**2. Effects of essential oils**

The effects of essential oils on CVDs are summarized in **Table 1**.

## **2.1. Dyslipidemia**

dyslipidemia, hypertension, and diabetes, cause oxidative stress. Fatty liver due to hyperlipidemia is also associated with increased lipid peroxidation [4]. Oxidative stress impairs vascular endothelial function, which is characterized by reduced nitric oxide (NO) bioavailability. Vascular dysfunction contributes to the impairment of vascular tone, characterized by a decrease in endothelium-dependent vasorelaxation [5]. Because endothelium-derived NO inhibits leukocyte adhesion, which causes inflammation [6] and inhibits platelet adhesion [7], endothelial dysfunction can lead to vascular inflammation and thrombosis. Activated platelets have been shown to increase inflammatory responses and the migration of vascular

Various drugs are prescribed to prevent and treat CVDs. For example, aspirin, clopidogrel, statins, beta-blockers and angiotensin converting enzyme (ACE) inhibitors are recommended for vascular protection in patients with stable angina [9]. Moreover, aspirin and statins have been reported to reduce the risks of atherosclerotic CVDs by 10 and 15%, respectively [10]. These drugs, however, have side effects [9]. For example, aspirin has been found to increase the risk of bleeding by 54% [10]. New drugs made of natural products with fewer side effects are therefore needed. Essential oils are natural substances extracted from various organs of aromatic plants. Because these oils have pharmacological effects, they have been widely used in traditional medicines since the Middle Ages [11]. Studies have shown that essential oils and their main components have various biological properties in relation to CVDs. For example, neroli essential oil showed vasorelaxant activity, mediated by the NO-soluble guanylyl cyclase pathway and by ryanodine receptors, in mouse aortic rings [12]. Bergamot essential oil also induced

**Figure 1.** Flow chart showing the mechanisms of CVDs. Various risk factors increase levels of oxidative stress, thereby increasing endothelial dysfunction. Endothelial dysfunction, in turn, promotes abnormalities, such as impaired vascular

tone, thrombosis, inflammation, and angiogenesis, which lead to CVDs.

smooth muscle cells (SMCs) [8] (**Figure 1**).

130 Potential of Essential Oils

Dyslipidemia is a major risk factor for CVDs. Reductions in low density lipoprotein cholesterol (LDL-C) levels have been associated with decreased risks of major vascular events [53], whereas elevated triglyceride (TG) level and total cholesterol (TC)/high density lipoprotein cholesterol (HDL-C) ratios have been associated with increased risks of coronary heart disease, regardless of LDL-C levels [54]. Essential oils have been shown to improve blood lipid levels. For example, *Allium cepa* and *A. sativum* essential oils were found to reduce serum cholesterol and serum TG levels and β/α lipoprotein ratios in cholesterol-fed rabbits, suggesting that these oils have antiatherosclerotic properties [16]. *Dendropanax morbiferus* essential oil also showed antiatherogenic activity by reducing plasma TC, TG, and LDL-C levels and by increasing plasma HDL-C levels in high-cholesterol fed rats [26]. Similarly, *Syzygium aromaticum* essential oil significantly improved dyslipidemia by reducing plasma TC, TG, and LDL-C levels and by increasing plasma HDL-C levels in rats with metabolic syndrome induced by a high fructose diet [4]. Supplementation of a hyperlipemic diet with *Oenothera biennis* essential oil reduced plasma TG and TC levels and increased plasma HDL-C levels [43, 44], and intake of *Linum usitatissimum L.* essential oil reduced blood TC, TG, and LDL-C levels, in patients diagnosed with metabolic syndrome [34].

Efforts have been made to determine the specific mechanisms by which essential oils improve lipid metabolism. *Curcuma longa L.* essential oil improved dyslipidemia in hyperlipidemic rats by modulating the expression of peroxisome proliferator-activated receptor-α, liver X receptor-α, sterol regulatory element-binding protein (SREBP)-2, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and genes involved in lipid regulation in the liver [24]. Oral administration of *Nigella sativa* essential oil to hyperlipidemic rats significantly reduced plasma TG levels and increased plasma HDL-C levels by reducing liver HMGCR activity [39]. Treatment of human hepatoma (HepG2) cells with *Pinus koraiensis* essential oil suppressed the expression of lipid-related genes, such as SREBP-1c, SREBP-2, HMGCR, fatty acid synthase, and glycerol-3-phosphate acyltransferase, increased the expression of low density lipoprotein receptors and inhibited the activation of human acyl-coenzyme A: cholesterol acyltransferases (hACAT) 1 and 2 [47]. Treatment of HepG2 cells with *Lippia alba* essential oil, especially the tagetenone chemotype, decreased lipid synthesis, lipid contents, and volume of lipid droplets via the mevalonate pathway [35]. Also, incubation of HepG2 cells with *Artemisia princeps* essential oil significantly increased LDL-R expression [21].


**Essential oil Subject/route Effects Disease /model Main component Reference**

High glucose induced injury

injury

Pulmonary thrombo embolism

Metabolic syndrome

Hyper lipidemia

Pulmonary thrombo embolism

Hyper lipidemia β-Phellandrene (16.4%)

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β-Phellandrene (16.4%)

Linalyl acetate (36.2%)

α-Linolenic acid (41.0% of total fatty

acid)

myrcenone (30.4%)

— Calarene (38%) [38]

Hyper tension Eugenol (43.7%) [40]

Hyper tension Eugenol (43.7%) [41]

cinnamaldehyde (27.8%)

Linoleic acid (71% of total fatty acid)

Trans-

Thymol (32.0%) [39]

— *L. alba* tagetenone:

Hyper tension Piperitenone oxide (95.9%)

— Piperitenone oxide (95.9%)

— 1,8-Cineole (16.9%) [31]

— Linalyl acetate (36.2%)

[29]

133

[30]

[32]

[33]

[34]

[35]

[36]

[37]

[42]

[43]

inflammation

HUVECs • Anti-oxidation oxLDL induced

• Blood pressure reduction • Vasorelaxation

> function improvement

• Anti-platelet • Anti-thrombosis

reduction • Lipid

improvement

improvement

reduction

• Blood pressure reduction • Vasorelaxation

• Vasorelaxation • NO production increase

improvement • Anti-oxidation

• Blood pressure reduction • Vasorelaxation

reduction

• Anti-platelet • Anti-thrombosis • Vasorelaxation

• Angiogenesis inhibition • Lipid

improvement

• Lipid

Wistar rat/IV • Blood pressure

Rabbit/PO • Anti-platelet

HUVECs • Anti-

Human/Inhalation • Endothelial

Human/PO • Blood pressure

Wistar rat/ IV, superior mesenteric artery of Wistar

Swiss mouse/PO, Guinea pig plasma

*Lippia alba* HepG2 cells • Lipid

*Mentha x villosa* Wistar rat/IV,

*Nigella sativa* Wistar albino rat/ PO

*Ocotea quixos* Swiss mouse/

*Nardostachys jatamasi*

*Ocimum gratissimum*

*Ocimum gratissimum*

*Oenothera biennis*

*Mentha x villosa* Wistar rat/IV • Blood pressure

thoracic aorta of Wistar rat

Thoracic aorta of Sprague-Dawley rat, HUVECs

Wistar rat/IV, thoracic aorta of Wistar rat

SC, thoracic aorta of Wistar rat, Guinea pig plasma

rat

*Fructus Alpiniae zerumbet*

*Fructus Alpiniae zerumbet*

*Hyptis fruticosa Salzm*

*Lavandula hybrida*

*Lavandula hybrida*

*Linum usitatissimum* L.


**Essential oil Subject/route Effects Disease /model Main component Reference**

infarction

Hyper lipidemia

Myocardial ischemia/ reperfusion injury

Hyper lipidemia

Pulmonary thrombo embolism

— *A. melegueta*: eugenol

Athero sclerosis *Allium cepa:* dimethyl-

(82.2%) *A. danielli*: eugenol (51.1%)

trisulfide (16.6%) *Allium ativum:* diallyltrisulfide (33.6%)

Diallyl-trisulfide (33.6%)

Hyper tension Terpinen-4-ol (28.1%) [18]

Hyper tension Terpinen-4-ol (57.4%) [19]

— Linalool (87.7%) [20]

— 1,8-cineole (20.1%) [21]

— d-Limonene (43.5%) [22]

Vascular injury d-Limonene (43.5%) [23]

Ar-turmerone (20.5%) [24]

Ar-turmerone (20.5%) [25]

γ-Elemene (18.6%) [26]

Anethole (75.8%) [28]

[27]

ethyl ester (46.1%)

Hyper tension Hexadecanoic acid,

[15]

[16]

[17]

• Anti-diabetes • Anti-oxidation • ACE inhibition

• Fibrinolysis • Lipid

*Allium sativum* Human/PO • Fibrinolysis Myocardial

improvement

reduction

• Blood pressure reduction • Vasorelaxation

• Blood pressure reduction • Vasorelaxation

• Anti-oxidation • Lipid

improvement

• Intracellular calcium influx inhibition

• Angiogenesis inhibition

improvement • Liver function improvement • Vasorelaxation

inflammation

improvement

• Blood pressure reduction • Vasorelaxation

• Anti-platelet • Anti-thrombosis • Vasorelaxation

• eNOS expression • Anti-platelet • Lipid

• Anti-

Wistar rat/IP • Anti-oxidation

*Aframomum melegueta, Aframomum danielli*

132 Potential of Essential Oils

*Allium cepa, Allium sativum*

*Artemisia princeps*

*Citrus bergamia Risso*

*Citrus bergamia Risso*

*Curcuma longa L.*

*Curcuma longa L.*

*Dendropanax morbiferus*

*Foeniculum vulgare*

*Euphorbiaceae* Wistar rat/IV,

Pancreas and heart

*Alpinia zerumbet* Wistar rat/IV • Blood pressure

thoracic aorta of Wistar rat

thoracic aorta of Wistar rat

HepG2 cells, isolated human

MOVAS cells, EA.hy926 cells

Golden Syrian hamster/PO

Wistar rat/PO, EA.hy926 cells

thoracic aorta of Wistar rat

Swiss mouse/SC, thoracic aorta of Wistar rat, Guinea pig plasma

Wistar rat/PO • Lipid

LDL

Indian albino rabbit /PO

of rat

*Alpinia zerumbet* Wistar rat/PO,

*Aniba rosaeodora* Wistar rat/IV,


**2.2. Hypertension**

motensive rats.

**2.3. Fatty liver**

**2.4. Diabetes**

effects, than *A. danielli* oil [15].

Hypertension is also a major risk factor for CVDs. In the United States, the prevalence of hypertension in adults aged over 60 years was 67.2% from 2011 to 2014 and hypertension was the third leading cause of death from CVDs [55]. Thus, aggressive blood pressure control is needed and essential oils are thought to be helpful. Intragastric administration of *Alpinia zerumbet* essential oil to N-nitro-l-arginine methyl ester (l-NAME)-induced hypertensive rats for 30 days reduced systolic arterial pressure, diastolic arterial pressure, and mean arterial pressure in a time-dependent manner. These hypotensive effects of *A. zerumbet* essential oil were due to its vasorelaxing and Ca2+ antagonist effects [19]. In spontaneously hypertensive rats, *Ribes nigrum* essential oil reduced systolic blood pressure (SBP) significantly when compared with sesame oil [45]. Although *Oenothera biennis* and *Borago officinalis* essential oils also reduced SBP, these effects were not statistically significant. In addition, intravenous administration of *Ribes nigrum* essential oil reduced mean arterial pressure (MAP) in spontaneously hypertensive rats. Intravenous administration of *Alpinia zerumbet* [18], *Euphorbiaceae* [27], *Mentha x villosa* [36], and *Ocimum gratissimum* [40, 41] essential oils to deoxycorticosteroneacetate (DOCA)-salt induced hypertensive rats, reduced MAP. Moreover, *Aniba rosaeodora* [20], *Hyptis fruticosa Salzm* [31], and *Mentha x villosa* essential oils [37] reduced MAP in nor-

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The antihypertensive effects of essential oils have also been demonstrated in human studies. In a randomized controlled trial, oral administration of *Linum usitatissimum* L. essential oil significantly reduced SBP and diastolic blood pressure (DBP) in patients with metabolic syndrome [34]. In addition, polyphenol-rich *Olea* essential oil reduced SBP and DBP in women

Several essential oils effective in the treatment of dyslipidemia also improved liver fat contents and liver function. Oral administration of *Syzygium aromaticum* essential oil, the main component of which is eugenol, to rats fed a high fructose diet, was found to reduce total fat, TC, and TG levels in the liver. In addition, *S. aromaticum* essential oil reduced the plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and direct bilirubin in these rats, thereby improving fatty liver and liver dysfunction [4]. Similarly, oral administration of *Curcuma longa* L. essential oil to hyperlipidemic hamsters not only reduced

diagnosed with stage 1 hypertension and those with high-normal blood pressure [46].

hepatic cholesterol levels but also decreased plasma ALT and AST concentrations [24].

Because chronic hyperglycemia associated with diabetes increases oxidative stress, a cause of vascular endothelial dysfunction, via several pathways such as polyol flux [56], the antidiabetic effect of essential oils is noteworthy. *In vitro* studies showed that the essential oils of *Aframomum melegueta* and *A. danielli*, the main component of which is eugenol, had antidiabetic properties. Although both essential oils inhibited α-glucosidase and α-amylase, *A. melegueta* essential oil had much higher inhibitory activities, indicating greater antidiabetic

**Table 1.** Effects of essential oils in CVDs.

#### **2.2. Hypertension**

**Essential oil Subject/route Effects Disease /model Main component Reference**

Athero sclerosis Linoleic acid (71% of

Hyper tension *Oenothera biennis*:

High-normal BP, stage 1 essential HTN

• Vasorelaxation — Acetic acid

TNF-α induced injury

Myocardial infarction, hypoxia damage

Metabolic syndrome

• Vasorelaxation — Thymol (38.1%) [52]

total fatty acid)

linoleic acid (71.0% of total fatty acid) *Ribes nigrum*: linoleic acid (45.0% of total fatty acid) *Borago officinalis:* linoleic acid (36.0% of total fatty acid)

oleic acid (55–83% of total fatty acid)\*

— Camphene (21.1%) [47]

— 3-Carene (32.1%) [48]

available)

(percentage was not

Borneol (43.6%) [50]

α-Cadinol (19.9%) [51]

Eugenol (75.2%) [4]

[44]

[45]

[46]

[49]

• Anti-oxidation • Anti-platelet • Anti-thrombosis

improvement

• Blood pressure reduction

reduction • Anti-oxidation • Endothelial function improvement

• Lipid

• Anti-

HUVECs • Angiogenesis

HASMCs • Anti-oxidation

improvement

inflammation • Angiogenesis inhibition

• Anti-oxidation • Anti-platelet

• Anti-oxidation

inflammation

improvement • Liver function improvement

• Anti-

• Lipid

inhibition

• Lipid

*Oenothera biennis*

134 Potential of Essential Oils

*Oenothera biennis*, *Ribes nigrum, Borago officinalis*

*Radix Angelica sinensis*

*Schisandra chinensis*

*Syringa pinnatifolia Hems1. var. alashanesis*

*Syzygium aromaticum*

*Trachyspermum ammi*

*Rosa indica L.* Thoracic aorta of rabbit

New Zealand rabbit/PO

Spontaneously hyper tensive rat/

*Olea* Human/PO • Blood pressure

*Pinus koraiensis* HepG2 cells • Anti-oxidation

Wistar rat/IG Kun ming mouse/IP Primary cultured rat myocyte

Sprague-Dawley

Thoracic aorta of Wistar albino rat

\*Polyphenol-rich olive oil was used in this study.

**Table 1.** Effects of essential oils in CVDs.

rat/PO

PO

Hypertension is also a major risk factor for CVDs. In the United States, the prevalence of hypertension in adults aged over 60 years was 67.2% from 2011 to 2014 and hypertension was the third leading cause of death from CVDs [55]. Thus, aggressive blood pressure control is needed and essential oils are thought to be helpful. Intragastric administration of *Alpinia zerumbet* essential oil to N-nitro-l-arginine methyl ester (l-NAME)-induced hypertensive rats for 30 days reduced systolic arterial pressure, diastolic arterial pressure, and mean arterial pressure in a time-dependent manner. These hypotensive effects of *A. zerumbet* essential oil were due to its vasorelaxing and Ca2+ antagonist effects [19]. In spontaneously hypertensive rats, *Ribes nigrum* essential oil reduced systolic blood pressure (SBP) significantly when compared with sesame oil [45]. Although *Oenothera biennis* and *Borago officinalis* essential oils also reduced SBP, these effects were not statistically significant. In addition, intravenous administration of *Ribes nigrum* essential oil reduced mean arterial pressure (MAP) in spontaneously hypertensive rats. Intravenous administration of *Alpinia zerumbet* [18], *Euphorbiaceae* [27], *Mentha x villosa* [36], and *Ocimum gratissimum* [40, 41] essential oils to deoxycorticosteroneacetate (DOCA)-salt induced hypertensive rats, reduced MAP. Moreover, *Aniba rosaeodora* [20], *Hyptis fruticosa Salzm* [31], and *Mentha x villosa* essential oils [37] reduced MAP in normotensive rats.

The antihypertensive effects of essential oils have also been demonstrated in human studies. In a randomized controlled trial, oral administration of *Linum usitatissimum* L. essential oil significantly reduced SBP and diastolic blood pressure (DBP) in patients with metabolic syndrome [34]. In addition, polyphenol-rich *Olea* essential oil reduced SBP and DBP in women diagnosed with stage 1 hypertension and those with high-normal blood pressure [46].

#### **2.3. Fatty liver**

Several essential oils effective in the treatment of dyslipidemia also improved liver fat contents and liver function. Oral administration of *Syzygium aromaticum* essential oil, the main component of which is eugenol, to rats fed a high fructose diet, was found to reduce total fat, TC, and TG levels in the liver. In addition, *S. aromaticum* essential oil reduced the plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and direct bilirubin in these rats, thereby improving fatty liver and liver dysfunction [4]. Similarly, oral administration of *Curcuma longa* L. essential oil to hyperlipidemic hamsters not only reduced hepatic cholesterol levels but also decreased plasma ALT and AST concentrations [24].

#### **2.4. Diabetes**

Because chronic hyperglycemia associated with diabetes increases oxidative stress, a cause of vascular endothelial dysfunction, via several pathways such as polyol flux [56], the antidiabetic effect of essential oils is noteworthy. *In vitro* studies showed that the essential oils of *Aframomum melegueta* and *A. danielli*, the main component of which is eugenol, had antidiabetic properties. Although both essential oils inhibited α-glucosidase and α-amylase, *A. melegueta* essential oil had much higher inhibitory activities, indicating greater antidiabetic effects, than *A. danielli* oil [15].

#### **2.5. Oxidative stress**

Excessive production of reactive oxygen species (ROS) induces endothelial dysfunction, an early stage of atherosclerosis [57]. Patients with coronary artery disease (CAD) have higher lipid peroxidation activity but significantly lower antioxidant enzyme activities than individuals without CAD [58], indicating the importance of maintaining a balance between ROS production and antioxidant defense systems. Several essential oils have shown the ability to reduce oxidative stress. For example, pretreatment of human aortic SMCs with *Schisandra chinensis* essential oil blocked tumor necrosis factor (TNF)-α-induced ROS [50]. *Fructus Alpiniae zerumbet* oil attenuated oxidative stress in human umbilical vein endothelial cells (HUVECs) exposed to ox-low density lipoprotein (LDL), not only by reducing malondialdehyde (MDA) contents but also by increasing the activities of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase, and catalase [30].

[32]. A randomized crossover study in women with stage 1 hypertension or high-normal BP found that a diet containing polyphenol-rich *Olea* essential oil increased hyperemic areas after

Many essential oils have been found to induce vascular relaxation *in vitro*. In a hyperlipidemic animal model, oral administration of *Curcuma longa* L. essential oil, at a dose of 300 mg/kg body weight for 28 days, restored acetylcholine-induced vasorelaxation, as well as increasing eNOS expression and decreasing cholesterol contents in the aorta [24]. *Ocimum gratissimum* essential oil showed partial endothelium-dependent vasorelaxing activity in aortic rings from DOCA-salt induced hypertensive rats. This vasorelaxant activity was mainly attributed to an inhibition of Ca2+ influx rather than Ca2+ release from the sarcoplasmic reticulum [40]. In addition, essential oils of *Aniba rosaeodora* [20], *Euphorbiaceae* [27], *Foeniculum vulgare* [28], *Mentha x villosa* [37], *Nardostachys jatamasi* [38], *Rosa indica L.* [49], and *Trachyspermum ammi* [52] were found to induce vasorelaxation in rat thoracic aorta pre-contracted with KCL or phenylephrine. In particular, the vasodilatory effects of *Nardostachys jatamasi* essential oil were mediated by increased NO production [38]. *Ocotea quixos* essential oil also relaxed aortic rings pre-contracted with U46619 [42]. *Alpinia zerumbet* essential oil was also shown to relax aortic rings pre-contracted with KCL or phenylephrine. *A.* 

tion of Ca2+ influx through voltage-operated and receptor-operated Ca2+ channels [19]. Similarly, the treatment of the rat superior mesenteric artery with *Hyptis fruticosa Salzm* essential oil resulted

dependent manner [31]. Adequate regulation of cytosolic Ca2+ is important in maintaining vascu-

Platelet aggregation and adhesion play important roles in thrombus formation. *Curcuma longa* L. essential oil has been shown to reduce hyperlipidemia-induced platelet activation by suppressing platelet aggregation and adhesion in hyperlipidemic hamsters [24]. Other essential oils were found to inhibit platelet aggregation or adhesion. For example, essential oils of *Foeniculum vulgare* [28], *Lavandula hybrida* [33], and *Ocotea quixos* [42] not only inhibited agonist-induced platelet aggregation *in vitro* but also inhibited thrombin-induced clot retraction in guinea pig plasma. In addition, these three essential oils prevented paralysis in an animal model of acute pulmonary thromboembolism, indicating that these oils had antithrombotic activity. *Syringa pinnatifolia Hems1. var. Alashanesis* essential oil was found to inhibit agonist-induced platelet aggregation in rat whole blood. This result, together with its antioxidant effects, suggests that *Syringa pinnatifolia Hems1. var. Alashanesis* oil has cardioprotective activity [51]. In addition, an atherogenic diet enriched with *Oenothera biennis* essential oil reduced agonist-induced platelet aggregation in whole blood and platelet thromboxane B2 production, thereby inhibiting platelet activation [44]. Both *Allium cepa* and *A. sativum* essential oils have been shown to increase the fibrinolytic activity of garlic and onions in atherosclerotic rabbits [16]. In addition, *A. sativum* essential oil was found to significantly increase the fibrinolytic activity in patients with chronic

lar tone. *Citrus bergamia Risso* essential oil inhibited Ca2+ influx into HUVECs [22].

myocardial infarction and in patients after acute myocardial infarction [17].



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cuff-induced ischemia, another test of vascular endothelial function [46].

**2.7. Impaired vascular tone**

*zerumbet* oil also inhibited CaCl2

**2.8. Thrombosis**

in vascular relaxation and inhibition of CaCl2

Essential oils have also been shown to be active in models of acute myocardial ischemia. For example, *Syringa pinnatifolia Hems1. var. alashanesis* essential oil inhibited the reduction of SOD activity and increased mitochondrial activity in cardiac myocytes [51]. *Aframomum melegueta* and *A. danielli* essential oils showed radical scavenging activity, as well as dose-dependently ameliorating lipid peroxidation in rat heart and pancreas [15]. Similarly, *Artemisia princeps* essential oil displayed radical scavenging activity and inhibited the production of thiobarbituric acid-reactive substances, a marker of LDL oxidation [21]. *Pinus koraiensis* [47] and *Olea* essential oils [46] also inhibited LDL oxidation.

In addition, essential oils have also been found to reduce MDA contents. For example, *Citrus bergamia Risso* essential oil reduced MDA production in carotid arteries injured by balloon angioplasty [23] and *Nigella sativa* essential oil reduced plasma MDA formation in hyperlipidemic rats [39]. In rabbits, an atherogenic diet supplemented with *Oenothera biennis* essential oil inhibited platelet MDA production [44]. Oral administration of *Syzygium aromaticum* essential oil to rats with metabolic syndrome reduced plasma MDA concentrations [4].

#### **2.6. Endothelial dysfunction**

NO is a typical vasodilatory substance produced from l-arginine by the enzyme endothelial NO synthase (eNOS) in vascular endothelial cells [59]. Thus, endothelial dysfunction is associated with decreased NO bioavailability [57]. In hyperlipidemic hamsters, *Curcuma longa* L. essential oil, at a concentration of 300 mg/kg body weight, increased the expression of aortic eNOS, suggesting that *C. longa* L. essential oil protects against endothelial dysfunction [24]. Treatment of HUVECs with *Nardostachys jatamansi* essential oil increased NO production by phosphorylating eNOS, a reaction mediated by the phosphatidylinositol 3-kinase/protein kinase B signaling pathway and changes in intracellular Ca2+ [38]. *Aframomum melegueta* and *A. danielli* essential oils were found to inhibit ACE activity *in vitro*, suggesting that these oils have antihypertensive activity, with *A. danielli* oil having greater activity than *A. melegueta* oil [15].

Flow mediated dilatation (FMD) is a widely used marker of vascular endothelial cell function. A study of night-shift medical workers found that FMD was significantly higher after a 30 min inhalation of *Lavandula hybrida* essential oil than before inhalation and than in a control group [32]. A randomized crossover study in women with stage 1 hypertension or high-normal BP found that a diet containing polyphenol-rich *Olea* essential oil increased hyperemic areas after cuff-induced ischemia, another test of vascular endothelial function [46].

#### **2.7. Impaired vascular tone**

**2.5. Oxidative stress**

136 Potential of Essential Oils

Excessive production of reactive oxygen species (ROS) induces endothelial dysfunction, an early stage of atherosclerosis [57]. Patients with coronary artery disease (CAD) have higher lipid peroxidation activity but significantly lower antioxidant enzyme activities than individuals without CAD [58], indicating the importance of maintaining a balance between ROS production and antioxidant defense systems. Several essential oils have shown the ability to reduce oxidative stress. For example, pretreatment of human aortic SMCs with *Schisandra chinensis* essential oil blocked tumor necrosis factor (TNF)-α-induced ROS [50]. *Fructus Alpiniae zerumbet* oil attenuated oxidative stress in human umbilical vein endothelial cells (HUVECs) exposed to ox-low density lipoprotein (LDL), not only by reducing malondialdehyde (MDA) contents but also by increasing the activities of antioxidant enzymes such as superoxide dis-

Essential oils have also been shown to be active in models of acute myocardial ischemia. For example, *Syringa pinnatifolia Hems1. var. alashanesis* essential oil inhibited the reduction of SOD activity and increased mitochondrial activity in cardiac myocytes [51]. *Aframomum melegueta* and *A. danielli* essential oils showed radical scavenging activity, as well as dose-dependently ameliorating lipid peroxidation in rat heart and pancreas [15]. Similarly, *Artemisia princeps* essential oil displayed radical scavenging activity and inhibited the production of thiobarbituric acid-reactive substances, a marker of LDL oxidation [21]. *Pinus koraiensis* [47] and *Olea*

In addition, essential oils have also been found to reduce MDA contents. For example, *Citrus bergamia Risso* essential oil reduced MDA production in carotid arteries injured by balloon angioplasty [23] and *Nigella sativa* essential oil reduced plasma MDA formation in hyperlipidemic rats [39]. In rabbits, an atherogenic diet supplemented with *Oenothera biennis* essential oil inhibited platelet MDA production [44]. Oral administration of *Syzygium aromaticum* essential

NO is a typical vasodilatory substance produced from l-arginine by the enzyme endothelial NO synthase (eNOS) in vascular endothelial cells [59]. Thus, endothelial dysfunction is associated with decreased NO bioavailability [57]. In hyperlipidemic hamsters, *Curcuma longa* L. essential oil, at a concentration of 300 mg/kg body weight, increased the expression of aortic eNOS, suggesting that *C. longa* L. essential oil protects against endothelial dysfunction [24]. Treatment of HUVECs with *Nardostachys jatamansi* essential oil increased NO production by phosphorylating eNOS, a reaction mediated by the phosphatidylinositol 3-kinase/protein kinase B signaling pathway and changes in intracellular Ca2+ [38]. *Aframomum melegueta* and *A. danielli* essential oils were found to inhibit ACE activity *in vitro*, suggesting that these oils have antihypertensive activity, with *A. danielli* oil having greater activity than *A. melegueta* oil [15]. Flow mediated dilatation (FMD) is a widely used marker of vascular endothelial cell function. A study of night-shift medical workers found that FMD was significantly higher after a 30 min inhalation of *Lavandula hybrida* essential oil than before inhalation and than in a control group

oil to rats with metabolic syndrome reduced plasma MDA concentrations [4].

mutase (SOD), glutathione peroxidase, and catalase [30].

essential oils [46] also inhibited LDL oxidation.

**2.6. Endothelial dysfunction**

Many essential oils have been found to induce vascular relaxation *in vitro*. In a hyperlipidemic animal model, oral administration of *Curcuma longa* L. essential oil, at a dose of 300 mg/kg body weight for 28 days, restored acetylcholine-induced vasorelaxation, as well as increasing eNOS expression and decreasing cholesterol contents in the aorta [24]. *Ocimum gratissimum* essential oil showed partial endothelium-dependent vasorelaxing activity in aortic rings from DOCA-salt induced hypertensive rats. This vasorelaxant activity was mainly attributed to an inhibition of Ca2+ influx rather than Ca2+ release from the sarcoplasmic reticulum [40]. In addition, essential oils of *Aniba rosaeodora* [20], *Euphorbiaceae* [27], *Foeniculum vulgare* [28], *Mentha x villosa* [37], *Nardostachys jatamasi* [38], *Rosa indica L.* [49], and *Trachyspermum ammi* [52] were found to induce vasorelaxation in rat thoracic aorta pre-contracted with KCL or phenylephrine. In particular, the vasodilatory effects of *Nardostachys jatamasi* essential oil were mediated by increased NO production [38]. *Ocotea quixos* essential oil also relaxed aortic rings pre-contracted with U46619 [42]. *Alpinia zerumbet* essential oil was also shown to relax aortic rings pre-contracted with KCL or phenylephrine. *A. zerumbet* oil also inhibited CaCl2 -induced vascular contraction, an effect resulting from the inhibition of Ca2+ influx through voltage-operated and receptor-operated Ca2+ channels [19]. Similarly, the treatment of the rat superior mesenteric artery with *Hyptis fruticosa Salzm* essential oil resulted in vascular relaxation and inhibition of CaCl2 -induced vascular contraction in a concentrationdependent manner [31]. Adequate regulation of cytosolic Ca2+ is important in maintaining vascular tone. *Citrus bergamia Risso* essential oil inhibited Ca2+ influx into HUVECs [22].

#### **2.8. Thrombosis**

Platelet aggregation and adhesion play important roles in thrombus formation. *Curcuma longa* L. essential oil has been shown to reduce hyperlipidemia-induced platelet activation by suppressing platelet aggregation and adhesion in hyperlipidemic hamsters [24]. Other essential oils were found to inhibit platelet aggregation or adhesion. For example, essential oils of *Foeniculum vulgare* [28], *Lavandula hybrida* [33], and *Ocotea quixos* [42] not only inhibited agonist-induced platelet aggregation *in vitro* but also inhibited thrombin-induced clot retraction in guinea pig plasma. In addition, these three essential oils prevented paralysis in an animal model of acute pulmonary thromboembolism, indicating that these oils had antithrombotic activity. *Syringa pinnatifolia Hems1. var. Alashanesis* essential oil was found to inhibit agonist-induced platelet aggregation in rat whole blood. This result, together with its antioxidant effects, suggests that *Syringa pinnatifolia Hems1. var. Alashanesis* oil has cardioprotective activity [51]. In addition, an atherogenic diet enriched with *Oenothera biennis* essential oil reduced agonist-induced platelet aggregation in whole blood and platelet thromboxane B2 production, thereby inhibiting platelet activation [44]. Both *Allium cepa* and *A. sativum* essential oils have been shown to increase the fibrinolytic activity of garlic and onions in atherosclerotic rabbits [16]. In addition, *A. sativum* essential oil was found to significantly increase the fibrinolytic activity in patients with chronic myocardial infarction and in patients after acute myocardial infarction [17].

#### **2.9. Inflammation**

The levels of expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in endothelial cells increase during inflammation [60], with the expression of these adhesion molecules being regulated by inflammatory cytokines such as interleukin (IL)-1 and TNF-α [61]. Several essential oils have been shown effective in inhibiting this process. For example, the treatment of HUVECs exposed to high glucose with *Fructus Alpiniae zerumbet* essential oil was shown to reduce the secretion of IL-8, TNF-α, ICAM-1, and VCAM-1 by inhibiting nuclear factor kappa B (NF-κB) signaling, suggesting that this essential oil has endothelial protective effects [29]. Similarly, the treatment of human aortic SMCs with *Schisandra chinensis* essential oil decreased TNF-α-induced matrix metalloproteinase-9 (MMP-9) activation, inducible NO synthase and cyclooxygenase-2 (COX-2) expression by inhibiting NF-κB signaling [50]. In an animal study, oral administration of *Curcuma longa* L. essential oil to rats exposed to myocardial ischemia/reperfusion injury reduced endothelial cell-induced inflammation by decreasing the expression of E-selectin and ICAM-1 [25]. Similarly, *Syzygium aromaticum* essential oil reduced plasma TNF-α concentration in rats fed a high-fructose diet [4].

**Acknowledgements**

**Conflict of interest**

**Author details**

Republic of Korea

**References**

Geun Hee Seol\* and You Kyoung Shin

S0140-6736(14)61682-2

[Accessed: 2018-01-19]

DOI: 10.1136/bmj.a2467

\*Address all correspondence to: ghseol@korea.ac.kr

A1B03931081).

None.

This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant number: 2016R1D1-

Essential Oils and Factors Related to Cardiovascular Diseases

http://dx.doi.org/10.5772/intechopen.77278

139

Department of Basic Nursing Science, School of Nursing, Korea University, Seoul,

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#### **2.10. Angiogenesis**

The proliferation and migration of vascular SMCs play essential roles in the pathophysiological changes of cardiovascular systems. *Radix angelica* essential oil was found to dosedependently inhibit HUVEC proliferation and migration, and, at concentrations above 20 μg/ ml, to reduce endothelial tube formation, indicating that *R. angelica* essential oil has antiangiogenic effects [48]. Similarly, *Schisandra chinensis* essential oil effectively decreased the TNF-αinduced migration of human aortic SMCs. These findings, together with the antiinflammatory and antioxidant effects of this oil, suggested that *Schisandra chinensis* oil has antiatherosclerotic activity [50].

Animal studies have also assessed the effects of essential oils on angiogenesis. For example, supplementation of a hyperlipidemic diet with *Oenothera biennis* essential oil for 6 weeks reduced endothelial lesions of the aorta and neointimal proliferation of the arterial wall in rabbits [43]. *Citrus bergamia Risso* essential oil reduced the neointima/media ratio and the cross-sectional area of the carotid artery in rats that underwent balloon-induced vascular injury, with these effects accompanied by decreased expression of lectin-like receptor for oxidized LDL [23].
