# Antioxidant Food Components for the Prevention and Treatment of Cardiovascular Diseases: Effects, Mechanisms, and Clinical Studies

Authors: Dan-Dan Zhou; Min Luo; Ao Shang; Qian-Qian Mao; Bang-Yan Li; Ren-You Gan; Hua-Bin Li
Journal: Oxidative Medicine and Cellular Longevity
 (2021)

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## Abstract

Cardiovascular diseases (CVDs) have gained increasing attention because of their high prevalence and mortality worldwide. Epidemiological studies revealed that intake of fruits, vegetables, nuts, and cereals could reduce the risk of CVDs, and their antioxidants are considered as the main contributors. Moreover, experimental studies showed that some antioxidant natural products and their bioactive compounds exerted beneficial effects on the cardiovascular system, such as polyphenols, polysaccharides, anthocyanins, epigallocatechin gallate, quercetin, rutin, and puerarin. The mechanisms of action mainly included reducing blood pressure, improving lipid profile, ameliorating oxidative stress, mitigating inflammation, and regulating gut microbiota. Furthermore, clinical trials confirmed the cardiovascular-protective effect of some antioxidant natural products, such as soursop, beetroot, garlic, almond, and green tea. In this review, we summarized the effects of some antioxidant natural products and their bioactive compounds on CVDs based on the epidemiological, experimental, and clinical studies, with special attention paid to the relevant mechanisms and clinical trials.


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## Body

## 1. Introduction

Cardiovascular diseases (CVDs), such as coronary heart disease (CHD), hypertensive heart disease, heart failure, and stroke, are the leading cause of death worldwide [1]. CVDs could be caused by hypertension, dyslipidemia, atherosclerosis, oxidative stress, inflammation, and enteric dysbacteriosis [2–4]. Several synthetic drugs have been used to treat CVDs, but they showed some adverse effects, such as gastrointestinal reaction, hyperkalemia, and arrhythmias [5, 6]. On the other hand, accumulating evidence has shown that some antioxidant natural products could be a safe and effective alternative for the prevention and treatment of CVDs [7–11].Natural products are rich in dietary fibers, polyphenols, vitamins, minerals, and other beneficial components, and possess many bioactivities, such as antioxidant, anti-inflammatory, anticancer, antidiabetic, antiobesity, hepatoprotective, immunoregulatory, antibacterial, and cardiovascular-protective effects [12–20]. Epidemiological studies found that people consuming more fruits, vegetables, teas, cereals, and nuts had a lower risk of CVDs, and the antioxidants in these natural products were considered as the main contributors [21–23]. Additionally, experimental researches showed that some antioxidant natural products and their active compounds could prevent and treat CVDs through different mechanisms of action [24–32]. Furthermore, clinical trials provided more reliable human evidence on some antioxidant natural products for the prevention and treatment of CVDs [33, 34]. The purpose of this review is to summarize the effect of some antioxidant natural products and their bioactive compounds on CVDs from the results of epidemiological, experimental and clinical studies in the last five years, and special attention was paid to the mechanisms of action and clinical trials.


## 2. Epidemiological Studies

Increasing epidemiological studies have suggested that the intake of some antioxidant natural products significantly attenuated the risk factors of CVDs (Table1).Table 1
The effects of antioxidant natural products on CVDs from epidemiological studies.
PlantsComponentsStudy typeSubjectsResultsRef.FruitNACohort study512,891 ChineseLowering SBP and blood glucose, reducing the risks of cardiovascular death (HR: 0.60; 95% CI, 0.54-0.67), incident major coronary event (HR: 0.66; 95% CI, 0.58-0.75), ischemic stroke (HR: 0.75; 95% CI, 0.72-0.79), and hemorrhagic stroke (HR: 0.64; 95% CI, 0.56-0.74)[38]FruitNACross-sectional study1,590 adultsLow fruit consumption was associated with increased BP in 50–59-year-old group (PR: 1.62; 95% CI, 1.09-2.41)[43]FruitAnthocyanin, flavanoneCohort study43.880 healthy menHigher anthocyanin intake was inversely associated with nonfatal myocardial infarction (HR: 0.87; 95% CI, 0.75-1.00). Higher flavanone intake was inversely associated with ischemic stroke (HR: 0.78; 95% CI, 0.62-0.97).[44]FruitFlavoneCross-sectional study7,963 women aged ≥30 yearsInversely associated with SBP, TG, and TG/HDL-C.[45]FruitNACohort study70,047 Chinese adults with CVD or hypertensionInversely associated with CVD mortality (HR: 0.79; 95% CI, 0.73-0.86)[46]FruitNACross-sectional study9,040 subjects aged ≥25 yearsInversely associated with CVD (OR: 0.86; 95% CI, 0.74-0.98)[47]VegetableNACross-sectional study18,757 adolescentsConsuming ≥3 servings of vegetables lowered the risk of hypertension (OR: 0.74; 95% CI, 0.58-0.94)[35]VegetableNitrateCohort study2,229 Australian aged ≥39 yearsInversely associated with CVD mortality (comparison of <69.5 mg/day intake of vegetable, 69.5-99.6 mg/day (HR: 0.53; 95% CI, 0.35-0.82), 99.7-137.8 mg/day (HR: 0.51; 95% CI, 0.32-0.80), and >137.8 mg/day (HR: 0.63; 95% CI, 0.41-0.95))[48]Allium vegetableNACohort studyAdult men and womenAssociated with a 64% reduced risk of CVD outcomes (HR: 0.36; 95% CI, 0.18-0.71)[39]NutNACohort study16,217 participants with diabetes mellitusInversely associated with the total CVD incidence (HR: 0.83; 95% CI, 0.71-0.98), CHD incidence (HR: 0.80; 95% CI, 0.67-0.96), and CVD mortality (HR: 0.66; 95% CI, 0.52-0.84)[49]NutNA3 large cohort studies76,364 women92,946 women41,526 menInversely associated with the total CVD (HR: 0.86; 95% CI, 0.79-0.93) and CHD (HR: 0.80; 95% CI, 0.72-0.89)[50]NutNA3 large cohort studies34,103 men77,815 women80,737 womenInversely associated with CVD (RR: 0.92; 95% CI, 0.86-0.98), CHD (RR: 0.94; 95% CI, 0.89-0.99), and stroke (RR: 0.89; 95% CI, 0.83-0.95)[51]NutNACohort study61,364 Swedish adultsInversely associated with risk of heart failure and atrial fibrillation1-3 times/month: heart failure (HR: 0.87; 95% CI, 0.80-0.94) and atrial fibrillation (HR: 0.97; 95% CI, 0.93-1.02)1-2 times/week: heart failure (HR: 0.80; 95% CI, 0.67-0.97) and atrial fibrillation (HR: 0.88; 95% CI, 0.79-0.99)3 times/week: heart failure (HR: 0.98; 95% CI, 0.76-1.27) and atrial fibrillation (HR: 0.82; 95% CI, 0.68-0.99)[42]LegumeNACohort study6,504 Iranian middle-aged and older peopleInversely related to the risk of CVD events in old-aged Iranians (HR: 0.66; 95% CI, 0.45-0.98) but not in middle-aged Iranians[52]Curry (turmeric)CurcuminCross-sectional studyIndividuals aged 19-64 yearsLowering blood glucose and TG levels[37]Fruit, vegetableNACross-sectional study1,596 adolescents and young people in Tanzania and UgandaLowering the risk of hypertension (OR: 0.7; 95% CI, 0.50-0.98)[53]Fruit, vegetableNACross-sectional study229 patients with primary hypertensionLowering BP, heart rate, and BMI[54]Fruit, vegetableNACohort study2,354 Ugandan newbornsLowering BP[21]Fruit, vegetableNACohort study8,997 aging subjectsFruit intake was inversely associated with BP but vegetable intake was not[55]Fruit, whole grainFiberCohort study17,007 young Mediterranean participantsFruit (HR: 0.51; 95% CI, 0.27-0.95) or whole grain (HR: 0.43; 95% CI, 0.20-0.93) intake was inversely associated with CVD events.[40]Fruit, vegetable, cerealFiberCross-sectional study18,433 American adultsTotal fiber (OR: 0.62; 95% CI, 0.52-0.75), cereal fiber (OR: 0.80; 95% CI, 0.69-0.98), and vegetable fiber (OR: 0.82; 95% CI, 0.69-0.98) were inversely associated with the risk of hypertension, but fruit fiber was not[36]Fruit, vegetable, legume, grain, nutFiberCohort study2,295 health professionalsLegume fiber (HR: 0.31; 95% CI, 0.15-0.65), fruit fiber (HR: 0.44; 95% CI, 0.22-0.89), and vegetable fiber (HR: 0.34; 95% CI, 0.16-0.72) were inversely associated with the CVD risks, but grain and nut fiber were not[41]Note. NA: not available; CVD: cardiovascular disease; CHD: coronary heart disease; HR: hazard ratio; PR: prevalence ratio; OR: odds ratio; RR: relative ratio; CI: confidence interval; BW: body weight; BP: blood pressure; SBP: systolic blood pressure; TG: triglyceride; BMI: body mass index; HDL-C: high-density lipid protein cholesterol.Several cross-sectional studies found that some dietary plants were beneficial for the prevention and management of CVDs. For instance, a cross-sectional study of 18,757 Chinese adolescents aged 13-17 years revealed that daily intake of at least 3 servings of vegetables (1 serving of vegetable was the size of an adult’s fist) lowered the risk of hypertension (oddsratioOR=0.74; 95% confidence interval (CI): 0.42-0.95) compared with daily consumption of vegetable <1 serving [35]. Additionally, an analysis of 18,433 American adults found that compared with the lowest tertile consumption of cereals, vegetables, and fruit fibers as well as their total fiber, the OR (95% CI) of hypertension for the highest tertile were 0.80 (0.69-0.98), 0.82 (0.69-0.98), 0.86 (0.71-1.04), and 0.62 (0.52-0.75), respectively, indicating that cereals, vegetables, and total fibers were inversely related with hypertension, but fruit fiber was not [36]. Moreover, the data from the Korea National Health and Nutrition Examination Survey showed that overweight older males and younger females who consumed a moderate amount of curry (2-3 times a month or once a week), mainly composed of turmeric, had significantly lower levels of blood glucose and triglyceride (TG) than a group who had low curry consumption (almost never, or once a month) [37].A negative correlation between the intake of several edible plants and the incidence as well as mortality of CVDs was also observed in some cohort studies. A follow-up study recruiting 521,891 Chinese adults aged 30-79 years reported that participants who consumed fresh fruit daily had lower systolic blood pressure (SBP) and blood glucose level compared to those who never or rarely ate fresh fruit. The HR (95% CI) for cardiovascular death, incident major coronary events, ischemic stroke, and hemorrhagic stroke were 0.60 (0.54-0.67), 0.66 (0.58-0.75), 0.75 (0.72-0.79), and 0.64 (0.52-0.74), respectively, elucidating the protective effect of fresh fruit on the cardiovascular system [38]. Moreover, another analysis of 3,052 adults indicated that the habitual consumption of allium vegetables, such as garlic and onion, was related to a 64% decreased risk of CVD outcomes (HR=0.36; 95% CI: 0.18-0.71) [39]. Additionally, a cohort study of young Mediterranean populations found that compared to the lowest quintile of fruit intake or whole grain intake, the HR (95% CI) of the risk of CVD events for the highest quintile were 0.51 (0.27-0.95) and 0.43 (0.20-0.93), respectively, showing the benefits of fruit or whole grain to prevent CVDs [40]. Furthermore, a prospective study of 2,295 Iranian adults pointed out that compared to the lowest tertile of dietary fiber intakes from grains, legumes, nuts, fruits, and vegetables, the hazard ratios (HR) (95% CI) of CVD risks for the highest tertile were 0.90 (0.44-1.86), 0.31 (0.15-0.65), 0.49 (0.24-1.02), 0.44 (0.22-0.89), and 0.34 (0.16-0.72), respectively, suggesting that dietary fiber from legumes, fruits, and vegetables were negatively related to CVDs, while fiber from grains and nuts had no significant association with CVDs [41]. However, a cohort study found that nut intake significantly lowered the risk of CVDs [42]. The reason could be that it was not fiber but other bioactive compounds in nuts that play a vital role in the prevention of CVDs, or that there were disparities of population, study design, and confounding factors in different studies, which need to be further investigated in the future.In short, the collected epidemiological investigations illuminated the protective effects of some antioxidant natural products and their bioactive components on CVDs, although there were inconsistent results. In addition, based on the beneficial role of some plants in CVDs, it is advisable to increase the intake of some plant-based foods, such as fresh fruits, vegetables, legumes, cereals, and nuts, to reduce the risk of CVDs.


## 3. Experimental Studies

Many experimental studies investigated the effects of some antioxidant natural products and their bioactive compounds on CVDs (Table2), and the relevant mechanisms are discussed below (Figure 1).Table 2
The effects of antioxidant natural products on CVDs from experimental studies.
PlantsComponentsStudy typeSubjectsDose & TimeEffects and mechanismsRef.Winged bean seedPeptideIn vitroIn vivoACE and SD rats1 mM peptides, 3 h; 150 and 300 mg/kg BW, 24 hInhibiting ACE activityLowering BP[61]Solanum macrocarponPolyphenolsIn vitroIn vivoSHRs100 and 500 mg/kg BWInhibiting ACE/renin activitiesLowering DBP and heart rate[62]Citrus paradisi and Ocimum sanctumEpigallocatechin gallate and quercetinIn vivoSD rats2 g dried ground material in 200 mL water, 4 monthsReducing BP (renin and angiotensinogen↓) and reducing renal TG accumulation and lipid/protein oxidation (Citrus paradisi)Reducing BP via other mechanisms (Ocimum sanctum)[63]Pigeon peaProteinIn vitroIn vivoACE and SHRs100 mg/kg BW, 24 hInhibiting ACE/renin activities and scavenging free radicalsLowering BP[24]Ficus deltoidea var. KunstleriNAIn vivoSHRs500, 800, 1000, and 1300 mg/kg BW, 4 weeksLowering BP (ACE, angiotensin, aldosterone↓, and eNOS↑) and improving antioxidant capacity[97]Pueraria lobataPuerarinIn vivoSHRs40 and 80 mg/kg, 9 weeksLowering BP (eNOS, NO, and cGMP↑)[98]White mulberry fruitPolysaccharidesIn vitroIn vivoMesenteric artery and endothelial cells; SD rats and SHRs0.5 mg/mL; 5 mg/kg, 5 minInducing endothelium-dependent relaxation in rat mesenteric arteries and NO production in endothelial cellsLowering mean arterial BP[67]Grape seedPolyphenolsIn vivoHypertensive rats375 mg/kgLowering BP (eNOS and Sirtuin-1↑)[68]Morus albaRutinIn vitroIn vivoMesenteric arteries;wild-type and eNOS-deficient mice8 mg/mL; 100, 200, and 400 mg/kgInducing endothelial vasorelaxation via a NO-dependent pathwayDecreasing BP in wild-type mice, not in eNOS-deficient mice[66]Phyllanthus niruriNAIn vitroIn vivoEndothelium-intact/denuded aorta rings; SHRs0.125-4 mg/mL; 1000 mg/kg BW, 2 weeksInducing vasorelaxation on endothelium-intact aorta ringsDecreasing BP[99]Scutellaria baicalensis GeorgiBaicalinIn vitroIn vivoThoracic aortas; SHRs0.1 mg/mL; 10, 50, 100, and 200 mg/kg BW, 0, 30, 60, 90, and 120 minRelaxing SHR aortas in an endothelium-independent mannerReducing BP[100]Heliotropium strigosumPolyphenolsIn vivoDiabetic rabbits21 daysImproving lipid profile (TC, TG, and LDL-C↓) and lowering blood glucose[25]Mung bean sproutsNAIn vivoSD rats1 mL/200 g BW, 8 weeksLowering BP and improving lipid profile (LDL-C↓)[72]Red dragon fruitNAIn vivoSD rats4 weeksImproving lipid profile (TC, TG, and LDL-C↓) and lowering blood glucose[73]Red dragon fruit peelNAIn vivoHyperlipidemia male mice50, 100, 150, and 200 mg/kg BW, 30 daysImproving lipid profile (TC, TG↓, and HDL-C↑)[74]Citrus maximaNAIn vivoWistar rats300 and 600 mg/kg BW, 14 daysImproving lipid profile (TC, TG↓, and HDL-C↑), lowering blood glucose, and increasing BW[75]Bitter melonβ-SitosterolIn vivoHyperglycemia rats71.1 mg, 4 weeksImproving lipid profile (TC, TG, LDL-C, fecal cholesterol secretion, cholesterol absorption↓, and HDL-C↑) and lowering blood glucose[76]Dried chokeberryAnthocyaninsIn vivoSHRs50 mg/kg and 4 weeksAmeliorating oxidative stress (TBARS↓ and FRAP↑) and lowering SBP and pulse pressure[26]Sweet cherryPolyphenolsIn vivoWistar rats5% and 10% (w/w) in food (fruits); 1% and 3% (w/w) in food (leaves), 12 weeksDecreasing BW gain, ameliorating oxidative stress (SOD, GPx, CAT↑, and TBARS↓), and improving lipid profile (LDL-C+VLDL-C↓)[82]Wild riceNAIn vivoHyperlipidemic ratsNA and 8 weeksAmeliorating oxidative stress (TAC, SOD↑, and MAD↓), improving lipid profile (TG and TC↓), and mitigating inflammation (CRP and TNF-α↓)[80]Sambucus nigra L.PolyphenolsIn vivoWistar rats0.046 g/kg BW, 8 weeksAmeliorating oxidative stress (TAC↑), lowering BP, and improving lipid profile (HDL-C↑)[81]Nepeta deflersianaNAIn vivoWistar rats50 and 100 mg/kg BW, 25 daysAttenuating myocardial injuries, mitigating inflammation (TNF-α, IL-6, and IL-10↓), and improving oxidative stress (CAT, SOD, NO↑, and MDA↓)[29]SpinachNitrateIn vivoSwiss-Kunming mice15, 30, and 60 mg/kg of nitrate, 28 daysMitigating inflammation (CRP, TNF-α, and IL-6↓) and improving vascular endothelial function (NO↑ and endothelin-1↓), lipid profile (TC, TG, LDL-C↓, and HDL-C↑), and insulin resistance[88]Zygophyllum album rootsNAIn vivoWistar rats400 mg/kg BW, 60 daysAttenuating myocardial injuries, improving oxidative stress (MDA, PC↓, CAT, SOD, and GPx↑), and mitigating inflammation (TNF-α, IL-1β, IL-6, and nuclear factor-kappa B↓)[84]Spinacia oleraceaLuteinIn vivoWistar rats100, 200, and 300 mg/kg BWAmeliorating myocardial necrosis via mitigating inflammation (TNF-α, IL-1β and IL-6↓)[89]Antidesma buniusNAIn vivoSD rats0.38, 0.76, and 1.52 g/kg, 12 weeksImproving oxidative stress (MDA↓) and mitigating inflammation (TNF-α, IL-6, VCAM-1, and MCP-1↓)[90]Rice branProteinIn vivoSD rats250 and 500 mg/kg, 6 weeksLowering BP (ACE↓, NO, and eNOS↑) and reducing arterial stiffening, vascular remodeling, and oxidative stress (SOD and MDA↓)[83]Polygoni multiflori Radix2,3,5,4′-Tetrahydroxy-stilbene-2-O-beta-D-glucosideIn vivoApoE(-/-) mice1.125 mg/g, 8 weeksInhibiting atherosclerotic plaque formation, improving lipid profile (TG and ox-LDL↓), mitigating inflammation (TNF-α, IL-6, VCAM-1, and ICAM-1↓), and regulating gut microbiota composition (Firmicutes/Bacteroidetes, Akkermansia↑, Proteobacteria, Tenericutes, and Helicobacter pylori↓)[28]WasabiAllyl isothiocyanateIn vivoWistar rats5% (w/w) in food, 8 weeksRegulating gut microbiota composition to prevent the development of hypertension (Allobaculum, Sutterella, Uncl. S247, Uncl. Coriobacteriaceae, and Bifidobacterium↑)[93]Lycium ruthenicum MurrayAnthocyaninsIn vivoC57BL/6 mice200 mg/kg, 12 weeksImproving oxidative stress (TAC, SOD, GPx↑, and MDA↓) and inflammation (TNF-α, IL-6, and IL-1β↓), regulating gut microbiota (Barnesiella, Alistipes, Eisenbergiella, Coprobacter, and Odoribacter↑), and increasing SCFA in cecal and feces[94]TeaPolyphenolsIn vivoApoE(-/-) mice1.6, 0.8, and 0.4 g/L tea polyphenols in drinking waterLowering TC and LDL-C, decreasing the plaque area/lumen area, and promoting the proliferation of the intestinalBifidobacteria[95]Berry mixturePolyphenolsIn vivoDahl salt-sensitive rats2 g, 9 weeksMitigating changes in the microbiota composition caused by the high-salt diet (phylumBacteroidetes↑, Firmicutes, and Proteobacteria↓)[96]Note. NA: not available; SHRs: spontaneously hypertensive rats; SD rats: Sprague-Dawley rats; BW: body weight; w/w: weight in weight; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure; ACE: angiotensin-1 converting enzyme; NO: nitric oxide; eNOS: endothelial nitric oxide synthase; cGMP: cyclic guanosine monophosphate; TC: total cholesterol; TG: triglyceride; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; VLDL-C: very-low-density lipoprotein cholesterol; ox-LDL: oxidized low-density lipoprotein; TAC: total antioxidant capacity; FRAP: ferric ion-reducing antioxidant power; MDA: malondialdehyde; PC: protein carbonyls; TBARS: thiobarbituric acid reactive substances; SOD: superoxide dismutase; GPx: glutathione peroxidase; GR: glutathione reductase; CAT: catalase; TNF-α: tumor necrosis factor α; CRP: C reactive protein; IL-1β: interleukin-1β; IL-6: interleukin-6; IL-10: interleukin-10: VCAM-1: vascular cell adhesion molecule 1; ICAM-1: intercellular adhesion molecule 1; MCP-1: monocyte chemotactic protein 1; SCFA: short-chain fatty acids.Figure 1
The mechanisms of natural products against cardiovascular diseases. Natural products could stimulate the activity of endothelial nitric oxide synthase (eNOS) and promote the release of nitric oxide (NO) to lower blood pressure; they can also inhibit the activity of angiotensin-1 converting enzyme (ACE) and decrease angiotensin-1 and renin to lower blood pressure. Natural products could promote the activities of antioxidant enzymes, like superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx), and decrease the concentration of peroxidative products, like malondialdehyde (MDA) and protein carbonyls (PC), to ameliorate oxidative stress. Through the nuclear factor-kappa B (NF-κβ) signaling pathway, natural products could decrease levels of inflammatory markers, like tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and vascular cell adhesion molecule-1 (VCAM-1), to mitigate inflammation. Natural products could decrease the levels of total cholesterol (TC), triglyceride (TG), and low-density lipid protein cholesterol (LDL-C) and increase the level of high-density lipid protein cholesterol (HDL-C) to improve lipid profile. Natural products could increase the abundance of beneficial bacteria, like Bacteroides, and decrease the abundance of harmful bacteria, like Firmicutes and Proteobacteria, to regulate gut microbiota.


### 3.1. Reducing Blood Pressure

It’s widely known that hypertension is an important risk factor for CVDs [56]. An analysis pointed out that every 10 mm Hg reduction in SBP markedly decreased the risk of major cardiovascular disease events in patients with a history of CVDs [57]. Some natural products are effective in the prevention and treatment of CVDs via reducing blood pressure. The hypotensive effect of these natural products was mainly related to the regulation of the renin-angiotensin system (RAS) and the release of nitric oxide (NO).


#### 3.1.1. Regulating the Renin-Angiotensin System

Blood pressure regulation is a sophisticated process involving various organs and systems, among which RAS plays an important role in elevating blood pressure [58]. Regulating the activity of RAS, such as inhibiting the synthesis of angiotensin-1 converting enzyme (ACE) as well as the secretion of renin/angiotensin, is helpful to ameliorate blood pressure [59, 60]. Many experimental studies revealed that some natural products performed the blood pressure lowering efficacy mainly though the regulation of RAS. For example, a study showed a potent in vitro ACE inhibitory property of winged bean seed hydrolysate, as well as the in vivo hypotensive effect of the hydrolysate in a dose-dependent manner in Sprague-Dawley (SD) rats, indicating that the hydrolysate lowered blood pressure via suppressing the activity of ACE [61]. Another study found that Solanum macrocarpon leaf extract suppressed the in vitro activities of renin and ACE. The oral administration of the extract decreased SBP, diastolic blood pressure (DBP), and heart rate in spontaneously hypertensive rats. Rutin, caffeic acid, and myricetin were the major polyphenols in the extract [62]. Furthermore, a study pointed out that Ocimum sanctum and Citrus paradisi infusions possessed a hypotensive property. The infusion of Ocimum sanctum downregulated the gene expression of renin and angiotensinogen and reduced renal triglyceride accumulation and lipid/protein oxidation in SD rats, while the hypotensive effect of Citrus paradisi could be associated with other mechanisms [63].


#### 3.1.2. Increasing the Release of NO

Accumulating evidence has proven that the generation of NO in endothelial cells is mainly activated by endothelial nitric oxide synthase (eNOS). NO could induce the relaxation of blood vessels, leading to the reduction of blood pressure [64, 65]. Hence, promoting the production of NO is an effective way to decrease blood pressure, which will protect the function of the cardiovascular system. There are findings suggesting that some natural products showed an antihypertensive effect via accelerating the release of NO, holding tremendous promise to prevent the development of hypertension and CVDs. For example, Morus alba induced endothelial vasorelaxation in mesenteric arteries via a NO-dependent pathway, and decreased blood pressure in wild-type mice. However, it failed to exert a hemodynamic effect in eNOS-deficient mice, which further testified to the antihypertensive action of Morus alba through a NO-dependent pathway [66]. Moreover, a study found that white mulberry fruit polysaccharides could provoke endothelium-dependent relaxation in rat mesenteric arteries and NO production in endothelial cells, and its intravenous injection induced the reduction of blood pressure in both normotensive rats and spontaneously hypertensive rats, while this effect was markedly attenuated in normotensive rats pretreated with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). These results suggested that the hypotensive effect of white mulberry fruit was mediated by the NO pathway [67]. Additionally, grape seed polyphenol extract promoted the production of NO and reduced the blood pressure in hypertensive rats via upregulating the expression of eNOS and Sirtuin-1 [68].


### 3.2. Improving Lipid Profile

Hyperlipidemia results from the metabolic abnormalities of lipids, leading to higher levels of lipids in plasma than normal ones, which can be generally characterized as higher levels of total cholesterol (TC), triglyceride (TG), and low-density lipid protein cholesterol (LDL-C) and a lower level of high-density lipid protein cholesterol (HDL-C) [69]. Increasing evidence suggested that hyperlipidemia was closely associated with atherosclerosis, playing an important role in the development of CVDs [70, 71]. Several experimental studies revealed the hypolipidemic effect of natural products. For example, an in vivo study found that after the treatment of mung bean sprouts, the SBP and LDL-C levels of SD rats in the high-fat diet group significantly lowered to the normal level [72]. Additionally, supplementing obese rats with red dragon fruit flour for 4 weeks markedly reduced the blood glucose, TC, TG, and LDL-C levels, while HDL-C had no significant difference [73]. Also, another study found that after oral administration of red dragon fruit peel powder for 30 days, TC, TG, and LDL-C levels of hyperlipidemic male mice declined in a dose-dependent manner, accompanied by an increase in HDL-C levels [74]. The two studies above showed that both the pulp and peel of red dragon fruit possessed promising blood lipid-lowering efficacy. Furthermore, after administration with Citrus maxima juice for 14 days, male Wistar rats showed a significant decrease of TC and TG, along with an increase of HDL-C [75]. Furthermore, feeding with fresh bitter melon fruit juice for 4 weeks markedly dropped down the levels of blood glucose, TG, TC, and LDL-C in hyperglycemia rats compared with the initial levels, but the HDL-C level was dramatically elevated. Meanwhile, bitter melon effectively improved the fecal cholesterol secretion and suppressed cholesterol absorption, posing a potent ability to improve lipid profile [76].


### 3.3. Ameliorating Oxidative Stress

Oxidative stress, a major cause of the CVDs, is the result of the reduction of antioxidant capacity and the production of excessive reactive oxygen species (ROS) [77–79]. Some natural products could improve oxidative stress via promoting the activities of antioxidant enzymes, like superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) and decreasing the concentration of peroxidative products, like malondialdehyde (MDA) and protein carbonyls, hence promising to prevent and treat CVDs. A study showed that the intake of North American or Chinese wild rice effectively inhibited the formation of oxidative stress in hyperlipidemic rats via improving total antioxidant capacity, increasing SOD activity, and reducing MDA concentration. In addition, two wild rice varieties were also effective in suppressing hyperlipidemia and inflammation in rats [80]. Moreover, the polyphenol extract of Sambucus nigra L. ameliorated oxidative stress by enhancing total antioxidant capacity, and reduced both SBP and DBP in Wistar rats. Its combination with a renin inhibitor (Aliskiren) generated a superior antioxidant effect compared to administering the two separately, and it could also reduce the side effects of the antihypertensive agent [81]. Furthermore, the effects of dried chokeberry fruit extract on haemodynamic parameters, lipid profile, and oxidative stress were evaluated in spontaneously hypertensive rats, and anthocyanins, phenolic acids, and flavonoids in the extract were determined by the HPLC/DAD method. The extract rich in anthocyanins significantly reduced systolic and pulse pressures via increased diuresis. The thiobarbituric acid reactive substances (TBARS) in plasma and erythrocytes were significantly decreased in the treated group. The consumption of the extract also reduced lipid peroxidation through improving the ferric ion-reducing antioxidant power (FRAP) of plasma, but the activity of SOD in the treated group was significantly lower compared to the control group [26]. Additionally, the supplement of sweet cherry fruit and leaves to the high-fat–high-cholesterol diet in Wistar rats decreased body gain, improved liver function, and reduced inflammation and oxidative stress (by provoking the activities of SOD, GPx, GR, and CAT, and reducing the level of TBARS). The fruit and leaves reduced lipid accumulation in the liver and improved the lipid profile in serum. These effects could be from the regulation of the expression of fatty acid synthesis and oxidation-related genes [82]. In a previous study, the effects of rice bran protein hydrolysate on arterial stiffening, vascular remodeling, and oxidative stress were evaluated in rats fed a high-carbohydrate and high-fat diet. The hydrolysate supplementation significantly alleviated hyperglycemia, insulin resistance, dyslipidemia, hypertension, increased aortic pulse wave velocity, aortic wall hypertrophy, and vascular remodeling. The hydrolysate reduced the levels of ACE and tumor necrosis factor-alpha in plasma. The hydrolysate also alleviated oxidative stress by decreasing plasma MDA, reducing superoxide production, and suppressing p47 (phox) NADPH oxidase expression in the vascular tissues. The hydrolysate increased plasma nitrate/nitrite level and upregulated eNOS expression in the aortas of model group rats, indicating that the hydrolysate increased NO production [83]. In another study, Zygophyllum album root extract was analyzed using HPLC-DAD-ESI-QTOF-MS/MS, and twenty-six molecules were identified, including phenolic compounds and saponins. The extract significantly improved the heart injury markers, lipid peroxidation, protein oxidation, antioxidant capacity (SOD, CAT, and GPx), and DNA structure. The extract reduced the expressions of NF-kappa B, decreased plasmatic proinflammatory cytokine concentration, and suppressed the myocardial collagen deposition [84]. An in vivo study showed that apple polyphenol extract possessed a positive effect on vascular oxidative stress and endothelium function [85].


### 3.4. Mitigating Inflammation

Inflammatory response is a prominent pathological change in the development of CVDs, which can be characterized by increased levels of inflammatory markers, like tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), C reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1) [86, 87]. It has been reported that some natural products were able to downregulate the expression of these cytokines and mitigate inflammation, which was a way of lowering the risk of CVDs. For example, an in vivo study pointed out that Nepeta deflersiana ethanolic extract effectively attenuated the myocardial injuries in Wistar rats by improving oxidative stress, inhibiting apoptosis, and mitigating inflammation. Nepeta deflersiana exerted an anti-inflammatory effect via the downregulation of the gene expression of TNF-α, IL-6, and IL-10 [29]. Another study found that the oral administration of Zygophyllum album root extract ameliorated the myocardial injuries in Wistar rats though the improvement of oxidative stress and the alleviation of inflammation. Zygophyllum album root extract decreased the plasma concentration of proinflammatory cytokines, like TNF-α, IL-1β, and IL-6 [84]. Additionally, spinach nitrate significantly lowered the elevated levels of serum CRP, TNF-α, and IL-6 induced by a high-fat and high-fructose diet in male mice, showing a strong anti-inflammatory capacity [88]. Also, a study demonstrated that Spinacia oleracea leaf methanolic extract dose-dependently attenuated isoproterenol-induced myocardial necrosis in male Wistar rats via mitigating the levels of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6 [89]. Moreover, Antidesma bunius extract significantly ameliorated the expressions of genes involved with proinflammatory cytokines, such as TNF-α, IL-6, VCAM-1, and MCP-1, showing great anti-inflammatory capacity [90].


### 3.5. Regulating Gut Microbiota

Recent interest has focused on the impact of gut microbiota on chronic diseases, especially CVDs. Increasing evidence has shown that gut microbiota was closely associated with the function of the cardiovascular system via contributing to the fermentation of dietary fiber in the colon, the production of short-chain fatty acids (SCFA), and the intestinal absorption of phytochemicals [91, 92]. Hence, it is of great significance to maintain the balance of intestinal flora to protect against CVDs. Some studies revealed that several natural products could regulate the homeostasis of gut microbiota. For example, a study demonstrated that wasabi powder prevented the development of hypertension in Wistar rats via changing the composition of gut microbiota, increasing the abundance of Allobaculum, Sutterella, Uncl. S247, Uncl. Coriobacteriaceae, and Bifidobacterium [93]. Moreover, treatment with anthocyanins extracted from Lycium ruthenicum Murray could not only improve oxidative stress and inflammation in C57BL/6 mice but also promote the proliferation of Barnesiella, Alistipes, Eisenbergiella, Coprobacter, and Odoribacter and increase the production of SCFA in cecal and feces [94]. Additionally, a study found that except for the improvement of lipid profile and inflammation, Polygoni multiflori Radix extract significantly inhibited atherosclerosis plaque formation in ApoE(-/-) mice via regulating gut microbiota composition [28]. Also, a study pointed out that tea polyphenols dose-dependently increased the abundance of intestinal Bifidobacteria in high-fat diet-fed ApoE(-/-) mice, and this increase negatively correlated with plaque area/lumen area ratios, suggesting that tea polyphenols could reduce atherosclerosis plaque induced by high-fat diet via increasing intestinal Bifidobacteria [95]. Furthermore, the intake of berry mixture, including blueberries, blackberries, raspberries, Portuguese crowberry, and strawberry tree fruit, increased the abundance of phylum Bacteroidetes, decreased the abundance of Firmicutes, and reduced the elevated abundance of Proteobacteria induced by a high-salt diet in Dahl salt-sensitive rats [96].In brief, based on thein vitro and in vivo experimental studies, we summarized the potential mechanisms of some natural products protecting against CVDs, including reducing blood pressure, improving the lipid profile, ameliorating oxidative stress, mitigating inflammation, and regulating gut microbiota.


## 3.1. Reducing Blood Pressure

It’s widely known that hypertension is an important risk factor for CVDs [56]. An analysis pointed out that every 10 mm Hg reduction in SBP markedly decreased the risk of major cardiovascular disease events in patients with a history of CVDs [57]. Some natural products are effective in the prevention and treatment of CVDs via reducing blood pressure. The hypotensive effect of these natural products was mainly related to the regulation of the renin-angiotensin system (RAS) and the release of nitric oxide (NO).


### 3.1.1. Regulating the Renin-Angiotensin System

Blood pressure regulation is a sophisticated process involving various organs and systems, among which RAS plays an important role in elevating blood pressure [58]. Regulating the activity of RAS, such as inhibiting the synthesis of angiotensin-1 converting enzyme (ACE) as well as the secretion of renin/angiotensin, is helpful to ameliorate blood pressure [59, 60]. Many experimental studies revealed that some natural products performed the blood pressure lowering efficacy mainly though the regulation of RAS. For example, a study showed a potent in vitro ACE inhibitory property of winged bean seed hydrolysate, as well as the in vivo hypotensive effect of the hydrolysate in a dose-dependent manner in Sprague-Dawley (SD) rats, indicating that the hydrolysate lowered blood pressure via suppressing the activity of ACE [61]. Another study found that Solanum macrocarpon leaf extract suppressed the in vitro activities of renin and ACE. The oral administration of the extract decreased SBP, diastolic blood pressure (DBP), and heart rate in spontaneously hypertensive rats. Rutin, caffeic acid, and myricetin were the major polyphenols in the extract [62]. Furthermore, a study pointed out that Ocimum sanctum and Citrus paradisi infusions possessed a hypotensive property. The infusion of Ocimum sanctum downregulated the gene expression of renin and angiotensinogen and reduced renal triglyceride accumulation and lipid/protein oxidation in SD rats, while the hypotensive effect of Citrus paradisi could be associated with other mechanisms [63].


### 3.1.2. Increasing the Release of NO

Accumulating evidence has proven that the generation of NO in endothelial cells is mainly activated by endothelial nitric oxide synthase (eNOS). NO could induce the relaxation of blood vessels, leading to the reduction of blood pressure [64, 65]. Hence, promoting the production of NO is an effective way to decrease blood pressure, which will protect the function of the cardiovascular system. There are findings suggesting that some natural products showed an antihypertensive effect via accelerating the release of NO, holding tremendous promise to prevent the development of hypertension and CVDs. For example, Morus alba induced endothelial vasorelaxation in mesenteric arteries via a NO-dependent pathway, and decreased blood pressure in wild-type mice. However, it failed to exert a hemodynamic effect in eNOS-deficient mice, which further testified to the antihypertensive action of Morus alba through a NO-dependent pathway [66]. Moreover, a study found that white mulberry fruit polysaccharides could provoke endothelium-dependent relaxation in rat mesenteric arteries and NO production in endothelial cells, and its intravenous injection induced the reduction of blood pressure in both normotensive rats and spontaneously hypertensive rats, while this effect was markedly attenuated in normotensive rats pretreated with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). These results suggested that the hypotensive effect of white mulberry fruit was mediated by the NO pathway [67]. Additionally, grape seed polyphenol extract promoted the production of NO and reduced the blood pressure in hypertensive rats via upregulating the expression of eNOS and Sirtuin-1 [68].


## 3.1.1. Regulating the Renin-Angiotensin System

Blood pressure regulation is a sophisticated process involving various organs and systems, among which RAS plays an important role in elevating blood pressure [58]. Regulating the activity of RAS, such as inhibiting the synthesis of angiotensin-1 converting enzyme (ACE) as well as the secretion of renin/angiotensin, is helpful to ameliorate blood pressure [59, 60]. Many experimental studies revealed that some natural products performed the blood pressure lowering efficacy mainly though the regulation of RAS. For example, a study showed a potent in vitro ACE inhibitory property of winged bean seed hydrolysate, as well as the in vivo hypotensive effect of the hydrolysate in a dose-dependent manner in Sprague-Dawley (SD) rats, indicating that the hydrolysate lowered blood pressure via suppressing the activity of ACE [61]. Another study found that Solanum macrocarpon leaf extract suppressed the in vitro activities of renin and ACE. The oral administration of the extract decreased SBP, diastolic blood pressure (DBP), and heart rate in spontaneously hypertensive rats. Rutin, caffeic acid, and myricetin were the major polyphenols in the extract [62]. Furthermore, a study pointed out that Ocimum sanctum and Citrus paradisi infusions possessed a hypotensive property. The infusion of Ocimum sanctum downregulated the gene expression of renin and angiotensinogen and reduced renal triglyceride accumulation and lipid/protein oxidation in SD rats, while the hypotensive effect of Citrus paradisi could be associated with other mechanisms [63].


## 3.1.2. Increasing the Release of NO

Accumulating evidence has proven that the generation of NO in endothelial cells is mainly activated by endothelial nitric oxide synthase (eNOS). NO could induce the relaxation of blood vessels, leading to the reduction of blood pressure [64, 65]. Hence, promoting the production of NO is an effective way to decrease blood pressure, which will protect the function of the cardiovascular system. There are findings suggesting that some natural products showed an antihypertensive effect via accelerating the release of NO, holding tremendous promise to prevent the development of hypertension and CVDs. For example, Morus alba induced endothelial vasorelaxation in mesenteric arteries via a NO-dependent pathway, and decreased blood pressure in wild-type mice. However, it failed to exert a hemodynamic effect in eNOS-deficient mice, which further testified to the antihypertensive action of Morus alba through a NO-dependent pathway [66]. Moreover, a study found that white mulberry fruit polysaccharides could provoke endothelium-dependent relaxation in rat mesenteric arteries and NO production in endothelial cells, and its intravenous injection induced the reduction of blood pressure in both normotensive rats and spontaneously hypertensive rats, while this effect was markedly attenuated in normotensive rats pretreated with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). These results suggested that the hypotensive effect of white mulberry fruit was mediated by the NO pathway [67]. Additionally, grape seed polyphenol extract promoted the production of NO and reduced the blood pressure in hypertensive rats via upregulating the expression of eNOS and Sirtuin-1 [68].


## 3.2. Improving Lipid Profile

Hyperlipidemia results from the metabolic abnormalities of lipids, leading to higher levels of lipids in plasma than normal ones, which can be generally characterized as higher levels of total cholesterol (TC), triglyceride (TG), and low-density lipid protein cholesterol (LDL-C) and a lower level of high-density lipid protein cholesterol (HDL-C) [69]. Increasing evidence suggested that hyperlipidemia was closely associated with atherosclerosis, playing an important role in the development of CVDs [70, 71]. Several experimental studies revealed the hypolipidemic effect of natural products. For example, an in vivo study found that after the treatment of mung bean sprouts, the SBP and LDL-C levels of SD rats in the high-fat diet group significantly lowered to the normal level [72]. Additionally, supplementing obese rats with red dragon fruit flour for 4 weeks markedly reduced the blood glucose, TC, TG, and LDL-C levels, while HDL-C had no significant difference [73]. Also, another study found that after oral administration of red dragon fruit peel powder for 30 days, TC, TG, and LDL-C levels of hyperlipidemic male mice declined in a dose-dependent manner, accompanied by an increase in HDL-C levels [74]. The two studies above showed that both the pulp and peel of red dragon fruit possessed promising blood lipid-lowering efficacy. Furthermore, after administration with Citrus maxima juice for 14 days, male Wistar rats showed a significant decrease of TC and TG, along with an increase of HDL-C [75]. Furthermore, feeding with fresh bitter melon fruit juice for 4 weeks markedly dropped down the levels of blood glucose, TG, TC, and LDL-C in hyperglycemia rats compared with the initial levels, but the HDL-C level was dramatically elevated. Meanwhile, bitter melon effectively improved the fecal cholesterol secretion and suppressed cholesterol absorption, posing a potent ability to improve lipid profile [76].


## 3.3. Ameliorating Oxidative Stress

Oxidative stress, a major cause of the CVDs, is the result of the reduction of antioxidant capacity and the production of excessive reactive oxygen species (ROS) [77–79]. Some natural products could improve oxidative stress via promoting the activities of antioxidant enzymes, like superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) and decreasing the concentration of peroxidative products, like malondialdehyde (MDA) and protein carbonyls, hence promising to prevent and treat CVDs. A study showed that the intake of North American or Chinese wild rice effectively inhibited the formation of oxidative stress in hyperlipidemic rats via improving total antioxidant capacity, increasing SOD activity, and reducing MDA concentration. In addition, two wild rice varieties were also effective in suppressing hyperlipidemia and inflammation in rats [80]. Moreover, the polyphenol extract of Sambucus nigra L. ameliorated oxidative stress by enhancing total antioxidant capacity, and reduced both SBP and DBP in Wistar rats. Its combination with a renin inhibitor (Aliskiren) generated a superior antioxidant effect compared to administering the two separately, and it could also reduce the side effects of the antihypertensive agent [81]. Furthermore, the effects of dried chokeberry fruit extract on haemodynamic parameters, lipid profile, and oxidative stress were evaluated in spontaneously hypertensive rats, and anthocyanins, phenolic acids, and flavonoids in the extract were determined by the HPLC/DAD method. The extract rich in anthocyanins significantly reduced systolic and pulse pressures via increased diuresis. The thiobarbituric acid reactive substances (TBARS) in plasma and erythrocytes were significantly decreased in the treated group. The consumption of the extract also reduced lipid peroxidation through improving the ferric ion-reducing antioxidant power (FRAP) of plasma, but the activity of SOD in the treated group was significantly lower compared to the control group [26]. Additionally, the supplement of sweet cherry fruit and leaves to the high-fat–high-cholesterol diet in Wistar rats decreased body gain, improved liver function, and reduced inflammation and oxidative stress (by provoking the activities of SOD, GPx, GR, and CAT, and reducing the level of TBARS). The fruit and leaves reduced lipid accumulation in the liver and improved the lipid profile in serum. These effects could be from the regulation of the expression of fatty acid synthesis and oxidation-related genes [82]. In a previous study, the effects of rice bran protein hydrolysate on arterial stiffening, vascular remodeling, and oxidative stress were evaluated in rats fed a high-carbohydrate and high-fat diet. The hydrolysate supplementation significantly alleviated hyperglycemia, insulin resistance, dyslipidemia, hypertension, increased aortic pulse wave velocity, aortic wall hypertrophy, and vascular remodeling. The hydrolysate reduced the levels of ACE and tumor necrosis factor-alpha in plasma. The hydrolysate also alleviated oxidative stress by decreasing plasma MDA, reducing superoxide production, and suppressing p47 (phox) NADPH oxidase expression in the vascular tissues. The hydrolysate increased plasma nitrate/nitrite level and upregulated eNOS expression in the aortas of model group rats, indicating that the hydrolysate increased NO production [83]. In another study, Zygophyllum album root extract was analyzed using HPLC-DAD-ESI-QTOF-MS/MS, and twenty-six molecules were identified, including phenolic compounds and saponins. The extract significantly improved the heart injury markers, lipid peroxidation, protein oxidation, antioxidant capacity (SOD, CAT, and GPx), and DNA structure. The extract reduced the expressions of NF-kappa B, decreased plasmatic proinflammatory cytokine concentration, and suppressed the myocardial collagen deposition [84]. An in vivo study showed that apple polyphenol extract possessed a positive effect on vascular oxidative stress and endothelium function [85].


## 3.4. Mitigating Inflammation

Inflammatory response is a prominent pathological change in the development of CVDs, which can be characterized by increased levels of inflammatory markers, like tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), C reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1) [86, 87]. It has been reported that some natural products were able to downregulate the expression of these cytokines and mitigate inflammation, which was a way of lowering the risk of CVDs. For example, an in vivo study pointed out that Nepeta deflersiana ethanolic extract effectively attenuated the myocardial injuries in Wistar rats by improving oxidative stress, inhibiting apoptosis, and mitigating inflammation. Nepeta deflersiana exerted an anti-inflammatory effect via the downregulation of the gene expression of TNF-α, IL-6, and IL-10 [29]. Another study found that the oral administration of Zygophyllum album root extract ameliorated the myocardial injuries in Wistar rats though the improvement of oxidative stress and the alleviation of inflammation. Zygophyllum album root extract decreased the plasma concentration of proinflammatory cytokines, like TNF-α, IL-1β, and IL-6 [84]. Additionally, spinach nitrate significantly lowered the elevated levels of serum CRP, TNF-α, and IL-6 induced by a high-fat and high-fructose diet in male mice, showing a strong anti-inflammatory capacity [88]. Also, a study demonstrated that Spinacia oleracea leaf methanolic extract dose-dependently attenuated isoproterenol-induced myocardial necrosis in male Wistar rats via mitigating the levels of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6 [89]. Moreover, Antidesma bunius extract significantly ameliorated the expressions of genes involved with proinflammatory cytokines, such as TNF-α, IL-6, VCAM-1, and MCP-1, showing great anti-inflammatory capacity [90].


## 3.5. Regulating Gut Microbiota

Recent interest has focused on the impact of gut microbiota on chronic diseases, especially CVDs. Increasing evidence has shown that gut microbiota was closely associated with the function of the cardiovascular system via contributing to the fermentation of dietary fiber in the colon, the production of short-chain fatty acids (SCFA), and the intestinal absorption of phytochemicals [91, 92]. Hence, it is of great significance to maintain the balance of intestinal flora to protect against CVDs. Some studies revealed that several natural products could regulate the homeostasis of gut microbiota. For example, a study demonstrated that wasabi powder prevented the development of hypertension in Wistar rats via changing the composition of gut microbiota, increasing the abundance of Allobaculum, Sutterella, Uncl. S247, Uncl. Coriobacteriaceae, and Bifidobacterium [93]. Moreover, treatment with anthocyanins extracted from Lycium ruthenicum Murray could not only improve oxidative stress and inflammation in C57BL/6 mice but also promote the proliferation of Barnesiella, Alistipes, Eisenbergiella, Coprobacter, and Odoribacter and increase the production of SCFA in cecal and feces [94]. Additionally, a study found that except for the improvement of lipid profile and inflammation, Polygoni multiflori Radix extract significantly inhibited atherosclerosis plaque formation in ApoE(-/-) mice via regulating gut microbiota composition [28]. Also, a study pointed out that tea polyphenols dose-dependently increased the abundance of intestinal Bifidobacteria in high-fat diet-fed ApoE(-/-) mice, and this increase negatively correlated with plaque area/lumen area ratios, suggesting that tea polyphenols could reduce atherosclerosis plaque induced by high-fat diet via increasing intestinal Bifidobacteria [95]. Furthermore, the intake of berry mixture, including blueberries, blackberries, raspberries, Portuguese crowberry, and strawberry tree fruit, increased the abundance of phylum Bacteroidetes, decreased the abundance of Firmicutes, and reduced the elevated abundance of Proteobacteria induced by a high-salt diet in Dahl salt-sensitive rats [96].In brief, based on thein vitro and in vivo experimental studies, we summarized the potential mechanisms of some natural products protecting against CVDs, including reducing blood pressure, improving the lipid profile, ameliorating oxidative stress, mitigating inflammation, and regulating gut microbiota.


## 4. Clinical Trials

The benefits of reducing the risk of CVD events through the consumption of antioxidant natural products and their active ingredients have been studied in multiple clinical trials. Here, we summarize the protective effects of some natural products on CVDs (Table3).Table 3
The effects of antioxidant natural products on CVDs from clinical studies.
Plant typesComponentsStudy typeSubjectsDose and timeOutcomesRef.FruitsGuavaNARCT45 healthy students400 g/day, 6 weeksLowering BP, TC, TG, and LDL-C[101]SoursopNARCT143 hypertensive subjects2×100g/day, 3 monthsLowering BP[102]Orange juiceHesperidin and naringinControlled nonrandomized clinical study10 healthy women300 mL/day, 2 monthsImproving LDL-C, blood glucose, insulin sensitivity, and gut microbiota metabolism[103]Haskap berryAnthocyaninCross-over study20 adults aged 62-81 years400 mg anthocyaninsLowering BP and improving episodic memory[104]Cherry juiceAnthocyaninPilot cross-over study6 young and 7 old adults300 mL or 100 mL, 3 timesLowering BP and heart rate[126]Pomegranate extractPolyphenolsRCT55 subjects without any symptomatic diseaseContaining 210 mg punicalagins, 328 mg other pomegranate polyphenols, and 0-37 mg anthocyanins, 8 weeksLowering SBP[127]Plum juiceAnthocyaninsPilot cross-over dose-timing study12 older (65+ years) and 12 younger (18-45 years) adults300 mL or 100 mL, 3 timesReducing BP and cardiovascular responses[128]Noni and chokeberry juicesNARCT88 young adultsNoni juice 30 mL; chokeberry juice 200 mLLowering SBP, DBP, heart rate, and blood glucose (noni juice)Slightly lowering DBP (chokeberry juice)[129]VegetablesTomato extractNARCT65 patients with hypertension and a high risk of CVD213 mg/day, 4 weeksLowering DBP and mean arterial pressure[105]Beetroot juiceNitrateOpen-label cross-over study17 patients with chronic kidney diseaseContaining 300 mg nitrate, 4 hoursLowering peripheral BP and mean arterial pressure[130]Beetroot juiceNitrateDouble-blind cross-over study20 subjects with treated yet uncontrolled hypertensionContaining 12.9 mmol nitrate, 7 daysIncreasing plasma nitrite and reducing BP[131]Beetroot juiceNitrateFeasibility trial40 hypertensive pregnant women70 mL/day, 8 daysLowering DBP[106]Sateria palmifoliaNAQuasiexperiment10 pregnant womenNALowering BP[132]Eggplant powderNARCT100 stressed participants with normal-high BP or stage 1 hypertension1.2 g/day, 12 weeksImproving BP and psychological state[107]Beetroot, rocket salad and spinachNitrateSemirandomized cross-over study11 men and 7 womenEach group containing 800 mg nitrateLowering BP[133]SpicesSatureja hortensis L.NARCT47 patients with metabolic syndrome450 mg/day, 10 weeksLowering TC, TG, and LDL-C and increasing HDL-C[109]CardamomNARCT80 overweight and obese prediabetic women3 g, 2 monthsLowering TC and LDL-C[108]Garlic and cuminNARCT75 patients with T2DMGarlic powder: 300 mg/three times a day; cumin extract: 100 mg/twice a day, 2 monthsLowering BP[110]Cinnamon, cardamom, saffron, and gingerNARCT204 patients with T2DM3 g cinnamon, 3 g cardamom, 1 g saffron, and 3 g ginger in a glass of black tea, respectively, 8 weeksAll showed potent effects on controlling BP and improving endothelial function[33]NutsAlmondNARCT86 overweight or obese adults15% energy from almond, 12 weeksLowering truncal and total body fat as well as DBP[114]WalnutsNARCT211 participants30 g/day, 3 monthsLowering BP[134]WalnutsNARCT100 overweight and obese participants15% energy from walnut, 6 monthsReducing BW, BMI, waist circumference, SBP, TC, and LDL-C[115]Walnutsα-Linolenic acidRCT42 adults at cardiovascular risk57–99 g/day, 6 weeksRegulating gut microbiota[135]Cashew nutNARCT300 Asian Indians with T2DM30 g/day, 12 weeksDecreasing SBP and increasing HDL-C[116]Cashew nutNARCT42 adults42 g/day, 4 weeksNo effect on risk factors of CVD[136]Mixed nutsNARCT48 overweight and obese adults250 kcal, 4 and 8 weeksImproving BW and glucose regulation[117]TeasGreen teaCatechinRCT1,075 postmenopausal womenContaining 1,315 mg catechins, 6 and 12 monthsLowering TC, LDL-C, and non-HDL-C[118]Kosen-chaCatechinOpen-label pilot study6 obese subjects5 g/L, 12 weeksLowering BW, BMI, waist circumferences, and serum TG levels and improving insulin resistance, vascular function, and cardiac hypertrophy[120]Goishi teaPolyphenolsRCT77 subjectsContaining 122 mg of polyphenols, 12 weeksIncreasing HDL-C and lowering TG[137]Black teaPhytosterolRCTSubjects with mild hypercholesterolemiaPhytosterol-enriched functional black tea, 4 weeksLowering TC, LDL-C, and apolipoprotein B and improving oxidative stress[119]OthersHibiscus sabdariffaNACross-over study25 men with 1% to 10% CVD risk250 mL, 0, 2, and 4 hReducing endothelial dysfunction and CVD risk[138]Hibiscus sabdariffaNARCT46 patients with stage 1 hypertension2 cup/morning, 1 monthReducing BP[123]ChamomileNARCT50 diabetic patients200 mL/day, 4 weeksLowering TC, LDL-C, and creatinine[139]Soy flourNA3×3 completely randomized repeated study75 postmenopausal women with prediabetes and prehypertension25 and 45 g/day, 12 weeksLowering fasting plasma glucose, fasting insulin, insulin resistance, and DBP[124]Navy beans and rice branNAPilot RCT38 children with abnormal cholesterol17.5 g/day cooked navy bean powder; 15 g/day heat-stabilized rice bran; 9 g/day navy beans and 8 g/day rice bran, 4 weeksModulating the plasma metabolome and reducing CVD risk[140]Oat noodlesNARCT84 healthy and mild hypercholesterolemic subjects100 g/day (replacing 1 or 2 meals of staple food), 10 weeksReducing TC/HDL-C and LDL-C/HDL-C ratios and blood pressure[125]Green coffee beanNARCTPatients with the metabolic syndrome400 mg twice/day, 8 weeksReducing SBP, insulin resistance, and abdominal obesity and inhibiting appetite[141]Note. NA: not available; RCT: randomized controlled trial; CVD: cardiovascular disease; T2DM: type 2 diabetes mellitus; BW: body weight; BMI: body mass index; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure; TC: total cholesterol; TG: triglyceride; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol.


### 4.1. The Effects of Fruits on CVDs

Several clinical trials revealed the inverse relationship between the consumption of fruits and risk of CVDs. A randomized controlled trial (RCT) found that guava pulp significantly improved lipid profile by decreasing the levels of TC, TG, and LDL-C and increasing the level of HDL-C [101]. Another RCT pointed out that intake of 100 g soursop fruit twice per day for 3 months markedly decreased the levels of SBP, DBP, and serum uric acid in prehypertensive participants compared to the control group [102]. Additionally, a controlled nonrandomized clinical study showed that consuming 300 mL of orange juice for 2 months improved LDL-C, blood glucose, insulin sensitivity, and gut microbiota metabolism in healthy women [103]. Furthermore, a cross-over study found that after the intervention of 200 or 400 mg anthocyanin from haskap berry, the blood pressure levels in participants aged 62-81 years were significantly reduced [104]. Hence, consuming some fruits, like guava, soursop, and orange, is an effective way to prevent and manage CVDs.


### 4.2. The Effects of Vegetables on CVDs

Some vegetables also showed a protective effect on CVDs. An RCT found that the intake of 213 mg tomato extract for 4 weeks lowered DBP and mean arterial pressure in patients with hypertension and high risk of CVDs [105]. Moreover, several studies revealed the potent hypotensive efficacy of beetroot which was associated with its high content of nitrate. For example, a study demonstrated that consuming 70 mL beetroot juice significantly lowered the level of DBP in hypertensive pregnant women [106]. Additionally, daily consumption of 1.2 g eggplant powder markedly improved blood pressure and the psychological state of stressed participants with normal-high blood pressure or stage 1 hypertension [107]. Therefore, it is advisable to increase the intake of tomato, beetroot, and eggplant to protect the health of the cardiovascular system.


### 4.3. The Effects of Spices on CVDs

Similarly, some spices effectively reduced the risk of CVDs. An RCT showed that after intervention with 3 g cardamom for 2 months, the levels of TC and LDL-C in overweight and obese prediabetic women were remarkably lowered, while SBP, DBP, glycemic indices, and serum lipid values in the cardamom group did not significantly differ from the placebo group [108]. Another study compared the cardiovascular-protective effect of cardamom, cinnamon, saffron, and ginger, demonstrating that all of them showed potent abilities in controlling blood pressure and improving endothelial function [33]. Besides, daily ingestion of Satureja hortensis L. effectively improved the lipid profile in patients with metabolic syndrome by lowering TC, TG, and LDL-C and increasing HDL-C [109]. Moreover, garlic and cumin showed a strong hypotensive effect on patients with type 2 diabetes [110]. In brief, some spices, like cardamom, cinnamon, saffron, ginger, garlic, and cumin, hold great promise in preventing and treating CVDs.


### 4.4. The Effects of Nuts on CVDs

Nuts contain several antioxidant components and possess many bioactivities [111–113]. Moderate intake of nuts also attenuated the risk factors of CVDs. An RCT found that consumption of almond which provided 15% energy significantly lowered truncal and total body fat as well as DBP in overweight or obese adults [114]. Another 6-month-long RCT demonstrated that intake of walnut remarkably reduced body weight, body mass index, waist circumference, SBP, TC, and LDL-C [115]. Moreover, supplementing type 2 diabetes participants with cashew nut considerably reduced SBP and increased HDL-C, while significant differences were not observed in body weight, body mass index, glycemic, and other lipid variables [116]. Additionally, intake of mixed nuts, including almonds, cashews, hazelnuts, pecans, Brazil nuts, macadamia nuts, pistachios, walnuts, and peanuts, could attenuate CVD risk factors by improving body weight and glucose regulation, without exerting the negative effects on lipids compared with a common carbohydrate-rich snack [117].


### 4.5. The Effects of Teas on CVDs

As the second-most consumed beverage worldwide, the nutrition value of teas is extensively investigated. Several studies found that the consumption of teas could ameliorate the risk factors of CVDs. For example, supplementation with green tea extract, which contained 1,315 mg catechins, could significantly improve lipid profile in postmenopausal women by reducing the levels of TC, LDL-C, and non-HDL-C [118]. Furthermore, a study pointed out that the consumption of phytosterol-enriched functional black tea could lower TC, LDL-C, and apolipoprotein B in mild hypercholesterolemia subjects, accompanied with the amelioration of oxidative stress [119]. Moreover, an open-label pilot study found that after daily administration of 2 g/L kosen-cha, obese subjects showed a significant reduction of body weight, BMI, waist circumferences, and serum TG levels, as well as the improvement of insulin resistance, vascular function, and cardiac hypertrophy [120].


### 4.6. The Effects of Other Plants on CVDs

Other natural products also possessed the ability to protect the health of the cardiovascular system, such as cereals, legumes, and herbs [121, 122]. For example, drinking 2 cups of Hibiscus sabdariffa in the morning effectively reduced blood pressure in patients with stage 1 hypertension [123]. Besides, a 3×3 completely randomized repeated study showed that daily consumption of 25 g or 45 g soy flour markedly lowered the levels of fasting plasma glucose, fasting insulin, insulin resistance, and DBP in postmenopausal women with prediabetes and prehypertension [124]. Additionally, using oat noodles to replace 1 or 2 meals of staple food could reduce blood pressure, and improve lipid profile by lowering TC/HDL-C and LDL-C/HDL-C ratios [125]. Hence, supplementing the consumption of Hibiscus sabdariffa, soy, and oat helps to reduce the risk of CVDs.In short, clinical trials involving different conditions of subjects illustrated that some antioxidant natural products could improve cardiovascular health and reduce the risk of CVDs, which might be related to decreasing blood pressure, regulating serum lipids, lowering blood glucose, and lowering body weight.


## 4.1. The Effects of Fruits on CVDs

Several clinical trials revealed the inverse relationship between the consumption of fruits and risk of CVDs. A randomized controlled trial (RCT) found that guava pulp significantly improved lipid profile by decreasing the levels of TC, TG, and LDL-C and increasing the level of HDL-C [101]. Another RCT pointed out that intake of 100 g soursop fruit twice per day for 3 months markedly decreased the levels of SBP, DBP, and serum uric acid in prehypertensive participants compared to the control group [102]. Additionally, a controlled nonrandomized clinical study showed that consuming 300 mL of orange juice for 2 months improved LDL-C, blood glucose, insulin sensitivity, and gut microbiota metabolism in healthy women [103]. Furthermore, a cross-over study found that after the intervention of 200 or 400 mg anthocyanin from haskap berry, the blood pressure levels in participants aged 62-81 years were significantly reduced [104]. Hence, consuming some fruits, like guava, soursop, and orange, is an effective way to prevent and manage CVDs.


## 4.2. The Effects of Vegetables on CVDs

Some vegetables also showed a protective effect on CVDs. An RCT found that the intake of 213 mg tomato extract for 4 weeks lowered DBP and mean arterial pressure in patients with hypertension and high risk of CVDs [105]. Moreover, several studies revealed the potent hypotensive efficacy of beetroot which was associated with its high content of nitrate. For example, a study demonstrated that consuming 70 mL beetroot juice significantly lowered the level of DBP in hypertensive pregnant women [106]. Additionally, daily consumption of 1.2 g eggplant powder markedly improved blood pressure and the psychological state of stressed participants with normal-high blood pressure or stage 1 hypertension [107]. Therefore, it is advisable to increase the intake of tomato, beetroot, and eggplant to protect the health of the cardiovascular system.


## 4.3. The Effects of Spices on CVDs

Similarly, some spices effectively reduced the risk of CVDs. An RCT showed that after intervention with 3 g cardamom for 2 months, the levels of TC and LDL-C in overweight and obese prediabetic women were remarkably lowered, while SBP, DBP, glycemic indices, and serum lipid values in the cardamom group did not significantly differ from the placebo group [108]. Another study compared the cardiovascular-protective effect of cardamom, cinnamon, saffron, and ginger, demonstrating that all of them showed potent abilities in controlling blood pressure and improving endothelial function [33]. Besides, daily ingestion of Satureja hortensis L. effectively improved the lipid profile in patients with metabolic syndrome by lowering TC, TG, and LDL-C and increasing HDL-C [109]. Moreover, garlic and cumin showed a strong hypotensive effect on patients with type 2 diabetes [110]. In brief, some spices, like cardamom, cinnamon, saffron, ginger, garlic, and cumin, hold great promise in preventing and treating CVDs.


## 4.4. The Effects of Nuts on CVDs

Nuts contain several antioxidant components and possess many bioactivities [111–113]. Moderate intake of nuts also attenuated the risk factors of CVDs. An RCT found that consumption of almond which provided 15% energy significantly lowered truncal and total body fat as well as DBP in overweight or obese adults [114]. Another 6-month-long RCT demonstrated that intake of walnut remarkably reduced body weight, body mass index, waist circumference, SBP, TC, and LDL-C [115]. Moreover, supplementing type 2 diabetes participants with cashew nut considerably reduced SBP and increased HDL-C, while significant differences were not observed in body weight, body mass index, glycemic, and other lipid variables [116]. Additionally, intake of mixed nuts, including almonds, cashews, hazelnuts, pecans, Brazil nuts, macadamia nuts, pistachios, walnuts, and peanuts, could attenuate CVD risk factors by improving body weight and glucose regulation, without exerting the negative effects on lipids compared with a common carbohydrate-rich snack [117].


## 4.5. The Effects of Teas on CVDs

As the second-most consumed beverage worldwide, the nutrition value of teas is extensively investigated. Several studies found that the consumption of teas could ameliorate the risk factors of CVDs. For example, supplementation with green tea extract, which contained 1,315 mg catechins, could significantly improve lipid profile in postmenopausal women by reducing the levels of TC, LDL-C, and non-HDL-C [118]. Furthermore, a study pointed out that the consumption of phytosterol-enriched functional black tea could lower TC, LDL-C, and apolipoprotein B in mild hypercholesterolemia subjects, accompanied with the amelioration of oxidative stress [119]. Moreover, an open-label pilot study found that after daily administration of 2 g/L kosen-cha, obese subjects showed a significant reduction of body weight, BMI, waist circumferences, and serum TG levels, as well as the improvement of insulin resistance, vascular function, and cardiac hypertrophy [120].


## 4.6. The Effects of Other Plants on CVDs

Other natural products also possessed the ability to protect the health of the cardiovascular system, such as cereals, legumes, and herbs [121, 122]. For example, drinking 2 cups of Hibiscus sabdariffa in the morning effectively reduced blood pressure in patients with stage 1 hypertension [123]. Besides, a 3×3 completely randomized repeated study showed that daily consumption of 25 g or 45 g soy flour markedly lowered the levels of fasting plasma glucose, fasting insulin, insulin resistance, and DBP in postmenopausal women with prediabetes and prehypertension [124]. Additionally, using oat noodles to replace 1 or 2 meals of staple food could reduce blood pressure, and improve lipid profile by lowering TC/HDL-C and LDL-C/HDL-C ratios [125]. Hence, supplementing the consumption of Hibiscus sabdariffa, soy, and oat helps to reduce the risk of CVDs.In short, clinical trials involving different conditions of subjects illustrated that some antioxidant natural products could improve cardiovascular health and reduce the risk of CVDs, which might be related to decreasing blood pressure, regulating serum lipids, lowering blood glucose, and lowering body weight.


## 5. Conclusions

As a public health problem of global concern, CVDs have attracted considerable attention. Some antioxidant natural products have been proven capable of preventing CVDs. Multiple epidemiological investigations enrolling participants from different countries, different ages, and so on, suggested that the consumption of antioxidant natural products was beneficial to reduce the risk of CVD events. Moreover, results from experimental studies showed that some natural products exerted cardiovascular-protective effects via different mechanisms of action, such as reducing blood pressure, improving the lipid profile, ameliorating oxidative stress, mitigating inflammation, and regulating gut microbiota. Furthermore, clinical trials confirmed that some antioxidant natural products could prevent and treat CVDs. Supported by current evidence, some antioxidant natural products and their active compounds could be developed into functional foods or medicine for the prevention and treatment of CVDs. In the future, the effects of more antioxidant natural products on CVDs should be evaluated to find out more cardiovascular-protective natural products, and relative bioactive components should be isolated and identified. In addition, the mechanisms of action should be elucidated further. Furthermore, special attention should be paid to the safety of relative natural products and functional foods.



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*Source: 6627355-2021-01-29.xml*