoke the expression and production of adhesion molecules, chemokines, interferons and NO (I and II) that all may have beneficial effect in acute inflammation but harmful effects in the uncontrolled mode of chronic inflammation [46] (Figure 1). In particular, Toll like receptors TLR-2and TLR-4 play an important role in atherosclerosis as activators of the innate immune system and a major part of the mechanism underlying the state of chronic inflammation. Administration of exogenous binding molecules or pathogens themselves, accelerate the atherosclerotic process, and exogenous binding molecules such as PAF analogues lead to increased atherosclerosis. Binding of the above molecules onto TLR-2 and TLR-4 causes their activation followed by recruitment of several proteins known as the adaptor proteins. After that, MAP kinases (JNK, ERK, p38a) and pro-inflammatory transcription factors (NF-kB, AP1, Elk1) are activated and followed by the expression of various inflammatory molecules such as IL-6, IL-1b and TNF-a [46]. It is also noted that the PAF analog Ox-PAPC inhibits the binding of LPS to their binding proteins (LPS-binding protein), a step that is required in order for LPS to be exposed for recognition from TLR-4. This suggests a dual role for the activity of PAF and its analogs since it seems that in acute inflammation conditions through bacterial agents act as anti-inflammatory agents inhibiting the pathway of NFkB [47] (Figure 1), while in chronic inflammation conditions their activity appears to be responsible for development of the pathological condition, this time through NF-kB pathway enhancement [32].

Macronutrients and micronutrients

The MD is high in monounsaturated fatty acids, which have beneficial effects on HDL- and LDL- cholesterol and improve endothelial function, increase insulin sensitivity, reduce platelet aggregation and increase fibrinolysis [48]. The main source of monounsaturated fatty acids in the MD is olive oil [7]. Despite research data indicating that oleic acid may exert a protective effect against cardiovascular diseases [49], it is worth mentioning that oleic acid is a key component not only of the MD but also of a Western-style diet, as meat contains a considerable amount of it [50]. This observation supports the view that possibly other olive oil components contribute to its protective effects (see below). Furthermore, the MD is low in cholesterol, saturated and Tran's fatty acids and high in omega-3 fatty acids due to the presence of fish, vegetables, fruit and snails [51].

Indeed, omega-3 fatty acids have beneficial effects in reducing triacylglycerols, heart rate, blood pressure, platelet aggregation while they improve inflammation and atherosclerosis [52]. Moreover, they may prevent sudden death of cardiovascular cause and have an antiarrhythmic effect [53]. The actions of fish oils are extended to the reduction of heart rate [54,55], and the improvement of ventricular function in humans [54,56], possibly by increasing the elastic properties of myocardial cells [57] and increasing the release of NO [58]. Omega-3 fatty acids exert their antithrombotic effect possibly by reducing thromboxane synthesis [59], the expression of platelet derived growth factor -A and -B [60] and PAF production [61]. More specifically linoleic (18:2) inhibits the binding of monocytes to endothelium by inhibiting PAF biosynthesis [62] and docosahexaenoic acid (DHA, 22: 6) inhibits the in vivo actions of PAF [63,64]. Preliminary results of our group show that omega-3 inhibit the in vitro PAF induced platelet aggregation. It is likely that the protective effect of omega-3 in atherogenesis, depend on the relative ratio of omega-3/ omega-6, since - as demonstrated by Jian-Bo Wan et al.- omega-3 inhibit atherogenesis in modified mice at a ratio of omega-6/omega-3 = 1 [65]. It is noted that the ratio of omega-6 / omega-3 fatty acids was 1 to 2/1 in the traditional Cretan diet while in Europe and the United States, the ratio is about 10 to 20/1 [51]. Moreover, the intake of omega-3 fatty acids should be viewed within the context of the MD, since their supplementary intake in secondary prevention have not shown any beneficial effects according to recent studies: Diet and Omega-3 Intervention Trial [66], ORIGIN [67] and The Risk and Prevention Study [68].

It is worth mentioning that a small number of studies on the interaction of food ingredients with TLRs have shown that saturated fatty acids stimulate the inflammatory process by activating NF-kB through TLR-4. On the other hand monounsaturated fatty acids and fish origin omega-3 fatty acids inhibit the binding of saturated fatty acids onto TLRs, inhibiting this way the activation of TLR and finally the activation of NF-kB [69]. Food that may seem with naked eye unspoiled are believed to contain LPS that, as a heat-stable molecule under cooking conditions, results to cooked food containing active molecules that may stimulate TLRs. In a recent study these active molecules were detected in meat and processed food products, typical in western diet, while they were in minute quantities or undetectable in fruits and vegetables, typical in Mediterranean type diets [70]. Although PAF inhibitors of food origin have not been studied for their effect on TLR's activation, the fact that Ox-LDL (containing PAF), PAF and PAF analogs bind to TLR-4, strongly indicates that food origin PAF inhibitors, such as those found in Mediterranean type diet foodstuffs, may inhibit TLR's activation. In a recent study, statins, medicines that exert pleiotropic effects and are well known for their hypolipidemic effect, have been shown to inhibit TLR's stimulation, exerting an anti-inflammatory activity [71]. Interestingly we have previously shown that statins are also PAF inhibitors [72].

The MD also includes foods rich in fiber, such as whole grains, legumes, fruits and vegetables. The high dietary fiber content of the MD goes hand in hand with its low glycemic load and glycemic index [73]. Furthermore, foods rich in fiber can also act as prebiotics inducing the production of short chain fatty acids by colonic bacteria, which in turn inhibit cholesterol synthesis, glucose digestion and thus influence systemic lipid and carbohydrate metabolism [74].

The traditional Mediterranean diet meets the requirements for micronutrients as it was demonstrated though menu analysis [75]. Several foods i.e. wine, fruit, vegetables, herbs and olive oil, which are key features of the MD, contain a plethora of micronutrients such as vitamin C, E, folate and carotenoids and phytochemicals [51]. It is also worth mentioning the low sodium and high potassium content of the MD which is a key element for proper endothelial function and blood pressure regulation [76].

Phytochemicals and antioxidants

Polyphenols exert pleiotropic cardio protective actions as it has been shown by in vivo and in vitro studies: they reduce the oxidation of LDL, increase the release of NO, reduce lipid concentration, have an anti-inflammatory activity, protect against atherothrombotic events, and reduce platelet aggregation [77] and PAF production [78-80]. MD foods such as wine, fruit, vegetables, herbs and olive oil are rich in polyphenols and other phytochemicals [51]. Olive oil, in particular, contains terpenes, phytosterols, phenolics, beta carotene [48] and polar lipids, which act as PAF antagonists [43,81]. Its phenolics have antioxidant and anti-inflammatory properties, inhibit lipoproteins oxidation and improve endothelial function [48]. Moreover, frying with olive oil form sonly few oxidized fatty acids, unlike other vegetable oils, as a result of monounsaturated fat and antioxidants [82]. Interestingly, the long term adoption of the MD results in beneficial effects in oxidative balance, as it was recently shown in the PREDIMED study [83,84] and previously shown in the ATTICA study [85] and other works [86].

Recently, our research team showed that circulating PAF was inversely correlated to the dietary antioxidant capacity and antioxidant-rich foods intake (herbal drinks and coffee) in healthy volunteers after adjustment for multiple covariates [87]. Moreover, the biosynthetic enzyme of PAF, Lyso-PAF-AT, was also negatively associated with the dietary antioxidant capacity and a healthy eating pattern (rich in fruits, nuts and herbal drinks, and a pattern rich in olive oil and whole-wheat products) [87] (Figure 2).

Figure 2: PAF metabolism and effect of dietary components on its key metabolic enzymes.

    

    
    

    

    Figure 2:  PAF metabolism and effect of dietary components on its key metabolic enzymes.

Postprandial metabolism

Deregulation of postprandial metabolism coupled with high glucose and lipids spikes is considered as a risk factor for diabetes, atherosclerosis and cardiovascular disease [88,89] since it triggers inflammation, oxidative stress, endothelial dysfunction and hypercoagulability [73]. Mediterranean diet may favorably affect postprandial metabolism as recently reviewed by our group [90]. From the few studies examining the long-term effects of MD on the postprandial state it was shown that postprandial glucose and insulin levels [91,92], postprandial TAG [93,94] and B-48 [93] were reduced.

The beneficial effects of the MD are explained if its macronutrient content is considered. Briefly, the high fat content of the MD delays gastric emptying, resulting in a lower glycemic response. Moreover, the type of fat included in the MD seems to play a beneficial role in postprandial lipemia. Monounsaturated fatty acids may attenuate postprandial lipemia [95], increase chylomicron clearance [94], increase HDL-cholesterol and GLP-1 [89,96] and decrease FVIIc [97]. Moreover, omega-3 fatty acids reduce postprandial triacylglycerols up to 16-40% via a reduction in VLDL secretion and an efficient chylomicrons clearance [73,98,99]. Dietary fiber is related to the decreased glycemic index and load of the Mediterranean diet [73]. Indeed, diets containing dietary fiber, vegetables, fruits, whole grains, olive oil, fish, legumes, fruit and vegetable drinks, such as the MD can improve the postprandial glycemic and lipid response [100,101]. For example, the consumption of nuts together with bread or mashed potatoes reduces postprandial glucose levels by 30-50% and also reduces postprandial oxidative stress [73]. Additionally, the mixture of olive oil and vinegar added abundantly in Mediterranean salads reduces postprandial glucose levels [100]. This is probably due to slowed gastric emptying due to acetic acid (vinegar) [100]. The cinnamon is used in many Mediterranean sweets and when added to a high glycemic index meal also reduces postprandial glucose levels by partly slowing gastric emptying [73]. The intake of protein of high biological value without parallel intake of saturated fat (e.g. egg white, fish, and whey proteins) improves postprandial hyperglycemia and inflammation [73].

Wine with food has been shown to reduce LDL oxidation and improve endothelial function compared to an isocaloric aqueous alcoholic solution, probably because of contained antioxidants [102]. Dark chocolate, tea and pomegranate also have beneficial effects on postprandial oxidative stress [73]. Finally, data from our research group as part of a European study showed that the incorporation of wild greens of Crete in a meal with bread and olive oil resulted in lower postprandial glucose levels in healthy subjects [103] and reduced platelet aggregation in individuals with the metabolic syndrome [104].

Endothelial function

Endothelial dysfunction resulting from reduced NO production and/or increased oxidative stress is implicated in the development of hypertension and other diseases of the cardiovascular system [105]. The MD and its components may have a protective effect in this process by increasing NO bioavailability and decreasing cytokine production and oxidative stress [106]. Indeed, MD improves endothelial function in patients with abdominal obesity [107] and hypercholesterolemia [108] and acts favorably on the regenerative activity of the endothelium [109], although not all studies have shown an effect [110]. As far as postprandial endothelial function is concerned, MD as well as several of its components has been reported to exert beneficial effects [106]. Moreover, the combination of foods within the MD may also play a role in endothelium function. For example, the combination of olive oil and red wine has a beneficial effect on postprandial endothelial function [111]. It is noteworthy that NO perturbations are connected to PAF synthesis modulation, since NO inhibits PAF action as well as PAF synthesis [112], which may have further beneficial results regarding cardiovascular disease.

PAF inhibitors and PAF levels

An additional mechanism by which the MD exerts its beneficial effects is through PAF inhibitors, which reduce platelet aggregation and possibly inflammation [113-115]. A particular class of PAF inhibitors includes compounds found in food extracts. Our research group has examined many foods of the MD for the presence of PAF inhibitors. In particular, extracts of olive oil [116], wine [115,117], fish [118,119], honey [120], egg yolk [121], milk and yoghurt [122] have a PAF inhibitory activity. PAF inhibitors have been also found in extracts of Mediterranean meals [113,123]. In all these cases PAF inhibitors were isolated, tested and identified. Search for PAF inhibitors in various stages of olive oil production and olive pomace processing showed that the bioactive ingredients against PAF are mainly the byproducts of the procedure [114] and are removed during refining and treatment. Studies by other researchers have shown the existence of PAF inhibitors in garlic [124] and onion [125], which are also used in many recipes of the MD. It is also noted that vitamin E, which is one of the main micronutrients of the MD displays inhibitory activity against PAF-induced platelet aggregation [126] and has been found to inhibit atherogenesis in vitro [127]. Vitamin D, which is a PAF inhibitor, has been also found to inhibit the formation of atherosclerotic plaques in animals [128].

It is noted that PAF inhibitors have been found in many traditional plants of Mediterranean and non-Mediterranean origin, which are used as drugs and have also an atheroprotective effects. One of the best known PAF antagonists is Gingolide B or BN 52021, which derives from the Ginkgo biloba tree and it, inhibits the formation of atherosclerotic plaques [129]. Another traditional herbal medicine is flaxseed containing lignans, which are widespread in nature. A specific lignan, secoisolariciresinol diglucoside, is a PAF inhibitor and it also inhibits the development of atherosclerotic plaques in experimental animals [130]. Moreover, the black pepper extract inhibits atherogenesis in rabbits [131] and contains PAF inhibitors [132]. The results of our group and other investigators have shown that several phenolic compounds inhibit the activity of PAF in vitro, in vivo and its biosynthesis as well [87,133,134]. A PAF inhibitory activity has been reported foroleuropein, tyrosol and resveratrol, which indeed is modified and enhanced by acetylation [135,136].

It can be thus assumed that the MD contains foods with PAF inhibitors, which protect against atherosclerosis. This viewpoint has been also demonstrated from in vivo animal experiments. Specifically, rabbits fed an atherorogenic diet supplemented with PAF inhibitors (for example olive oil or its by-products) or statins do not develop atherosclerotic plaques [43,137]. This supports the theory of atherogenesis with PAF involvement, which recognizes that even with the presence of high levels of cholesterol inhibitors of PAF can inhibit atherogenesis [138]. In addition, we have shown that some fish oil polar lipids (other than omega-3 fatty acids) have anti-atherogenic actions through their ability to inhibit the biological actions of PAF in vitro [139] and in vivo by inhibiting the formation of atherosclerotic plaques [140].

From human studies it has been shown that the adoption of the MD from patients with type 2diabetes for one month reduces PAF induced platelet aggregation [113,123]. A recent study even showed that wild greens of Crete, when consumed by patients with the metabolic syndrome have a postprandial PAF inhibitory effect [104].

Apart from the action of the MD in inhibiting the actions of PAF, it should be noted that several of its components may act on its metabolic enzymes, affecting the final levels of circulating PAF (Figure 2) [141]. Briefly, PAF is synthesized via the remodeling and the de novo pathway, key enzymes of which are acetyl-CoA: lyso-PAF acetyltransferase (lyso-PAF-AT) and DTT-insensitive CDP-choline: 1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase (PAF-CPT), correspondingly. PAF-acetylhydrolase (PAF-AH) and its extracellular isoform lipoprotein-associated phospholipase-A2 (Lp-PLA2) catabolize and deactivate PAF. In this context, Proanthocyanidins [78], luteolin [80], quercetin [80,142], hesperidin [142] naringin and oleic acid [142] reduce the activity of lyso-PAF-AT. Moreover, lyso- PAF-AT, has been negatively associated with the dietary antioxidant capacity and a healthy diet (a pattern rich in fruits, nuts and herbal drinks, and a pattern rich in olive oil and whole-wheat products) [87]. From in vitro data of our research group in mesangial cells it has been shown that olive oil polar lipids, fish polar lipids as well as resveratrol are inhibitors of another PAF biosynthetic enzyme, PAFCPT [143]. Recently, PAF-CPT was negatively associated with the glycemic index of the diet, coffee intake and positively associated with dietary cholesterol in healthy volunteers [87]. Furthermore, fish polar lipids were found to decrease PAF biosynthesis [44] and increase PAF catabolism [44,137], while an atherogenic diet was found to increase PAF-CPT in rabbits [44].

As far as the PAF catabolic enzyme is concerned PAF-AH or its extracellular isoform Lp-PLA2, the bibliography is less clear regarding its relation to diet. Olive oil and/ or its polar lipids appear to increase the enzyme's activity in hypercholesterolemia rabbits [42,137] or to have no effect [43]. Flavonoids have also been shown to increase or not to affect the enzyme activity in vitro [142,144]. Two studies in humans have focused on the relationship of omega-3 fatty acids on Lp-PLA2 and have shown reverse [145] or no association [146]. Additional data on the correlation between the activity of Lp-PLA2 with dietary factors derive from the Bruneck study in which, the enzyme activity was inversely related to serum retinol levels while no significant relation with energy intake, fat intake, levels of carotene and tocopherol in plasma was observed [147]. Furthermore, it has been found that the replacement of 5% of energy of carbohydrate with protein was associated with decreased activity of Lp-PLA2 [148]. Recently, PAF-AH was negatively associated to coffee and positively associated to alcohol consumption [87]. In summary, various components of the diet may reduce the actions of PAF and its production while the relation between diet and the PAF's catabolic enzyme Lp-PLA2 is less clear.

Gene-diet interactions

Recent data suggest that the MD can affect the expression of genes associated with inflammation and oxidative stress, such as the gene for interferon-γ, interleukin receptor, the β2 adrenergic receptor, etc. [149]. The adoption of the MD in the elderly for 3 months led to lower postprandial expression of MCP-1and metalloproteinase MMP- 9relative to a diet rich in saturated fat and a lower expression of TNF- acompared to a diet rich in carbohydrates [150]. The adoption of a MD pattern enriched with olive oil also resulted in lower expression of proinflammatory molecules, cyclooxygenase-1 andMCP-1 [151]. Various components of olive oil can affect gene expression directly or indirectly (through reduction of oxidative stress). Such gene examples are those of vascular cell adhesion molecule-1, NF-kB, cyclooxygenase-2, and antioxidant enzymes (catalase and glutathione peroxidase) [152]. Several interactions of MD components and polymorphisms have been identified: tetrahydrofolic acid reductase [153], PPARγ [154], IL-6 [155], adiponectin etc.[156]. Last but not least, MD components may regulate gene expression via epigenetic mechanisms [157].

Conclusion

The MD is a pattern high in monounsaturated fat, low in saturated and trans fats, which provides a high amount of dietary fiber, vitamins, folic acid and natural antioxidants, moderate amounts of animal protein and a moderate amount of alcohol mainly in the form of wine. The Seven Countries firstly highlighted the beneficial effects of MD for cardiovascular disease prevention, while further studies have corroborated its results. Mediterranean diet interventions have shown a reduction of cardiovascular events in primary (PREDIMED study) and secondary prevention (Lyon Heart Study and other studies). The main mechanisms of action include its macronutrients and micronutrients profile, the content of antioxidants, its beneficial effects on postprandial lipemia and glycemia as well as endothelial function and gene-diet interactions. Finally, the proposed theory of atherosclerosis with PAF implication in conjunction with the presence of PAF inhibitors in the MD provides an additional explanation of its cardio-protective effects.

References

  1. Nestle M. Mediterranean diets: historical and research overview. Am J Clin Nutr. 1995; 61: 1313S-1320S.
  2. Allbaugh LG. Crete: a case study of an undeveloped area. Princeton: Princeton University Press. 1953.
  3. Keys A, Menotti A, Karvonen MJ, Aravanis C, Blackburn H, Buzina R, et al. The diet and 15-year death rate in the seven countries study. Am J Epidemiol. 1986; 124: 903-915.
  4. Menotti A, Kromhout D, Blackburn H, Fidanza F, Buzina R, Nissinen A. Food intake patterns and 25-year mortality from coronary heart disease: cross-cultural correlations in the Seven Countries Study. The Seven Countries Study Research Group. Eur J Epidemiol. 1999; 15: 507-515.
  5. Simini B. Serge Renaud: from French paradox to Cretan miracle. Lancet. 2000; 355: 48.
  6. Keys A, Keys M. Eat Well and Stay Well. New York: Doubleday. 1959.
  7. Trichopoulou A. The Mediterranean diet: definition. Epidemiological aspects and current patterns. In: Matalas A, Stavrinos V, Wolinsky I, editors. Mediterranean Diet: Constituents and Health Promotion. Washington: CRC Press. 2001.
  8. Fragopoulou E, Demopoulos CA, Antonopoulou S. Lipid minor constituents in wines. A biochemical approach in the French paradox. International Journal of Wine Research. 2009; 1: 131-143.
  9. Unesco. The Mediterranean diet. Inscribed in 2010 on the Representative. List of the Intangible Cultural Heritage of Humanity. 2010.
  10. Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr. 2010; 92: 1189-1196.
  11. Atkins JL, Whincup PH, Morris RW, Lennon LT, Papacosta O, Wannamethee SG. High diet quality is associated with a lower risk of cardiovascular disease and all-cause mortality in older men. J Nutr. 2014; 144: 673-680.
  12. Bertoia ML, Triche EW, Michaud DS, Baylin A, Hogan JW, Neuhouser ML, et al. Mediterranean and Dietary Approaches to Stop Hypertension dietary patterns and risk of sudden cardiac death in postmenopausal women. Am J Clin Nutr. 2014; 99: 344-351.
  13. Chiuve SE, Fung TT, Rexrode KM, Spiegelman D, Manson JE, Stampfer MJ, et al. Adherence to a low-risk, healthy lifestyle and risk of sudden cardiac death among women. JAMA. 2011; 306: 62-69.
  14. Cuenca-Garcia M, Artero EG, Sui X, Lee DC, Hebert JR, Blair SN. Dietary indices, cardiovascular risk factors and mortality in middle-aged adults: findings from the Aerobics Center Longitudinal Study. Ann Epidemiol. 2014; 24: 297-303.
  15. Gardener H, Wright CB, Gu Y, Demmer RT, Boden-Albala B, Elkind MS, et al. Mediterranean-style diet and risk of ischemic stroke, myocardial infarction, and vascular death: the Northern Manhattan Study. Am J Clin Nutr. 2011; 94: 1458-1464.
  16. Guallar-Castillon P, Rodriguez-Artalejo F, Tormo MJ, Sanchez MJ, Rodriguez L, Quiros JR, et al. Major dietary patterns and risk of coronary heart disease in middle-aged persons from a Mediterranean country: the EPIC-Spain cohort study. Nutr Metab Cardiovasc Dis. 2012; 22: 192-199.
  17. Hoevenaar-Blom MP, Spijkerman AM, Boshuizen HC, Boer JM, Kromhout D, Verschuren WM. Effect of using repeated measurements of a Mediterranean style diet on the strength of the association with cardiovascular disease during 12 years: the Doetinchem Cohort Study. Eur J Nutr. 2014; 53: 1209-1215.
  18. Martinez-Gonzalez MA, Garcia-Lopez M, Bes-Rastrollo M, Toledo E, Martinez-Lapiscina EH, Delgado-Rodriguez M, et al. Mediterranean diet and the incidence of cardiovascular disease: a Spanish cohort. Nutr Metab Cardiovasc Dis. 2011; 21: 237-244.
  19. Menotti A, Alberti-Fidanza A, Fidanza F, Lanti M, Fruttini D. Factor analysis in the identification of dietary patterns and their predictive role in morbid and fatal events. Public Health Nutr. 2012; 15: 1232-1239.
  20. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013; 368: 1279-1290.
  21. de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994; 343: 1454-1459.
  22. De Lorgeril M, Salen P, Martin JL, Mamelle N, Monjaud I, Touboul P, et al. Effect of a mediterranean type of diet on the rate of cardiovascular complications in patients with coronary artery disease. Insights into the cardioprotective effect of certain nutriments. J Am Coll Cardiol. 1996; 28: 1103-1108.
  23. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999; 99: 779-785.
  24. Singh RB, Rastogi SS, Verma R, Laxmi B, Singh R, Ghosh S, et al. Randomised controlled trial of cardioprotective diet in patients with recent acute myocardial infarction: results of one year follow up. BMJ. 1992; 304: 1015-1019.
  25. Singh RB, Dubnov G, Niaz MA, Ghosh S, Singh R, Rastogi SS, et al. Effect of an Indo-Mediterranean diet on progression of coronary artery disease in high risk patients (Indo-Mediterranean Diet Heart Study): a randomized single-blind trial. Lancet. 2002; 360: 1455-1461.
  26. Tuttle KR, Shuler LA, Packard DP, Milton JE, Daratha KB, Bibus DM, et al. Comparison of low-fat versus Mediterranean-style dietary intervention after first myocardial infarction (from The Heart Institute of Spokane Diet Intervention and Evaluation Trial). Am J Cardiol. 2008; 101: 1523-1530.
  27. Ross R, Glomset J, Harker L. Response to injury and atherogenesis. Am J Pathol. 1977; 86: 675-684.
  28. Poole JC, Florey HW. Changes in the endothelium of the aorta and the behaviour of macrophages in experimental atheroma of rabbits. J Pathol Bacteriol. 1958; 75: 245-251.
  29. Gimbrone MA Jr, Buchanan MR. Interactions of platelets and leukocytes with vascular endothelium: in vitro studies. Ann N Y Acad Sci. 1982; 401: 171-183.
  30. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999; 340: 115-126.
  31. Demopoulos CA, Pinckard RN, Hanahan DJ. Platelet-activating factor. Evidence for 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine as the active component (a new class of lipid chemical mediators). J Biol Chem. 1979; 254: 9355-9358.
  32. Leitinger N. Oxidized phospholipids as modulators of inflammation in atherosclerosis. Curr Opin Lipidol. 2003; 14: 421-430.
  33. Frostegard J, Huang YH, Ronnelid J, Schafer-Elinder L. Platelet-activating factor and oxidized LDL induce immune activation by a common mechanism. Arterioscler Thromb Vasc Biol. 1997; 17: 963-968.
  34. Liapikos TA, Antonopoulou S, Karabina SP, Tsoukatos DC, Demopoulos CA, Tselepis AD. Platelet-activating factor formation during oxidative modification of low-density lipoprotein when PAF-acetylhydrolase has been inactivated. Biochim Biophys Acta. 1994; 1212: 353-360.
  35. Marathe GK, Davies SS, Harrison KA, Silva AR, Murphy RC, Castro-Faria-Neto H, et al. Inflammatory platelet-activating factor-like phospholipids in oxidized low density lipoproteins are fragmented alkyl phosphatidylcholines. J Biol Chem. 1999; 274: 28395-28404.
  36. Prescott SM, McIntyre TM, Zimmerman GA, Stafforini DM. Inflammation as an early component of atherosclerosis and vascular damage--a role for P-selectin and platelet-activating factor. Jpn Circ J. 1996; 60: 137-141.
  37. Weyrich AS, McIntyre TM, McEver RP, Prescott SM, Zimmerman GA. Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-alpha secretion. Signal integration and NF-kappa B translocation. J Clin Invest. 1995; 95: 2297-2303.
  38. Mehta JL, Saldeen TG, Rand K. Interactive role of infection, inflammation and traditional risk factors in atherosclerosis and coronary artery disease. J Am Coll Cardiol. 1998; 31: 1217-1225.
  39. Demopoulos C, Karantonis H, Antonopoulou S. Platelet activating factor - a molecular link between atherosclerosis theories. Eur J Lipid Sci Technol. 2003; 105: 705-716.
  40. Antonopoulou S, Nomikos T, Karantonis HC, Fragopoulou E, Demopoulos CA. PAF, a potent lipid mediator. In: Tselepis AD, editor. Bioactive Phospholipids Role in Inflammation and Atheroslerosis. India: Tranworld Research Network. 2008; 85-134.
  41. Dentan C, Lesnik P, Chapman MJ, Ninio E. Phagocytic activation induces formation of platelet-activating factor in human monocyte-derived macrophages and in macrophage-derived foam cells. Relevance to the inflammatory reaction in atherogenesis. Eur J Biochem. 1996; 236: 48-55.
  42. Karantonis HC, Antonopoulou S, Perrea DN, Sokolis DP, Theocharis SE, Kavantzas N, et al. In vivo antiatherogenic properties of olive oil and its constituent lipid classes in hyperlipidemic rabbits. Nutr Metab Cardiovasc Dis. 2006; 16: 174-185.
  43. Tsantila N, Karantonis HC, Perrea DN, Theocharis SE, Iliopoulos DG, Antonopoulou S, et al. Antithrombotic and antiatherosclerotic properties of olive oil and olive pomace polar extracts in rabbits. Mediators Inflamm. 2007; 2007: 36204.
  44. Nasopoulou C, Tsoupras AB, Karantonis HC, Demopoulos CA, Zabetakis I. Fish polar lipids retard atherosclerosis in rabbits by down-regulating PAF biosynthesis and up-regulating PAF catabolism. Lipids Health Dis. 2011; 10: 213.
  45. Shimizu T. Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. Annu Rev Pharmacol Toxicol. 2009; 49: 123-150.
  46. Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006; 86: 515-581.
  47. Bochkov VN, Kadl A, Huber J, Gruber F, Binder BR, Leitinger N. Protective role of phospholipid oxidation products in endotoxin-induced tissue damage. Nature. 2002; 419: 77-81.
  48. Huang CL, Sumpio BE. Olive oil, the mediterranean diet, and cardiovascular health. J Am Coll Surg. 2008; 207: 407-416.
  49. Ryan M, McInerney D, Owens D, Collins P, Johnson A, Tomkin GH. Diabetes and the Mediterranean diet: a beneficial effect of oleic acid on insulin sensitivity, adipocyte glucose transport and endothelium-dependent vasoreactivity. QJM. 2000; 93: 85-91.
  50. US Department of Agriculture. Composition of foods raw, processed, prepared USDA National Nutrient Database for Standard Reference, Release 24. 2011.
  51. Simopoulos AP. The Mediterranean diets: What is so special about the diet of Greece? The scientific evidence. J Nutr. 2001; 131: 3065S-73S.
  52. Din JN, Newby DE, Flapan AD. Omega 3 fatty acids and cardiovascular disease--fishing for a natural treatment. BMJ. 2004; 328: 30-35.
  53. Kar S. Role of omega-3 fatty acids in the prevention of atrial fibrillation. Rev Cardiovasc Med. 2013; 14: e82-91.
  54. Grimsgaard S, Bonaa KH, Hansen JB, Myhre ES. Effects of highly purified eicosapentaenoic acid and docosahexaenoic acid on hemodynamics in humans. Am J Clin Nutr. 1998; 68: 52-59.
  55. Mozaffarian D, Gottdiener JS, Siscovick DS. Intake of tuna or other broiled or baked fish versus fried fish and cardiac structure, function, and hemodynamics. Am J Cardiol. 2006; 97: 216-222.
  56. Ventura HO, Milani RV, Lavie CJ, Smart FW, Stapleton DD, Toups TS, et al. Cyclosporine-induced hypertension. Efficacy of omega-3 fatty acids in patients after cardiac transplantation. Circulation. 1993; 88: 281-285.
  57. McLennan PL, Barnden LR, Bridle TM, Abeywardena MY, Charnock JS. Dietary fat modulation of left ventricular ejection fraction in the marmoset due to enhanced filling. Cardiovasc Res. 1992; 26: 871-877.
  58. Nishimura M, Nanbu A, Komori T, Ohtsuka K, Takahashi H, Yoshimura M. Eicosapentaenoic acid stimulates nitric oxide production and decreases cardiac noradrenaline in diabetic rats. Clin Exp Pharmacol Physiol. 2000; 27: 618-624.
  59. Swann PG, Venton DL, Le Breton GC. Eicosapentaenoic acid and docosahexaenoic acid are antagonists at the thromboxane A2/prostaglandin H2 receptor in human platelets. FEBS Lett. 1989; 243: 244-246.
  60. Kaminski WE, Jendraschak E, Kiefl R, von Schacky C. Dietary omega-3 fatty acids lower levels of platelet-derived growth factor mRNA in human mononuclear cells. Blood. 1993; 81: 1871-1879.
  61. Mayer K, Merfels M, Muhly-Reinholz M, Gokorsch S, Rosseau S, Lohmeyer J, et al. Omega-3 fatty acids suppress monocyte adhesion to human endothelial cells: role of endothelial PAF generation. Am J Physiol Heart Circ Physiol. 2002; 283: H811-818.
  62. Sneddon AA, McLeod E, Wahle KW, Arthur JR. Cytokine-induced monocyte adhesion to endothelial cells involves platelet-activating factor: suppression by conjugated linoleic acid. Biochim Biophys Acta. 2006; 1761: 793-801.
  63. Weber C, Aepfelbacher M, Lux I, Zimmer B, Weber PC. Docosahexaenoic acid inhibits PAF and LTD4 stimulated [Ca2+]i-increase in differentiated monocytic U937 cells. Biochim Biophys Acta. 1991; 1133: 38-45.
  64. Mori TA, Beilin LJ, Burke V, Morris J, Ritchie J. Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease. Arterioscler Thromb Vasc Biol. 1997; 17: 279-286.
  65. Wan JB, Huang LL, Rong R, Tan R, Wang J, Kang JX. Endogenously decreasing tissue n-6/n-3 fatty acid ratio reduces atherosclerotic lesions in apolipoprotein E-deficient mice by inhibiting systemic and vascular inflammation. Arterioscler Thromb Vasc Biol. 2010; 30: 2487-2494.
  66. Einvik G, Klemsdal TO, Sandvik L, Hjerkinn EM. A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk. Eur J Cardiovasc Prev Rehabil. 2010; 17: 588-592.
  67. Origin Trial Investigators, Bosch J, Gerstein HC, Dagenais GR, Díaz R, Dyal L, Jung H. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012; 367: 309-318.
  68. Risk and Prevention Study Collaborative Group, Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013; 368: 1800-1808.
  69. Lee JY, Zhao L, Youn HS, Weatherill AR, Tapping R, Feng L, et al. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem. 2004; 279: 16971-16979.
  70. Erridge C. The capacity of foodstuffs to induce innate immune activation of human monocytes in vitro is dependent on food content of stimulants of Toll-like receptors 2 and 4. Br J Nutr. 2011; 105: 15-23.
  71. Lin H, Xiao Y, Chen G, Fu D, Ye Y, Liang L, et al. HMG-CoA reductase inhibitor simvastatin suppresses Toll-like receptor 2 ligand-induced activation of nuclear factor kappa B by preventing RhoA activation in monocytes from rheumatoid arthritis patients. Rheumatol Int. 2011; 31: 1451-1458.
  72. Tsantila N, Tsoupras AB, Fragopoulou E, Antonopoulou S, Iatrou C, Demopoulos CA. In vitro and in vivo effects of statins on platelet-activating factor and its metabolism. Angiology. 2011; 62: 209-218.
  73. O'Keefe JH, Gheewala NM, O'Keefe JO. Dietary strategies for improving post-prandial glucose, lipids, inflammation, and cardiovascular health. J Am Coll Cardiol. 2008; 51: 249-255.
  74. Lairon D, Play B, Jourdheuil-Rahmani D. Digestible and indigestible carbohydrates: interactions with postprandial lipid metabolism. J Nutr Biochem. 2007; 18: 217-227.
  75. Trichopoulou A, Vasilopoulou E, Georga K. Macro- and micronutrients in a traditional Greek menu. Forum Nutr. 2005; 135-146.
  76. Champagne CM. Dietary interventions on blood pressure: the Dietary Approaches to Stop Hypertension (DASH) trials. Nutr Rev. 2006; 64: S53-56.
  77. Massaro M, Scoditti E, Carluccio MA, De Caterina R. Nutraceuticals and prevention of atherosclerosis: focus on omega-3 polyunsaturated fatty acids and Mediterranean diet polyphenols. Cardiovasc Ther. 2010; 28: e13-19.
  78. Hartisch C, Kolodziej H, von Bruchhausen F. Dual inhibitory activities of tannins from Hamamelis virginiana and related polyphenols on 5-lipoxygenase and lyso-PAF: acetyl-CoA acetyltransferase. Planta Med. 1997; 63: 106-110.
  79. Sugatani J, Fukazawa N, Ujihara K, Yoshinari K, Abe I, Noguchi H, et al. Tea polyphenols inhibit acetyl-CoA:1-alkyl-sn-glycero-3-phosphocholine acetyltransferase (a key enzyme in platelet-activating factor biosynthesis) and platelet-activating factor-induced platelet aggregation. Int Arch Allergy Immunol. 2004; 134: 17-28.
  80. Yanoshita R, Chang HW, Son KH, Kudo I, Samejima Y. Inhibition of lysoPAF acetyltransferase activity by flavonoids. Inflamm Res. 1996; 45: 546-549.
  81. Demopoulos VJ, Tani E, Long JP. Synthesis and biological evaluation of 3-(2-aminoethyl)pyrrole derivatives. Arch Pharm (Weinheim). 1989; 322: 827-828.
  82. Andrikopoulos NK, Tzamtzis VA, Giannopoulos GA, Kalantzopoulos GK, Demopoulos CA. Deterioration of some vegetable oils during heating or frying of several foods. Revue Francaise de corps gras. 1989; 3: 127-129.
  83. Mitjavila MT, Fandos M, Salas-Salvado J, Covas MI, Borrego S, Estruch R, et al. The Mediterranean diet improves the systemic lipid and DNA oxidative damage in metabolic syndrome individuals. A randomized, controlled, trial. Clin Nutr. 2013; 32: 172-178.
  84. Zamora-Ros R, Serafini M, Estruch R, Lamuela-Raventos RM, Martinez-Gonzalez MA, Salas-Salvado J, et al. Mediterranean diet and non enzymatic antioxidant capacity in the PREDIMED study: evidence for a mechanism of antioxidant tuning. Nutr Metab Cardiovasc Dis. 2013; 23: 1167-1174.
  85. Pitsavos C, Panagiotakos DB, Tzima N, Chrysohoou C, Economou M, Zampelas A, et al. Adherence to the Mediterranean diet is associated with total antioxidant capacity in healthy adults: the ATTICA study. Am J Clin Nutr. 2005; 82: 694-699.
  86. Urquiaga I, Strobel P, Perez D, Martinez C, Cuevas A, Castillo O, et al. Mediterranean diet and red wine protect against oxidative damage in young volunteers. Atherosclerosis. 2010; 211: 694-699.
  87. Detopoulou P, Fragopoulou E, Nomikos T, Yannakoulia M, Stamatakis G, Panagiotakos DB, et al. The relation of diet with PAF and its metabolic enzymes in healthy volunteers. Eur J Nutr. 2014;.
  88. Blaak EE, Antoine JM, Benton D, Bjorck I, Bozzetto L, Brouns F, et al. Impact of postprandial glycaemia on health and prevention of disease. Obes Rev. 2012; 13: 923-984.
  89. Jackson KG, Poppitt SD, Minihane AM. Postprandial lipemia and cardiovascular disease risk: Interrelationships between dietary, physiological and genetic determinants. Atherosclerosis. 2012; 220: 22-33.
  90. Detopoulou P, Fragopoulou E, Nomikos T, Antonopoulou S. Mediterranean diet and the postprandial state: a focus on lipemia, glycemia and thrombosis. In: Preedy VR, Watson R, editors. The Mediterranean Diet: An Evidence-Based Approach To Disease Prevention Elsevier. 2014.
  91. Sloth B, Due A, Larsen TM, Holst JJ, Heding A, Astrup A. The effect of a high-MUFA, low-glycaemic index diet and a low-fat diet on appetite and glucose metabolism during a 6-month weight maintenance period. Br J Nutr. 2009; 101: 1846-1858.
  92. Paniagua JA, de la Sacristana AG, Sanchez E, Romero I, Vidal-Puig A, Berral FJ, et al. A MUFA-rich diet improves posprandial glucose, lipid and GLP-1 responses in insulin-resistant subjects. J Am Coll Nutr. 2007; 26: 434-444.
  93. Defoort C, Vincent-Baudry S, Lairon D. Effects of 3-month Mediterranean-type diet on postprandial TAG and apolipoprotein B48 in the Medi-RIVAGE cohort. Public Health Nutr. 2011; 14: 2302-2308.
  94. Perez-Martinez P, Ordovas JM, Garcia-Rios A, Delgado-Lista J, Delgado-Casado N, Cruz-Teno C, et al. Consumption of diets with different type of fat influences triacylglycerols-rich lipoproteins particle number and size during the postprandial state. Nutr Metab Cardiovasc Dis. 2011; 21: 39-45.
  95. Lopez S, Bermudez B, Ortega A, Varela LM, Pacheco YM, Villar J, et al. Effects of meals rich in either monounsaturated or saturated fat on lipid concentrations and on insulin secretion and action in subjects with high fasting triglyceride concentrations. Am J Clin Nutr. 2011; 93: 494-499.
  96. Rivellese AA, Maffettone A, Vessby B, Uusitupa M, Hermansen K, Berglund L, et al. Effects of dietary saturated, monounsaturated and n-3 fatty acids on fasting lipoproteins, LDL size and post-prandial lipid metabolism in healthy subjects. Atherosclerosis. 2003; 167: 149-158.
  97. Delgado-Lista J, Lopez-Miranda J, Cortes B, Perez-Martinez P, Lozano A, Gomez-Luna R, et al. Chronic dietary fat intake modifies the postprandial response of hemostatic markers to a single fatty test meal. Am J Clin Nutr. 2008; 87: 317-322.
  98. Xiao C, Lewis GF. Regulation of chylomicron production in humans. Biochim Biophys Acta. 2012; 1821: 736-746.
  99. Park Y, Harris WS. Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. J Lipid Res. 2003; 44: 455-463.
  100. Leighton F, Urquiaga I. The Mediterranean diets: Nutrition and gastronomy. In: Smith J, Charter E, editors. Functional food product development. Singapore: Blackwell Publishing. 2010.
  101. Jimenez-Gomez Y, Lopez-Miranda J, Blanco-Colio LM, Marin C, Perez-Martinez P, Ruano J, et al. Olive oil and walnut breakfasts reduce the postprandial inflammatory response in mononuclear cells compared with a butter breakfast in healthy men. Atherosclerosis. 2009; 204: 70-76.
  102. Natella F, Ghiselli A, Guidi A, Ursini F, Scaccini C. Red wine mitigates the postprandial increase of LDL susceptibility to oxidation. Free Radic Biol Med. 2001; 30: 1036-1044.
  103. Nomikos T, Detopoulou P, Fragopoulou E, Pliakis E, Antonopoulou S. Boiled wild artichoke reduces postprandial glycemic and insulinemic responses in normal subjects but has no effect on metabolic syndrome patients. Nutrition Research. 2007; 27: 741-749.
  104. Fragopoulou E, Detopoulou P, Nomikos T, Pliakis E, Panagiotakos DB, Antonopoulou S. Mediterranean wild plants reduce postprandial platelet aggregation in patients with metabolic syndrome. Metabolism. 2012; 61: 325-334.
  105. Desjardins F, Balligand JL. Nitric oxide-dependent endothelial function and cardiovascular disease. Acta Clin Belg. 2006; 61: 326-334.
  106. Delgado-Lista J, Perez-Martinez P, Garcia-Rios A, Perez-Caballero AI, Perez-Jimenez F, Lopez-Miranda J. Mediterranean Diet And Cardiovascular Risk: Beyond Traditional Risk Factors. Crit Rev Food Sci Nutr. 2014.
  107. Rallidis LS, Lekakis J, Kolomvotsou A, Zampelas A, Vamvakou G, Efstathiou S, et al. Close adherence to a Mediterranean diet improves endothelial function in subjects with abdominal obesity. Am J Clin Nutr. 2009; 90: 263-268.
  108. Fuentes F, Lopez-Miranda J, Sanchez E, Sanchez F, Paez J, Paz-Rojas E, et al. Mediterranean and low-fat diets improve endothelial function in hypercholesterolemic men. Ann Intern Med. 2001; 134: 1115-1119.
  109. Marin C, Ramirez R, Delgado-Lista J, Yubero-Serrano EM, Perez-Martinez P, Carracedo J, et al. Mediterranean diet reduces endothelial damage and improves the regenerative capacity of endothelium. Am J Clin Nutr. 2011; 93: 267-274.
  110. Ambring A, Friberg P, Axelsen M, Laffrenzen M, Taskinen MR, Basu S, et al. Effects of a Mediterranean-inspired diet on blood lipids, vascular function and oxidative stress in healthy subjects. Clin Sci (Lond). 2004; 106: 519-525.
  111. Karatzi K, Papamichael C, Karatzis E, Papaioannou TG, Voidonikola PT, Vamvakou GD, et al. Postprandial improvement of endothelial function by red wine and olive oil antioxidants: a synergistic effect of components of the Mediterranean diet. J Am Coll Nutr. 2008; 27: 448-453.
  112. Mariano F, Bussolati B, Migliori M, Russo S, Triolo G, Camussi G. Platelet-activating factor synthesis by neutrophils, monocytes, and endothelial cells is modulated by nitric oxide production. Shock. 2003; 19: 339-344.
  113. Antonopoulou S, Fragopoulou E, Karantonis HC, Mitsou E, Sitara M, Rementzis J, et al. Effect of traditional Greek Mediterranean meals on platelet aggregation in normal subjects and in patients with type 2 diabetes mellitus. J Med Food. 2006; 9: 356-362.
  114. Stamatakis G, Tsantila N, Samiotaki M, Panayotou GN, Dimopoulos AC, Halvadakis CP, et al. Detection and isolation of antiatherogenic and antioxidant substances present in olive mill wastes by a novel filtration system. J Agric Food Chem. 2009; 57: 10554-10564.
  115. Fragopoulou E, Antonopoulou S, Demopoulos CA. Biologically active lipids with antiatherogenic properties from white wine and must. J Agric Food Chem. 2002; 50: 2684-2694.
  116. Karantonis HC, Antonopoulou S, Demopoulos CA. Antithrombotic lipid minor constituents from vegetable oils. Comparison between olive oils and others. J Agric Food Chem. 2002; 50: 1150-1160.
  117. Fragopoulou E, Antonopoulou S, Nomikos T, Demopoulos CA. Structure elucidation of phenolic compounds from red/white wine with antiatherogenic properties. Biochim Biophys Acta. 2003; 1632: 90-99.
  118. Panayiotou A, Samartzis D, Nomikos T, Fragopoulou E, Karantonis HC, Demopoulos CA, et al. Lipid fractions with aggregatory and antiaggregatory activity toward platelets in fresh and fried cod (Gadus morhua): correlation with platelet-activating factor and atherogenesis. J Agric Food Chem. 2000; 48: 6372-6379.
  119. Rementzis J, Antonopoulou S, Argyropoulos D, Demopoulos CA. Biologically active lipids from S. scombrus. Adv Exp Med Biol. 1996; 416: 65-72.
  120. Koussissis S, Semidalas C, Hadzistavrou EC, Kalyvas V, Antonopoulou S, Demopoulos C. PAF antagonists in foods: Isolation and identification of PAF in honey and wax. Rev Fr Corp Gras. 1994; 41: 127-132.
  121. Nasopoulou C, Gogaki V, Panagopoulou E, Demopoulos C, Zabetakis I. Hen egg yolk lipid fractions with antiatherogenic properties. Anim Sci J. 2013; 84: 264-271.
  122. Antonopoulou S, Semidalas C, Koussissis S, Demopoulos C. Platelet-Activating Factor (PAF) antagonists in foods. A study of lipids, with PAF or anti-PAF like-activity, in cow's milk and yoghurt. J Agric Food Chem. 1996; 44: 3047-3051.
  123. Karantonis HC, Fragopoulou E, Antonopoulou S, Rementzis J, Phenekos C, Demopoulos CA. Effect of fast-food Mediterranean-type diet on type 2 diabetics and healthy human subjects' platelet aggregation. Diabetes Res Clin Pract. 2006; 72: 33-41.
  124. Lim H, Kubota K, Kobayashi A, Seki T, Ariga T. Inhibitory effect of sulfur-containing compounds in Scorodocarpus borneensis Becc. on the aggregation of rabbit platelets. Biosci Biotechnol Biochem. 1999; 63: 298-301.
  125. Phillips C, Poyser NL. Inhibition of platelet aggregation by onion extracts. Lancet. 1978; 1: 1051-1052.
  126. Antonopoulou S, Demopoulos CA. On the Mediterranean Diet. Inform. 1997; 8: 776.
  127. Thomas SR, Stocker R. Molecular action of vitamin E in lipoprotein oxidation: implications for atherosclerosis. Free Radic Biol Med. 2000; 28: 1795-1805.
  128. Mertens PR, Muller R. Vitamin D and cardiovascular risk. Int Urol Nephrol. 2010; 42: 165-171.
  129. Feliste R, Perret B, Braquet P, Chap H. Protective effect of BN 52021, a specific antagonist of platelet-activating factor (PAF-acether) against diet-induced cholesteryl ester deposition in rabbit aorta. Atherosclerosis. 1989; 78: 151-158.
  130. Prasad K. Reduction of serum cholesterol and hypercholesterolemic atherosclerosis in rabbits by secoisolariciresinol diglucoside isolated from flaxseed. Circulation. 1999; 99: 1355-1362.
  131. Amran AA, Zakaria Z, Othman F, Das S, Raj S, Nordin NA. Aqueous extract of Piper sarmentosum decreases atherosclerotic lesions in high cholesterolemic experimental rabbits. Lipids Health Dis. 2010; 9: 44.
  132. Koltai M, Braquet PG. Platelet-activating factor antagonists. Clin Rev Allergy. 1994; 12: 361-380.
  133. Tzeng SH, Ko WC, Ko FN, Teng CM. Inhibition of platelet aggregation by some flavonoids. Thromb Res. 1991; 64: 91-100.
  134. Izzo AA, Dicarlo N, Mascolo N, Capasso F. Antiulcer effect of flavonoids. Role of endogenous PAF. Phytotherapy Research. 1994; 8: 179-181.
  135. Fragopoulou E, Nomikos T, Karantonis HC, Apostolakis C, Pliakis E, Samiotaki M, et al. Biological activity of acetylated phenolic compounds. J Agric Food Chem. 2007; 55: 80-89.
  136. Andrikopoulos NK, Antonopoulou S, Kaliora AC. Oleuropein Inhibits LDL oxidation Induced by cooking oil frying by-products and platelet aggregation induced by platelet-activating factor. Food Science and Technology. 2002; 35: 479-484.
  137. Tsantila N, Karantonis HC, Perrea DN, Theocharis SE, Iliopoulos DG, Iatrou C, et al. Atherosclerosis regression study in rabbits upon olive pomace polar lipid extract administration. Nutr Metab Cardiovasc Dis. 2010; 20: 740-747.
  138. Demopoulos C, Karantonis H, Antonopoulou S. Platelet activating factor - a molecular link between atherosclerosis theories. Eur J Lipid Sci Technol. 2003; 105: 705-716.
  139. Nasopoulou C, Nomikos T, Demopoulos CA, Zabetakis I. Comparison of antiatherogenic properties of lipids obtained from wild and cultured sea bass (Dicentrarchus labrax) and gilthead sea bream (Sparus aurata) Food Chem. 2007; 100: 560-567.
  140. Nasopoulou C, Karantonis HC, Perrea DN, Theocharis SE, Iliopoulos DG, Demopoulos CA, et al. In vivo anti-atherogenic properties of cultured gilthead sea bream (Sparus aurata) polar lipid extracts in hypercholesterolaemic rabbits. Food Chemistry. 2010; 120: 831-836.
  141. Detopoulou P, Nomikos T, Fragopoulou E, Stamatakis G, Panagiotakos DB, Antonopoulou S. PAF and its metabolic enzymes in healthy volunteers: interrelations and correlations with basic characteristics. Prostaglandins Other Lipid Mediat. 2012; 97: 43-49.
  142. Balestrieri ML, Castaldo D, Balestrieri C, Quagliuolo L, Giovane A, Servillo L. Modulation by flavonoids of PAF and related phospholipids in endothelial cells during oxidative stress. J Lipid Res. 2003; 44: 380-387.
  143. Tsoupras AB, Fragopoulou E, Nomikos T, Iatrou C, Antonopoulou S, Demopoulos CA. Characterization of the de novo biosynthetic enzyme of platelet activating factor, DDT-insensitive cholinephosphotransferase, of human mesangial cells. Mediators Inflamm. 2007; 2007: 27683.
  144. Balestrieri C, Felice F, Piacente S, Pizza C, Montoro P, Oleszek W, et al. Relative effects of phenolic constituents from Yucca schidigera Roezl. bark on Kaposi's sarcoma cell proliferation, migration, and PAF synthesis. Biochem Pharmacol. 2006; 71: 1479-1487.
  145. Schmidt EB, Koenig W, Khuseyinova N, Christensen JH. Lipoprotein-associated phospholipase A2 concentrations in plasma are associated with the extent of coronary artery disease and correlate to adipose tissue levels of marine n-3 fatty acids. Atherosclerosis. 2008; 196: 420-424.
  146. Pedersen MW, Koenig W, Christensen JH, Schmidt EB. The effect of marine n-3 fatty acids in different doses on plasma concentrations of Lp-PLA2 in healthy adults. Eur J Nutr. 2009; 48: 1-5.
  147. Tsimikas S, Willeit J, Knoflach M, Mayr M, Egger G, Notdurfter M, et al. Lipoprotein-associated phospholipase A2 activity, ferritin levels, metabolic syndrome, and 10-year cardiovascular and non-cardiovascular mortality: results from the Bruneck study. Eur Heart J. 2009; 30: 107-115.
  148. Hatoum IJ, Nelson JJ, Cook NR, Hu FB, Rimm EB. Dietary, lifestyle, and clinical predictors of lipoprotein-associated phospholipase A2 activity in individuals without coronary artery disease. Am J Clin Nutr. 2010; 91: 786-793.
  149. Konstantinidou V, Covas MI, Munoz-Aguayo D, Khymenets O, de la Torre R, Saez G, et al. In vivo nutrigenomic effects of virgin olive oil polyphenols within the frame of the Mediterranean diet: a randomized controlled trial. FASEB J. 2010; 24: 2546-2557.
  150. Camargo A, Delgado-Lista J, Garcia-Rios A, Cruz-Teno C, Yubero-Serrano EM, Perez-Martinez P, et al. Expression of proinflammatory, proatherogenic genes is reduced by the Mediterranean diet in elderly people. Br J Nutr. 2012; 108: 500-508.
  151. Llorente-Cortes V, Estruch R, Mena MP, Ros E, Gonzalez MA, Fito M, et al. Effect of Mediterranean diet on the expression of pro-atherogenic genes in a population at high cardiovascular risk. Atherosclerosis. 2010; 208: 442-450.
  152. Covas MI, Konstantinidou V, Fito M. Olive oil and cardiovascular health. J Cardiovasc Pharmacol. 2009; 54: 477-482.
  153. Dedoussis GV, Panagiotakos DB, Chrysohoou C, Pitsavos C, Zampelas A, Choumerianou D, et al. Effect of interaction between adherence to a Mediterranean diet and the methylenetetrahydrofolate reductase 677C-->T mutation on homocysteine concentrations in healthy adults: the ATTICA Study. Am J Clin Nutr. 2004; 80: 849-854.
  154. Garaulet M, Smith CE, Hernandez-Gonzalez T, Lee YC, Ordovas JM. PPARY Pro12Ala interacts with fat intake for obesity and weight loss in a behavioural treatment based on the Mediterranean diet. Mol Nutr Food Res. 2011; 55: 1771-1779.
  155. Razquin C, Martinez JA, Martinez-Gonzalez MA, Fernandez-Crehuet J, Santos JM, Marti A. A Mediterranean diet rich in virgin olive oil may reverse the effects of the -174G/C IL6 gene variant on 3-year body weight change. Mol Nutr Food Res. 2010; 54 Suppl 1: S75-82.
  156. Razquin C, Martinez JA, Martinez-Gonzalez MA, Salas-Salvado J, Estruch R, Marti A. A 3-year Mediterranean-style dietary intervention may modulate the association between adiponectin gene variants and body weight change. Eur J Nutr. 2010; 49: 311-319.
  157. Corella D, Ordovas JM. How does the Mediterranean diet promote cardiovascular health? Current progress toward molecular mechanisms: gene-diet interactions at the genomic, transcriptomic, and epigenomic levels provide novel insights into new mechanisms. Bioessays. 2014; 36: 526-537.

Citation: Detopoulou P, Demopoulos CA, Karantonis HC and Antonopoulou S. Mediterranean Diet and Its Protective Mechanisms against Cardiovascular Disease: An Insight into Platelet Activating Factor (PAF) and Diet Interplay. Ann Nutr Disord & Ther. 2015;2(1): 1016. ISSN:2381-8891