Promising Nutritional Fruits Against Cardiovascular Diseases: An Overview of Experimental Evidence and Understanding Their Mechanisms of Action

Figures & data

Figure 1 Parts of the cardiovascular system and their functions. The upper two (or atria) chambers operate mainly as chambers for collection, while the lower two chambers (ventricles) are considerably stronger and are used to provide blood. The right atrium and ventricle are responsible for collecting blood from the body and pumping it to the lungs. Blood is collected from the lungs and pumped throughout the body by the left atrium and ventricle. The heart has a one-way flow of blood, which is maintained by a series of four valves. The tricuspid and bicuspid atrioventricular valves allow blood to pass only from the atria to the ventricles. Only blood from the ventricles can flow out of the heart through the semilunar valves (pulmonary and semilunar).³ In other side, it should be noted that in addition to pumping oxygen-rich blood into body tissues, the blood also circulates many other important substances for oxygen exchange for carbon dioxide. As example, digestive nutrients are collected from the small intestine and pumped into all the cells in the body by the circulatory system. The circulatory system transports waste materials from cells into the kidneys, extracted and transmitted into the bladder. An important function of the heart in this matter is the pumping of interstitial blood fluid into the extracellular space. The circulatory system then returns excess interstitial fluid through the lymphatic system.³ The heart is a rhythmic electromechanical pump as its performance is dependent on the formation and propagation of action potentials, followed by relaxation and a period of refractoriness before the next impulse is created. The inward of Na⁺ current and outward of K⁺ current carrying ion channels are sequentially activated and inactivated in myocardial action potentials. Due to variances in Na⁺, Ca²⁺, and K⁺ channel expression in different parts of the heart, action potential waveforms are diverse, and these differences contribute to the normal, unidirectional transmission of activity and the formation of normal cardiac rhythms.¹⁵⁴

Table 1 List of CVDs and Their Pathophysiology

Disorder/Disease	Causative Factor	Pathophysiology	Reference
Cerebrovascular disease (stroke)	Cerebral haemorrhage and ischemia	The narrowing of veins due to atherosclerosis causes thrombosis, which reduces blood flow. Plaque build-up gradually narrows the vascular chamber, causing clots and thrombotic stroke. Haemorrhagic stroke is the most common type of stroke, accounting for 10–15% of all strokes and having a high fatality rate. Blood vessels break due to tension in the tissue and internal harm in this illness. It has harmful effects on the vascular system, which can lead to infarction.	Kuriakose and Xiao,^Citation144 Markus^Citation145
Heart attacks	Smoking and coronary artery disease (CAD)	Plaque, a waxy substance that accumulates inside the lining of major coronary arteries, can block blood flow in the heart’s large arteries partially or entirely. An illness or injury that changes the way the heart’s arteries function might cause some types of this illness. Ischemia and subsequent myocardial infarction occur when a cardiac artery is fully blocked, resulting in a lack of oxygen and nutrients.	Libby and Theroux^Citation146
Raised blood pressure (hypertension)	Elevated serum cholesterol, salt intake, glucose intolerance, obesity, and stress.	Systemic vascular resistance, vascular stiffness, and vascular response to stimuli are all elevated.	Foëx and Sear^Citation147
Rheumatic heart disease	Congenital heart disease (CHD), mitral valve prolapse (MVP), acquired valve disease and changes in the valve of heart.	Cross-activation of antibodies and/or T cells directed against human proteins is caused by structural similarities between the infectious agent and human proteins. This cross-reactive immune response in acute rheumatic fever (ARF) causes rheumatic fever-like symptoms. It can affect many connective tissues in the heart that leads to inflammation.	Carapetis et al,^Citation148 Cunningham,^Citation149 Kumar and Tandon^Citation150
Heart failure	Valvular heart disease, hypertension, viral myocarditis, atrial fibrillation, alcohol, coronary artery disease, arrhythmias and pericardial disease.	This is characterized by the heart’s inability to pump enough blood into the circulation during systole, which is known as left ventricular systolic dysfunction. The most common test for left ventricular systolic function is echocardiography, with an ejection fraction of 40% suggesting compromised left ventricular systolic function. Furthermore, heart failure with preserved left ventricular ejection fraction (PLVEF) or “diastolic” heart failure can arise in patients with adequate left ventricular systolic function who require higher filling pressures to achieve a normal end-diastolic volume of the left ventricle.	Mosterd and Hoes^Citation151
Congenital heart disease	Maternal rubella infection, maternal systemic lupus erythematosus (SLE), maternal diabetes, Down’s Syndrome and Turner’s Syndrome.	This mechanism of damage results in pulmonary vascular endothelial damage and the destruction of endothelial barrier function. This activates vascular elastase and matrix metalloproteinases, causing extracellular matrix degradation and fibroblast growth factor (FGF) and transforming growth factor β1 (TGF-β1) release. Smooth muscle cell hypertrophy and proliferation, as well as the creation of neo-intima, are all caused by such release. Overall incidence increases asymmetrical septal hypertrophy.	Pascall and Tulloh^Citation152

Figure 2 Nutritional fruits conferring protection against CVDs.

Figure 3 Bioactive compounds present in apple (Malus domestica) and its cardioprotective effects. Apple polyphenols are abundant in the flesh and peel of the fruit and contribute to the improvement of blood pressure, endothelial function, and arterial stiffness in those at increased risk of cardiovascular disease (CVDs). A healthy heart permits blood to be pumped out via a network of blood channels known as arteries. The left side of the heart takes oxygen-rich blood from the lungs and pumps it out via a big artery called the aorta, while deoxygenated blood returns to the heart via blood vessels called veins. However, atherosclerosis, a buildup of plaque inside the arterial walls, may cause the arteries to narrow, making blood circulation more difficult. The combination of hypertension and atherosclerosis will eventually result in more significant issues such as myocardial infection, more often referred to as a heart attack.

Figure 4 Bioactive compounds found in avocados (Persea americana) and their influence on lipid and cholesterol levels. Avocados have a wide range of anticancer, antioxidant, and cardioprotective properties, including reducing cholesterol levels, due to the compounds contained in the seed (endocarp), the pulp (mesocarp), and peel (exocarp). Increased lipid and cholesterol levels contributed to the development of heart disease by clogging the arteries with fatty streaks. Avocado fruit and oil consumption reduces blood TG, LDL, VLDL levels. The mechanism of action involves inhibition of cholesterol synthesis. Avocado bioactive components such as quercetin may have the ability to decrease cholesterol levels via modulating HMG-CoA and SREBP.

Abbreviations: TG, triglycerides; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; SREBP, sterol regulatory element-binding protein-2.

Figure 5 Bioactive compounds present in grapes (Vitis vinifera) and its mechanisms of action in cardioprotection. Grape extracts significantly reduced cardiac and brain ischemia-induced oxidative stress. Grapes contain compounds that assist avoid oxidative stress, thus resulted in a significant impact on blood lipids such as decreasing LDL-oxidation (LDL-ox) and substantially enhance endothelial function. Additionally, it contributes to platelet aggregation inhibition, inflammation, and blood pressure reduction by decreasing endothelin-1 (ET-1) secretion and increasing endothelial nitric oxide synthase (eNOS) levels.

Abbreviations: IL-10, interleukin-10; TGF-ß, transforming growth factor beta; M-CSF, macrophage-colony stimulating factor; COX, cyclooxygenase; LOX, lipoxygenase; NFkB, nuclear factor kappa B, IL-35, Interleukin 35; VCAM-1, vascular cell adhesion protein 1; IL-6, Interleukin 6; IL-12, Interleukin 12; IL-1 β, Interleukin 1 beta; PI3K/NO/cGMP/PKG, phosphoinositide 3-kinases/nitric oxide/cyclic guanosine monophosphate/protein kinase-G; PI3K-AKT, phosphoinositide 3-kinases/protein kinase B; ERK1/2, extracellular regulated kinase 1/2; GSK-3β, glycogen synthase kinase-3β.

Figure 6 Bioactive compounds and cardioprotective effects of Mango (Mangifera indica). Mango has a high concentration of well-known bioactive components, such as vitamin C, carotenoids, and polyphenols. The strong oxidative impacts of reactive oxygen species (ROS) have been demonstrated to cause damage to biological molecules (eg, proteins, lipids, and nucleic acids) via structural and functional alterations. One of the phenolic compound present, Mangiferin which is highly abundant in Mango, have claimed to be important nutritional antioxidants in preventing and treating several chronic disorders, specifically CVDs by blocking the activation of pro-apoptotic signals, AGE, TNF-α, ROS and lipid peroxidation.

Abbreviations: AGE, advanced glycation end products; TNF-α, tumour necrosis factor α; Bcl-2, B-cell lymphoma 2; Bax, Bcl-2-associated X protein; t-Bid truncated Bid; Cyto C, cytochrome complex; poly (ADP-ribose) polymerase (PARP); PKCs, protein kinase C isoforms; MAPKs, mitogen-activated protein kinases; NF-kB, nuclear factor kappa B.

Figure 7 Bioactive compounds and protective effects of orange (Citrus sinensis) in on the monoamine oxidase (MAO) activity, phosphodiesterase (PDE) activity, and angiotensin-converting enzyme (ACE) activity in the heart. Orange extract/juice contains compounds that helps in modulation of the renin-angiotensin-aldosterone system (RAAS) thus helps in lowering the diastolic and systolic blood pressure.

Table 2 Mechanism of Action of Nutritional Fruits Against CVDs

Nutritional Fruits	Mechanism of Action	Reference
Apple	Protection of Vascular Endothelial Function •By improving endothelial function Blood Pressure Modulation •By maintaining pulse rate and systolic blood pressure Inflammation Reduction •By lowering CRP level in the body •By decreasing stroke mortality •By decreasing serious stomach aortic calcification Reduction of Cholesterol Levels •By decreasing TC and LDL levels •By increasing HDL levels	Bondonno et al,^Citation23 Hodgson et al,^Citation22 Ravn-Haren et al,^Citation25 Sandoval-Ramírez et al,^Citation21 Serra et al,^Citation29 Gonzalez et al^Citation30
Avocado	Platelet-Inhibiting Functions •By acting as anti-platelet and anti-thrombotic agents Thrombosis Suppression •By increasing coagulation times •By reducing thrombus formation Blood Pressure Modulation •By inducing bradycardia, vasorelaxation and hypotension Inflammation Reduction •By decreasing the levels of high-sensitivity CRP •By preventing the development of metabolic syndrome Reduce Cholesterol Level •By increasing serum HDL-c concentrations •By decreasing TG, VLDL and LDL levels	Carvajal-Zarrabal et al,^Citation33 Gouegni and Abubakar,^Citation39 Mahmassani et al,^Citation32 Park et al,^Citation36 Rodriguez-Sanchez et al,^Citation38 Dabas et al^Citation40
Grapes	Lipid-Metabolism Regulation •By exerting a positive effect on blood lipids •By inhibiting LDL oxidation Protection of Vascular Endothelial Function •By improving endothelial function Platelet-Inhibiting Functions •By inhibiting human platelet aggregation Blood Pressure Modulation •By preventing the production of high blood pressure •By protecting from hypertension Oxidative Stress Reduction •By increasing antioxidant levels Inflammation Reduction •By preventing some inflammatory-mediated diseases	Borde et al,^Citation53 Godse et al,^Citation54 Leifert and Abeywardena,^Citation57 Resende et al,^Citation51 Shanmuganayagam et al,^Citation45 Quiñones et al,^Citation52 Leibowitz et al,^Citation49 Luzak et al,^Citation50 Quintieri et al,^Citation55 Safwen et al^Citation44
Mango	Lipid-Metabolism Regulation •By reducing lipid levels in the induced dyslipidaemia model •By reducing the risk factors of hyperglycaemia, HF diet, dyslipidaemia and visceral adiposity •By increasing serum HDL-c in the hyperlipidaemic model Oxidative Stress Reduction •By enhancing antioxidant activity Reduce Cholesterol Level •By preventing the rapid onset of the atherosclerotic process	Fidrianny et al,^Citation60 Prabhu et al;^Citation61 Lobo et al^Citation62
Orange	Lipid-Metabolism Regulation • By inhibiting the production of Fe^2+-induced malondialdehyde in a concentration-dependent manner • By enhancing the lipid profile and peroxidation Blood Pressure Modulation • By reducing diastolic and systolic blood pressures Oxidative Stress Reduction • By enhancing antioxidant activity • By preventing oxidative damage Inflammation Reduction • By inhibiting MAO, PDE and ACE activities	Ademosun and Oboh,^Citation64 Asgary and Keshvari,^Citation65 Castello et al^Citation66
Kiwi	Lipid-Metabolism Regulation • By improving plasma lipid levels • By reducing TG levels in the blood • By improving dietary lipid absorptions and reabsorptions, as it also contains soluble fibre Platelet-Inhibiting Functions • By reducing platelet reactivity to collagen and ADP • By inhibiting fibrinolysis activity Blood Pressure Modulation • By inhibiting ACE activity • By decreasing diastolic and systolic blood pressures Thrombosis Suppression • By improving the efficacy of thrombosis prophylaxis Reduction of Cholesterol Levels • By inhibiting HMG-CoA reductase • By improving apolipoprotein B/apolipoprotein A1 ratio • By improving plasma HDL-c and TC/HDL-c ratio • By preventing atherosclerosis	Duttaroy and Jørgensen,^Citation73 Iwasawa et al,^Citation72 Jung et al,^Citation76 Karlsen et al,^Citation79 Padmanabhan and Paliyath,^Citation78 Stonehouse et al^Citation74
Pomegranate	Lipid-Metabolism Regulation • By reducing aortic sinus and coronary artery atherosclerosis • By reducing lipid peroxidation levels Protection of Vascular Endothelial Function • By reducing hypertension, coronary artery disease and peripheral artery disease Blood Pressure Modulation • By reducing ACE activity • By relieving hypertension Ischemic or Reperfusion Reduction • Reducing cellular ATP/ADP ratio in cardiomyocytes Oxidative Stress Reduction • By enhancing phase II enzyme activity in high-fibre diet-induced cardiovascular disorders • By giving strong antioxidant effects • By increasing antioxidant defences Inflammation Reduction • Reducing arrhythmia • By improving mitochondrial function in the paraventricular nucleus • By reducing Ca^2+ ATPase levels Reduce Cholesterol Level • By acting as atheroprotective	Al-Jarallah et al,^Citation116 Cao et al,^Citation85 Haghighian et al,^Citation94 Jadeja et al,^Citation90 Mohan et al,^Citation83 Shao et al,^Citation93 Sun et al,^Citation89 Hajipour et al^Citation87
Papaya	Lipid-Metabolism Regulation • By reducing fat absorption • By treating lipid abnormalities at the prediabetic stage • By preventing prediabetes patients from getting diabetes mellitus type 2 • By improving lipid profile • By reducing triglyceride levels Blood Pressure Modulation • By reducing arterial blood pressure • By having potent anti-hypertensive properties • By inhibiting ACE activity • By reducing cardiac hypertrophy Oxidative Stress Reduction • By ameliorating free radicals-induced damage Inflammation Reduction • By preventing heart attacks and strokes as well as decreasing cholesterol levels • By preventing morbidity and death	Brasil et al,^Citation100 Gayosso-García et al,^Citation97 Hiraga et al,^Citation98 Santana et al,^Citation95 Wilson et al^Citation96
Pineapple	Platelet-Inhibiting Functions • By performing fibrinolytic activity Ischemic or Reperfusion Reduction • Reducing ischemic conditions in the reperfusion of the skeletal muscles. Oxidative Stress Reduction • By increasing antioxidant activity Thrombosis Suppression • By inhibiting blood platelet aggregation, minimising the risks from having arterial thrombosis and embolism • By reducing coagulation via the interference of fibrinogen and facilitation of a good blood flow through the vessels Inflammation Reduction • By protecting cell membrane integrity • By improving isoproterenol-induced cardiac systolic/diastolic dysfunction • By reducing the degree of myocardial damage Reduce Cholesterol Level • By breaking down cholesterol plaques	Juhasz et al,^Citation108 Neumayer et al,^Citation153 Saxena and Panjwani,^Citation104 Wali^Citation102
Watermelon	Lipid-Metabolism Regulation • By reducing body weight, BMI and waist-to-hip ratio Blood Pressure Modulation • By reducing systolic blood pressure • By improving vascular health in hypertensive patients Oxidative Stress Reduction • By increasing total antioxidant capacity Reduce Cholesterol Level • By reducing the levels of TG, LDL and TBARS • By increasing HDL levels	Jumde and Shukla,^Citation113 Connolly et al,^Citation111 Shanely et al,^Citation112 WHO^Citation114

Notes: All the abbreviations are available in the main text.

Figure 8 Possible mechanisms of action of nutritional fruits in protecting heart from CVDs.

Figure 9 Bioactive compounds and protective effects of kiwifruit (Actinidia deliciosa), pomegranate (Punica granatum), papaya (Carica papaya), pineapple (Ananas comosus) and watermelon (Citrullus lanatus). The mechanism of action involves reduction of thrombosis, atherosclerosis and blood pressure via lowering platelets’ responsiveness to collagen and ADP, reducing ACE activity, oxidative stress, inflammation and regulation of blood cholesterol levels.

Abbreviations: ADP, adenosine diphosphate; ACE, angiotensin-converting enzyme.

Figure 10 Drug delivery strategies use in cardiovascular diseases (CVDs) and proposed future perspectives of liposomes-based drug delivery. Atherosclerosis began as a lesion before a lipid layer or fatty streak formed within the intima. Leukocytes and smooth muscle cells migrate into the arterial wall, causing plague and extracellular matrix degradation. Liposomes can be loaded with hydrophilic and lipophilic bioactive substances, which may help decrease plague development. Injured endothelium secretes adhesion molecules during atherosclerosis, thus liposomes can be modified to conjugate with E-selectin-binding peptide (eg, E-selectin, and P-selectin). This combination of bioactive molecules and targeted ligands will further aid in decreasing atherosclerosis.

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