A review on management of cardiovascular diseases by olive polyphenols

Abstract Noncommunicable diseases have increasingly grown the cause of morbidities and mortalities worldwide. Among them, cardiovascular diseases (CVDs) continue to be the major contributor to deaths. CVDs are common in the urban community population due to the substandard living conditions, which have a significant impact on the healthcare system, and over 23 million human beings are anticipated to suffer from the CVDs before 2030. At the moment, CVD physicians are immediately advancing both primary and secondary prevention modalities in high‐risk populations. The cornerstone of CVD prevention is a healthy lifestyle that is more cost‐effective than the treatments after disease onset. In fact, in the present scenario, comprehensive research conducted on food plant components is potentially efficacious in reducing some highly prevalent CVD risk factors, such as hypercholesterolemia, hypertension, and atherosclerosis. Polyphenols of olive oil (OO), virgin olive oil (VOO), and extra virgin olive oil contribute an essential role for the management of CVDs. Olive oil induces cardioprotective effects due to the presence of a plethora of polyphenolic compounds, for example, oleuropein (OL), tyrosol, and hydroxytyrosol. The present study examines the bioavailability and absorption of major olive bioactive compounds, for instance, oleacein, oleocanthal, OL, and tyrosol. This review also elucidates the snobbish connection of olive polyphenols (OP) and the potential mechanism involved in combating various CVD results taken up from the in vitro and in vivo studies, such as animal and human model studies.


TA B L E 1 Distribution of bioactive compounds present in various parts of olive
. Abbreviations: DM, Dry matter; EVOO, Extra virgin olive oil; OF, Olive fruit; OL, Olive leaves; OMW, Olive mill water; OPW, Olive pomace waste; TPC, Total phenolic content; VOO, Virgin olive oil.
In addition, CVDs are a group of disorders such as chronic heart disease, stroke, rheumatic heart disease, peripheral arterial disease, congenital heart disease, pulmonary embolism, and deep vein thrombosis and generally proliferate by accumulation of fatty deposits on the inner walls of the blood vessels causing a blockage and stoppage of blood circulation to the arms, legs, brain, and heart (Lanier, Bury, & Richardson, 2016;Roth et al., 2017). Strokes can also be produced by blood loss from a blood vessel. According to the WHO, it is estimated that 7.4 million deaths were due to coronary heart disease and 6.7 million people died due to stroke in 2015. Hypertension is also the most frequent and important intermediate risk factor in addition to diabetes, overweight, obesity, and hyperlipidemia (Roth et al., 2017) Vascular dysfunction has been studied over the past decades, and numerous advances have been made regarding its specific risk factors on the health (Buckland & Gonzalez, 2015). There are two main reasons for vascular diseases, that is, coronary heart diseases and cerebrovascular diseases, such as thromboembolism and atherosclerosis. Atherosclerosis is mainly caused by the accumulation of cholesterol, fat, and other compounds in or on the artery walls, which results in restriction of blood flow to the organs (Mendis et al., 2015). If atherogenesis is not reverted, it will result in smooth muscle cell procreation, production of the extracellular matrix and fibrous tissue, and formation of the necrotic core. Physical disruption of atherosclerotic plaque can cause arterial occlusion, clot formation, and arterial thrombosis (Longo & Mattson, 2014 IOC, 2012). In 2014/2015, the total world olive oil (OO) production was 2.39 million tons, and among this, European Union produced 1.53 million tons and it was mainly used for human consumption (IOC, 2014). Besides OO production, olive trees are also used for table olive (TO) production. OO and TO are the two main foods of the MD (Obied et al., 2012). The contemporary world needs natural polyphenols for medications of different types of diseases and increasing interest in the studies of OO and its polyphenols.
Therefore, this review discusses the advance research conducted on OO and its polyphenol bioavailability and health benefits with special emphasis regarding the CVDs.

| COMMERCIAL CL A SS IFI C ATI ON AND CHEMIC AL CONTENTS OF OLIVE OIL
Nowadays, OO consumption is abruptly increased on account of the health-promoting components such as polyphenols, tocopherols and carotenoids (Dias et al., 2018. Further

TA B L E 2 (Continued)
carotene, b-carotene, squalene (Dias et al., 2018;Eggersdorfer & Wyss, 2018), lipophilic phenols, in particular, tocopherols Borges, Carlos, et al., 2017), xanthophylls, color pigments (pheophytins, chlorophylls), ketones, waxes, and esters are also a part of the fractions of olive oil (Lombardo, Grasso, Lanciano, Loria, & Monetti, 2018). However, it should be well-known fact that the composition of more or less 230 complex chemical compounds of OO affected by farming methods, irrigation techniques, climate conditions, geographical regions, variety, and process, that is, extraction, can also affect the chemical contents of OO extract from olive fruit (OF) (Squeo et al., 2016). In case of VOO and EVOO, about 95% of them come from the mesocarp (fleshy mesocarp and epicarp) and only 5% come from the seed of the OF such as embryo and endosperm, after twice pressing, that is, by cold pressing without any chemicals, with small amount of heat applied Borges, Carlos, et al., 2017). In another study, the crop year and the density of olive tree affected the chemical composition of the OO obtained from OF (Rodrigues et al., 2018). In this sense, it can be concluded that the strength of the biological effects of OO differs as a result of chemical composition.

| OLIVE OIL P OLYPHENOL (OOP) B I OAVA I L A B I LIT Y
At the time of justification of the health benefits of food components, it is essential to consider the difference between bioavailability and absorbed contents of OOP (Difonzo et al., 2017). Altogether

| OP COMBATING C VDs
This section of the present review describes the studied published olive and its polyphenolic compounds combating CVDs. The summary of key studied results also presented in Table 2 and Figure 1.

| OP an d OXIDATIVE S TRE SS
The cells in the cardiovascular system contentiously generate reac- alter the postprandial hemostatic profile and protect from oxidative stress (Ruano et al., 2007). A number of studies confirmed that various parts of olive such as OO (Covas, Nyyssönen, et al., 2006), EVOO of biologically active compounds present in olive are hydroxytyrosol and their derivatives as described in Table 2 (Gonzalez-Santiago, Fonolla, & Lopez-Huertas, 2010;Raederstorff, 2009). It has been observed that these bioactive compounds are well absorbed even at low concentration (25 ml, 22 g olive oil) in the gut and transferred to bloodstream and protect from ROS formation (Covas, Nyyssönen, et al., 2006;Covas, Ruiz-Gutiérrez, et al., 2006;Gonzalez-Santiago et al., 2010;. However, an earlier study conducted by Vissers, Zock, and Katan (2004) reported that OO did not take a large part in the oxidation process. But, the results of Covas, Nyyssönen, et al. (2006)

| OP AND HYPERTEN S I ON
Hypertension, which is also known as high blood pressure (HBP), is one of the main risk factors for cardiovascular stroke and myocardial infarction. Hypertension makes structural alternation in the arterial walls of the heart, brain, and kidney. The endothelial dysfunction (decrease in endothelium nitric oxide synthase expression) due to less availability of functional components, oxidative stress (increase in ROS level), inflammation (increase in cytokines production, etc.), and vascular remodeling are the key factors that lead to hypertension. The prevalence of HBP is increasing day by day, and almost one billion people are suffering from this silent killer disease. Therefore, medicines such as angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, thiazide-type diuretics, and calcium channel blockers are used to balance the HBP but all caused numerous adverse effects and are out of range due to the expensive cost.
Plant-based medicines are considerable alternative to overcome the cost and less side effect (Armstrong & Joint National Committee, 2014;Turnbull, 2003). for 6 weeks reduced BP without the alternation in inflammation, glucose metabolism, and vascular function biomarkers in 60 experimental participants. In another randomized, single-blinded placebo control study, Rozati et al. (2015) observed that adding EVOO in the American diet (corn, soybean oil, and butter) reduced the BP after 3-month consumption of EVOO in old overweight/obese (age > 65) contributor (41n). Earlier, Ferrara et al. (2000) also reported that daily consumption of OO for 6 months reduced the BP significantly in (23n) participants present in the study trial.

Oleuropein is a key biphenol compound present in OL reported
to have a strong antihypertensive effect. Oleuropein reduced systolic blood pressure (SBP) in male SHR Sprague Dawley rats (Ghibu et al., 2015). The supplementation of OL extract EFLA ® 943 (500-1,000 mg) tablets to hypertensive monozygotic twins (40n, age: 16-60) showed significant reduction in BP after 8 weeks (Perrinjaquet-Moccetti et al., 2008). In another comparative study conducted by Susalit et al. (2011), the authors also found similar effects of OL extract EFLA ® 943 (500-1,000 mg twice daily) tablets and captopril (12.5 mg twice daily) to stage 1 hypertension patients (aged 25-60 year) after 8 weeks. A decrease in BP was also observed in stage 1 essential hypertension young women (24n), when they  (Schwingshackl et al., 2015). Recent study conducted by Romero et al. (2016) also claimed that oral administration of OL extract (30 mg/kg/day bw 5 weeks) to SHR reduces SBP by modulating the pro-oxidative and pro-inflammatory status and improves vascular function. and other inflammatory markers, such as high-sensibility C-reactive protein (hs-CRP) or IL-6 (Bogani, Galli, Villa, & Visioli, 2007;Fito et al., 2008). Contradictory results have been obtained concerning the effects of OOP on cell adhesion molecules. A decrease in ICAM-1 and vascular cell adhesion molecule-1 serum levels at postprandial state after VOO when compared to refined OO ingestion has been reported (Pacheco et al., 2007). However, no differences in ICAM-1 levels were reported after sustained virgin or refined OO consumption (Fito et al., 2008). In vitro study conducted by Talhaoui et al. (2016) observed that Andalusian OL extract inhibited pro-inflammatory mediator NO in LPS-stimulated RAW264.7 cells and showed anti-inflammatory properties. EVOO polyphenols (hydroxytyrosol and tyrosol) inhibited mitogen-activated protein kinase (MAPK) phosphorylation, ROS production, and reduced cytokine secretion induced by the oxysterols in peripheral blood mononuclear cells (Serra, Deiana, Spencer, & Corona, 2017). A double-blind, randomized, crossover study conducted by Lockyer, Corona, Yaqoob, Spencer, and Rowland (2015) reported that consumption of OLP (olive leaves polyphenols) (10 mg HT, 51 mg OL) for 4 weeks modulated the IL-8 production in 18 healthy volunteers (nine females and nine males). In another study , Cárdeno, (2014) claimed that EVOO exhibited inflammatory activity by decreasing NO and ROS production. Furthermore, EVOO also modulated COX-2, iNOS, and mPGES-1 protein expressions, reduced MAPK phosphorylation, and prevented the nuclear NFkB translocation in LPS-stimulated murine macrophages. A recent meta-analysis and systematic review figured out that OO consumption (1-50 mg) decreased in C-reactive protein and interleukin-6 (Schwingshackl et al., 2015). A double-blind randomized crossover study conducted by Lockyer et al. (2017) observed that consumption of olive polyphenols (6 mg hydroxytyrosol, 136 mg OL) for 6 weeks reduced the interleukin-8 in 60 experimental members.

| OP AND HYPERLIPIDEMIA
Hyperlipidemia is another CVDs referring to an elevated level of fasting and total cholesterol level in the blood. Postprandial lipemia and hyperglycemia are the key risk factors for causing atherosclerosis and other CVDs (Roche & Gibney, 2000). Types and concentration of fat intake also influenced postprandial lipemia.
It is reported that the daily intake of OO (25 ml) did not promote postprandial lipemia . Because, OO is rich in MUFA, which decreases LDL level and increases HDL.

F I G U R E 1 Effects of olive polyphenols on CVDs
Hydroxytyrosol and OL are potent antiplatelet compounds that are widely distributed in OO inhibit collagen-induced platelet activation or ADP (Petroni et al., 1995), whereas oleocanthal and oleacein possess antiplatelet activity by inhibiting COX and a 5-LOX inhibitor (Beauchamp et al., 2005;Vougogiannopoulou et al., 2014). Earlier, an in vitro study conducted by Singh, Mok, Christensen, Turner, and Hawley (2008) observed that OLP inhibited the platelet function in blood taken from 11 healthy males. In another study, OOP inhibited platelet aggregation by cAMP-PDE inhibition (Dell'Agli et al., 2008). A recently randomized crossover study conducted by Agrawal et al. (2017) reported that weekly consumption of EVOO (40 ml), which is rich in oleocanthal, resulted in the stoppage of the platelet aggregation.

| OP AND ATHEROSCLEROS IS
Atherosclerosis is a systemic lipid-driven inflammatory condition associated with endothelial dysfunction that results in accumulation and subsequent oxidation of lipids in the vessel wall or plaque development. These abnormalities trigger inflammatory cell infiltration and macrophage foam cell formation, leading to apoptosis and secondary necrosis and plaque advancement (Tabas, 2010).
Montserrat-de la Paz et al. (2016) reported that diets enrich with OO-protected atherosclerosis as compared to saturated fatty acidrich diet in niacin-treated mice. Another in vivo study conducted by Claro, Ogalla, Rodriguez-Rodriguez, Herrera, and de Sotomayor (2015) also claimed that EVOO polyphenols lowered the protein expression and macrophage accumulation of iNOS, VCAM-1, ICAM-1, NFκB, TNF-α, and superoxide anion production. Furthermore, EVOO polyphenols improved endothelial function and lowered lipid accumulation within the atherosclerotic lesion of Apo E-deficient mice. A randomized, double-blind, crossover, controlled trial, conducted by Fernández-Castillejo et al. (2016), reported that incorporation of thyme into VOO improved lipoprotein particle atherogenic ratios in 33 hypercholesterolemic individuals after 3 weeks. In the recent past, the research work of Valls et al. (2017) also stated that consumption of thyme and VOO 25 ml/day for three weeks improved endothelial function in 12 healthy subjects. Administration of squalene to atherosclerotic rabbits reversed endothelial activation and lowered cellularity in gingival mucosa (Bullon et al., 2009).

| SAFE T Y OF OP
Olive and its components do not possess toxicity to humans. An animal model study conducted by Lee-Huang, Zhang, and Huang (2003) reported that an administration of 1 g/kg bw for 7 days did not cause toxicity to the rats. In another in vitro human cell toxicity study, it was also confirmed that OL extract (1 mg/ml) was not toxic to human cell lines (Petkov & Manolov, 1972). Other studies conducted by various researchers reported that OO and its components were not toxic. OO polyphenols enriched with hydroxytyrosol is safe at the limit of 20 mg/kg daily (Christian et al., 2004;Soni, Burdock, Christian, & Botler, 2006).

| CON CLUS ION
Over the past few decades, the use of olive oil and its products in everyday life has a long history of nutrition and therapeutical actions. A large number of study results confirmed that OO and its metabolites are very beneficial for the handling of CVDs through several mechanisms and provide some important nutrimental bioactive compounds besides energy and fat-soluble vitamins. In the recent past, there was a growing trend to conduct a lot of research work on olive oil polyphenols and results found that olive oil polyphenols increase the HDL level, prevent from oxidative stress, reduce thrombogenic, endothelial dysfunction, BP, and inflammation, and alter gene expression responsible for atherosclerosis process. Furthermore, olive oil still needs clinical efficacy to elucidate the understanding of molecular mechanisms. From this point of view, the ingestion of olive oil and its products needs to be recommended not only due to its beneficial fatty acid profile but also in order to gain advantages from its very important bioactive components that have constructive effects on human health.

ACK N OWLED G EM ENTS
This article is for conveying up-to-date information regarding olive and its cardioprotective role. There were no experiments conducted in this paper because this is the review article. All the data used in this study are properly cited.

CO N FLI C T O F I NTE R E S T
The authors declare no conflicts of interest.