Good nutrition could maintain health and life. Polyphenols are common nutrient mainly derived from fruits, vegetables, tea, coffee, cocoa, mushrooms, beverages, and traditional medicinal herbs. They are potential substances against oxidative-related diseases, for example, cardiovascular disease, specifically, atherosclerosis-related ischemic heart disease and stroke, which are health and economic problems recognized worldwide. In this study, we reviewed the risk factors for atherosclerosis, including hypertension, diabetes mellitus, hyperlipidemia, obesity, and cigarette smoking as well as the antioxidative activity of polyphenols, which could prevent the pathology of atherosclerosis, including endothelial dysfunction, low-density lipoprotein oxidation, vascular smooth muscle cell proliferation, inflammatory process by monocytes, macrophages or T lymphocytes, and platelet aggregation. The strong radical-scavenging properties of polyphenols would exhibit antioxidative and anti-inflammation effects. Polyphenols reduce ROS production by inhibiting oxidases, reducing the production of superoxide, inhibiting OxLDL formation, suppressing VSMC proliferation and migration, reducing platelet aggregation, and improving mitochondrial oxidative stress. Polyphenol consumption also inhibits the development of hypertension, diabetes mellitus, hyperlipidemia, and obesity. Despite the numerous
Atherosclerosis-related ischemic heart disease (IHD) and stroke are the leading cause of morbidity or mortality worldwide for decades [
Reactive oxygen species (ROS) are generated as metabolic by-products by biological systems, including superoxide radicals (•O2−), hydrogen peroxide (H2O2), and hydroxyl radicals (•OH) [
ROS [
Polyphenols are common nutrient antioxidants, mainly derived from fruits, vegetables, tea, coffee, cocoa, mushrooms, beverages, and traditional medicinal herbs such as
The bioavailability of polyphenols predominantly depends on gut microflora activity [
Polyphenols are potential substances against cancers and cardiovascular, metabolic [
The current review focuses on the role of polyphenols and oxidative stress in atherosclerosis-related IHD and stroke. The keywords were entered “polyphenol and oxidative stress and atherosclerosis, or polyphenol and oxidative stress and ischemic heart disease, or polyphenol and oxidative stress and stroke.” Literature searches were performed using the Medicine, PubMed, EMBASE, Cochrane library, CINAHL, and Scopus databases. We exclude papers from nonabove databases or non-English-writing articles.
Hypertension is closely associated with atherosclerosis, which is related to IHD and stroke. One of the underlying mechanisms for the enhanced atherogenesis in hypertensive patients is oxidative stress [
Angiotensin II (AngII) is a significant factor in blood pressure regulation and is also involved in the process of atherosclerosis and in the remodeling through repairing processes of the myocardium following myocardial infarction [
In a randomized, single-blinded, and controlled trial with a 4-year follow-up, consumption of extravirgin olive oil significantly decreased diastolic blood pressure; however, no differences in systolic blood pressure changes were observed [
The relationship between oxidative stress and hypertension is noteworthy. Some animal studies have found that high blood pressure would be associated with increased oxidative stress [
Increasing ROS levels are an important trigger for insulin resistance [
Gut microbiota lipopolysaccharide (LPS) may translocate into the bloodstream and subsequently contribute to adipose tissue inflammation and oxidative stress, which in turn leads to insulin resistance [
Diabetic vasculopathy is characterized by abnormal angiogenesis [
Diabetes is a metabolic disease, and some comorbidities are related to IHD and stroke, such as hyperlipidemia, obesity, and hypertension. One randomized, placebo-controlled, double-blind study revealed that taking polyphenol-rich dark chocolate is effective in improving triglyceride levels in hypertensive patients with diabetes and in decreasing blood pressure and fasting blood sugar [
Hyperlipidemia is the most important risk factor for atherosclerosis [
AMP-activated protein kinase (AMPK) is an essential therapeutic target for obesity [
Because there are more thearubigins and theaflavins in black tea than in green tea, black tea extract could be more able to inhibit the emulsion of lipid droplets and reduce the surface area to decrease fat digestion [
Additionally, data show a good lipid excretion ability after polyphenol consumption. In subjects who had high-lipid diet, intake of polyphenol-enriched oolong tea increased lipid excretion in the feces [
Obesity is one of the most common nutritional diseases worldwide. According to the World Health Organization (WHO), obesity is a body mass index ≥ 30. In 2014, >1.9 billion adults, 18 years and older, were overweight. Of these, >600 million were obese [
Obesity results from a lipid metabolic imbalance and leads to fat accumulation in adipose tissues [
Green tea polyphenols may reduce leptin levels in the subcutaneous tissue of high-fat-diet-induced obese rats [
Cigarette smoking is associated with vascular endothelial dysfunction [
Smoking could induce the differentiation of monocytes into macrophages and a strong vascular proinflammatory response through upregulating endothelial proinflammatory genes, increasing the levels of proinflammatory cytokines, and activating matrix metalloproteinase. Being a strong vascular inflammatory primer, TS can accelerate the dysfunction of blood-brain barrier (BBB) and the loss of cerebral blood flow such as during ischemic stroke [
Cigarette smoking promotes glucose intolerance, increases the risk of developing type 2 diabetes mellitus, and thus is a leading high risk of cerebrovascular and neurological disorders like stroke via ROS generation, inflammation, and BBB impairment [
Cigarette smoking causes oxidative stress, hypertension, and endothelial dysfunction. Polyphenol-rich foods, which are good antioxidants, could prevent these conditions. Antioxidant supplementation reduced the oxidation and inflammation induced by TS in animals and cells [
Lining the interior surface of vessel cells, endothelial cells could play an essential role in homeostasis, immune, inflammation, cell adhesion, and regulation of thrombosis and fibrinolysis [
Endothelial dysfunction is often associated with increased oxidative stress [
Some articles showed hydroxytyrosol and the polyphenol extract from extravirgin olive oil may reverse the decreased endothelial NO synthase phosphorylation, intracellular NO levels, and increased ET-1 synthesis by the stimulation of ROS production with high glucose and linoleic and oleic acid levels. In addition, they also could revert the reduced NO and increased ET-1 levels by acetylcholine inducing with high glucose and free fatty acids [
Effects of polyphenols in endothelial cells and smooth muscle cells. AA: arachidonic acid; COX: cyclooxygenase; PGE2/H2/I2: prostaglandin E2/H2/I2; TXA2: thromboxane A2; eNOS: endothelial nitric oxide synthase; NO: nitric oxide; ET-1: endothelin-1; ETA/B: endothelin A/B receptor; LDL: low-density lipoprotein; PDGF: platelet-derived growth factor; NOX: NADPH oxidase; SOD: superoxidase dismutase; H2O2: hydrogen peroxide; GTP: guanosine triphosphate; sGC: soluble guanylate cyclase; cGMP: cyclic guanosine monophosphate; AngII: angiotensin II; AT1: angiotensin II receptor type 1; PPAR
The oxidation of low-density lipoprotein (LDL) is a complex process in which both the protein and the lipids undergo oxidative changes and form complex products. Oxidative stress and LDL oxidation might play a vital role in atherosclerosis, which has been studied for several years. Strong evidence about the close relationship between OxLDL and atherosclerosis exists [
All these reactions are oxidative in nature, and they are not uniformly amenable to inhibition by traditional antioxidants. Vitamin E or simple phenols, such as tyrosine or estradiol, actually enhance peroxidase-mediated LDL oxidation. Antioxidative ability and concentrations of antioxidants are positively related [
The term “French paradox” is first used in the newsletter of the International Organization of Vine and Wine in 1986. It says a high-fat diet with a low incidence of coronary atherosclerosis is due to moderate consumption of red wine. In 1991, Serge Renaud, a scientist from Bordeaux University, France, made a series of studies that strongly support the result [
Effects of polyphenols in LDL and inflammatory process with monocytes and macrophages. ROS: reactive oxygen species; LDL: low-density lipoprotein; OxLDL: oxidized low-density lipoprotein; MCP-1: monocyte chemoattractant protein 1; iNOS: inducible nitric oxide synthase; TNF-
VSMCs contribute to the pathogenesis of atherosclerotic lesions; their proliferation and migration are critical events for progressive intimal thickening and arterial wall sclerosis development. Platelet-derived growth factor (PDGF) is the most potent chemotactic and mitogenic agent for VSMCs at the atherosclerotic lesions. They are released by platelets, endothelial cells, and VSMCs themselves. PI3K [
Attenuation of the signals leading to VSMC proliferation and migration could also be a consequence of PDGF
As discussed in Section
Macrophages play a key role in atherogenesis through their proinflammatory action, which involves the production of IL-1 and tumor necrosis factor, and following more specific adaptive responses mediated by T cells [
The unsaturated aldehyde acrolein is proatherogenic. Acrolein exposure increases intracellular oxidative stress and stimulates cholesterol and triglyceride accumulation via enhanced biosynthesis rates and overexpression of key regulators of cellular lipid biosynthesis. Acrolein also demonstrates a major shift in the gut microbiota composition wherein a significantly increased prevalence of Ruminococcaceae and Lachnospiraceae, of which the
Platelet could maintain the hemostasis of the circulatory system [
Polyphenols, such as resveratrol, have antithrombotic effects, which could be attributed to reduced susceptibility to platelet activation and aggregation, reduced synthesis of prothrombotic mediators (eicosanoid synthesis), and decreased gene expression of tissue factor. Resveratrol has been shown to inhibit, in a concentration-dependent manner, platelet aggregation induced by collagen, ADP, and thrombin. Mattiello et al. compared the effect of pomegranate juice and that of the polyphenol-rich extract from pomegranate fruit on platelet aggregation, calcium mobilization, thromboxane A2 production, and hydrogen peroxide formation induced by collagen and arachidonic acid. Both the pomegranate juice and extract reduced all platelet responses, with the latter showing a stronger effect [
Cocoa and dark chocolate have been shown to prevent platelet aggregation by reducing ADP-, adrenaline-, and epinephrine-induced glycoprotein IIb/IIIa (GPIIb/IIIa) membrane activation; ADP-induced P-selectin membrane expression; and phospholipase A2 (PLA2) and cyclooxygenase activity [
Effects of polyphenols in platelets. ADP: adenosine diphosphate; NO: nitric oxide; TXA2: thromboxane A2; GP1b: glycoprotein Ib; GPIIb/IIIa: glycoprotein IIb/IIIa; vWF: Von Willebrand factor; PDGF: platelet-derived growth factor.
Risk factors and pathology process of atherosclerosis leading to ischemic heart disease or ischemic stroke.
Mechanisms of polyphenols in preventing atherosclerosis formation.
Pathology of atherosclerosis | Polyphenols/polyphenol-rich food | Preventing mechanism | Reference |
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Endothelial dysfunction | Hydroxytyrosol and EVOO polyphenol extract | ↑ eNOS phosphorylation, ↑ NO |
[ |
High- versus low-dose flavonoid dark chocolate (213 mg versus 46 mg procyanidins) | ↑ endothelium-dependent flow-mediated dilation of the brachial artery |
[ | |
Red wines and grapes | ↑ NO activity |
[ | |
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OxLDL | Red wine | ⊝ copper-catalyzed oxidation of LDL | [ |
(−)-Epicatechin gallate-enriched |
↓ OxLDL-dependent apoptosis | [ | |
Green tea catechins | Incorporated into LDL particles in nonconjugated forms |
[ | |
|
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VSMC proliferation |
Red wine | ⊝ inhibition of PDGF |
[ |
Pterostilbene, polyphenol compound in blueberries | ↓ VSMC migration |
[ | |
Resveratrol | ↑ serum BDNF concentrations |
[ | |
Curcumin | ↓ expression of p47phox |
[ | |
|
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Monocyte/macrophage and T lymphocytes inflammatory process | Tea flavonoids (theaflavin digallate, theaflavin, epigallocatechin gallate, epigallocatechin, and gallic acid) | ↓ cell-mediated LDL oxidation |
[ |
Pomegranate juice | ⊝ acrolein increases macrophage lipid accumulation and alters the gut microbiota composition | [ | |
Ellagic acid | ⊝ tautomerase activity of human macrophage MIF |
[ | |
Polyphenol-rich extract | ↓ MCP-1 |
[ | |
Resveratrol, isorhamnetin, curcumin, vanillic acid, and specific (poly)phenol mixtures | ↓ IL-6, interferon- |
[ | |
|
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Platelet aggregation | Pomegranate juice or the polyphenol-rich extract from pomegranate fruit | ⊝ collagen- and arachidonic acid-induced platelet aggregation |
[ |
Cocoa and dark chocolate | ↓ ADP-, adrenaline- and, epinephrine-induced GPIIb/IIIa membrane activation |
[ |
↑: increase; ↓: decrease; ↔: no change; ⊝: inhibit; ⊕: promote. EVOO: extra virgin olive oil; eNOS: endothelial nitric oxide synthase; NO: nitric oxide; ET-1: endothelin-1; LDL: low-density lipoprotein; ROS: reactive oxygen species; Erk: extracellular-signal-regulated kinase; PDGF: platelet-derived growth factor; VSMCs: vascular smooth muscle cells; MMP-2: matrix metalloproteinase-2; BDNF: brain-derived neurotrophic factor; MIF: migration inhibitory factor; MCP-1: monocyte chemoattractant protein 1; H2O2: hydrogen peroxide; ADP: adenosine diphosphate; GPIIb/IIIa: glycoprotein IIb/IIIa; PLA2: phospholipase A2; COX: cyclooxygenase; 8-iso-PGF2
Isoflavone in soybeans has antiatherosclerotic property to reduce risk of coronary artery disease and stroke in women [
A prospective study of forty healthy volunteer women consumed 200 g of açai (one polyphenol-rich fruit which is native to the Brazilian Amazon region) pulp/day for 4 weeks and the result showed açai consumption increased the transfer of cholesteryl esters to high-density lipoprotein and decreased ROS and OxLDL [
Cardio-ankle vascular index reflects arterial stiffness which related to atherosclerosis [
Plasminogen activator inhibitor type 1 levels are associated with thrombus formation and increased risk of atherosclerosis [
Lekakis et al., in his randomized controlled study of 30 male patients with coronary heart disease, demonstrated that grape polyphenol extract increases flow-mediated dilatation, peaking at 60 min, which was significantly higher than the baseline values or than that of water intake (placebo) [
Green tea polyphenols can inhibit H2O2− induced oxidative stress through the Akt/GSK-3
In a UK women’s cohort study, total fruit intake, especially polyphenol-rich fruit group such as grapes and citrus, was associated with lower risk of CVD and coronary heart disease mortality, with a 6-7% risk reduction for every 80 g/day portion consumed [
According to the WHO, cerebrovascular diseases are the second leading cause of death worldwide and the major cause of disability in adults [
Resveratrol provides protection from cerebral ischemic injury by regulating the expression of silent mating type information regulation 2 homolog 1 (SIRT1). Wan et al. proved that resveratrol provides neuroprotection by inhibiting phosphodiesterase and regulating the cAMP, AMPK, and SIRT1 pathways, which reduces ATP energy consumption during ischemia [
Wang et al. published a meta-analysis confirming that diets rich in flavonols (intake of 20 mg/day) was associated with a 14% decrease in the risk of developing stroke, specifically among men [
In the result of the study, polyphenol or polyphenol-rich diets exhibit antioxidative and anti-inflammation effects. Polyphenols reduce ROS production through inhibiting oxidases, reducing the production of superoxide, inhibiting OxLDL formation, inhibiting VSMC proliferation and migration, reducing platelet aggregation, and ameliorating mitochondrial oxidative stress. Polyphenol consumption also improves developing into hypertension, diabetes mellitus, hyperlipidemia, and obesity. However, in accordance with in vitro and in vivo laboratory evidence, well-designed clinical studies are necessary to confirm the efficacy of polyphenols in the treatment of atherosclerosis-related IHD and stroke.
Ischemic heart disease
Reactive oxygen species
Superoxide radicals
Hydrogen peroxide
Nitric oxide
Endothelial nitric oxide synthase
Inducible nitric oxide synthase
Oxidized low-density lipoprotein
Low-density lipoprotein
Vascular smooth muscle cells
Nitric oxide synthase
Angiotensin II
Nicotinamide adenine dinucleotide phosphate
Nuclear factor kappa B
NADPH oxidase
Lipopolysaccharide
Proliferator-activated receptor gamma
Manganese superoxide dismutase
Vascular endothelial growth factor
Fatty acid synthase
Epidermal growth factor
Phosphatidylinositol-3-kinase
Protein kinase B
AMP-activated protein kinase
Theaflavin-3,3
Forkhead box O3A
World Health Organization
Blood-brain barrier
Nuclear factor erythroid 2-related factor
Interleukin-1
Tumor necrosis factor-
Mitogen-activated protein kinase
Endothelin-1
Platelet-derived growth factor
Matrix metalloproteinase-2
Brain-derived neurotrophic factor
Migration inhibitory factor
Monocyte chemoattractant protein 1
Adenosine diphosphate
Epinephrine-induced glycoprotein IIb/IIIa
Phospholipase A2
Myocardial infarction
Cardiovascular disease
Mediterranean diet
Extravirgin olive oil
Silent mating type information regulation 2 homolog 1
Nerve growth factor.
The authors declare no conflict of interest.
Yu-Chen Cheng drafted the manuscript. Jer-Ming Sheen, Wen Long Hu, and Yu-Chiang Hung supervised the drafting of the manuscript. Yu-Chen Cheng and Yu-Chiang Hung contributed equally to this work. All the authors read and approved the final draft of the manuscript.