Atherosclerosis
Incidence and prevalence
Atherosclerosis is a chronic disease affecting arteries. It is considered a leading cause of vascular morbidity worldwide. It is complicated by several serious conditions such as ischemic heart disease, ischemic stroke, and peripheral arterial disease. However, some high-income countries have reported a decline in the incidence and mortality from such serious conditions, which could be explained by the recognition of many risk factors of atherosclerosis and modifying the lines of treatment. On the other hand, most developing countries of low- and middle-income have reported a decline in mortality from ischemic stroke, but variable mortality rates from ischemic heart disease (Herrington, Lacey, Sherliker, Armitage, & Lewington, 2016). The prevalence rate of atherosclerosis increases with age. Males are affected more than females, but they are almost equal in the age group of 60 years and above. Also, significant lesions are observed in chronic smokers, alcoholics and non-vegetarians (Babu, Nagaraja, & Reddy, 2016).
Pathophysiology
Better understanding of the pathophysiology of atherosclerosis has changed its concept from a lipid storage disease into a chronic inflammatory disease. Atheroma formation was thought to be a passive lipid collection in the arterial wall, but the modern era of atherosclerosis has focused on the inflammatory process and the proliferation of smooth muscle cells in the arterial intima as a nidus for forming atherosclerotic plaques (Libby, 2012).
Inflammation has shown to be involved in all aspects of atheromatous plaque formation including inception, progression and complication. Inflammation is defined as a local response to cellular injury that is characterized by capillary dilatation and inflammatory cells infiltration. Normally, the endothelial cells lining the arterial wall resist adhesion of leucocytes and promote fibrinolysis. Once exposed to damage, these cells express adhesion molecules that recruit many classes of leucocytes, most importantly, blood monocytes. As monocytes adhere to the endothelium, they receive chemoattractant signals from pro-inflammatory mediators known as chemokines; these signals drive them to enter the intima. Inside the intima, they mature into macrophages that express scavenger receptors. Scavenger receptors allow the macrophages to engulf modified lipoprotein particles, so they acquire the classic microscopic appearance of foam cells that appear in atherosclerotic lesions. Macrophages proliferate inside the intima and release growth factors and cytokines, then undergo apoptosis (Libby, Okamoto, Rocha, & Folco, 2010). Figure 1 illustrates the process of inflammatory response and formation of foam cells.
Figure 1. Dyslipidemia, represented by LDL particles, induces the endothelial injury. The injury triggers the inflammatory response that eventually leads to foam cell formation (Rocha & Libby, 2009).
Damage to the endothelium can result from various factors such as hypertension, dyslipidemia, obesity, insulin resistance, metabolic syndrome and cigarette smoking. These factors are considered the traditional risk factors for atherosclerosis, as they all share many common aspects of their pathophysiological concepts. Many studies have proven similarities between atherosclerosis and obesity-related metabolic disorders in their pathophysiology regarding the role of macrophages and inflammatory mediators and pathways (Rocha & Libby, 2009). As a result, a new relation between these risk factors and atherosclerosis has been established as shown in Figure 2.
Figure 2. The pro-inflammatory mediators represent a link between the traditional risk factors for atherosclerosis and the pathology affecting the arterial wall (Libby, 2012).
An early step of inflammation is the release of chemokines such as monocyte chemoattractant protein (MCP)-1, also known as chemokine ligand (CCL2) that interact with chemokine receptor CCR2, and other factors. These factors increase the expression of adhesion molecules such as intercellular adhesion molecule (ICAM)-1, which has a role in allowing monocytes/macrophages to enter the arterial intima by diapedesis. MCP-1 is believed to have a very important role in atherosclerosis formation. It enhances the migration of circulating monocytes to the sites of inflammation and formation of atheromatous plaques. It is considered a marker of adverse cardiovascular events, as its circulating level is greatly increased in patients with coronary or peripheral artery disease. It reflects the degree of endothelial dysfunction and atherosclerotic burden. Besides, it is used as a marker for coronary inflammation because it mediates the atherogenic effects of other risk factors for coronary artery atherosclerosis (Rabkin, Langer, Ur, Calciu, & Leiter, 2013). Some experimental studies have stated that deletion of MCP-1 prevents macrophage recruitment and atherosclerotic lesion development (Ma, Yabluchanskiy, Hall, & Lindsey, 2014). Furthermore, some studies have claimed that decreased expression of ICAM-1 is an important mechanism in the beneficial effect of certain agents on cardiovascular function (Agarwal, et al., 2013).
Allograft vasculopathy represents another evidence for ending the old theory of considering atherosclerosis as a lipid storage disease. It is represented by an accelerated intimal hyperplastic lesion that leads to progressive vascular stenosis, so it is considered the major long-term limitation to successful transplantation of a solid organ. It involves the donor arteries and spares the host arteries, hence it is regarded as a special example of immune-mediated atherosclerosis (Mitchell, 2013).
Prevention and treatment
Many researches have proved that inflammatory mediators and cytokines, generation of reactive oxygen species (ROS) through activation of NADPH oxidase in a process known as oxidative stress, and the renin-angiotensin system (RAS) have a critical role in the pathophysiology of atherosclerosis. These new trends have paid the attention for new treatment strategies such as anti-inflammatory agents, RAS blockers and anti-oxidants in treatment of atherosclerosis (Husain, Hernandez, Ansari, & Ferder, 2015). These new strategies do not reduce the importance of controlling the traditional risk factors, and the importance of life style modification in order to prevent atherosclerosis. Healthy life style include regular exercise, weight loss if needed and consumption of balanced diet rich in fruits and vegetables and low in saturated fat (Babu, Nagaraja, & Reddy, 2016).
Thymoquinone
Source
Thymoquinone (TQ) is a derivative of a medicinal plant called Nigella Sativa (also known as black cumin or black seed). It has the chemical formula of 2-Isopropyl-5-methyl-1, 4-benzoquinone. It has a historical and religious background. In the Islamic tradition, it has been used for its healing powers. Also, it has been used as a traditional medicine in the Middle and Far East for treating several diseases such as bronchial asthma, headache, hypertension, dysentery and gastrointestinal problems. Nigella Sativa ingredients contain about 36% fixed oil, and about 0.45-2.5% volatile oil. Figure 3 illustrates the important active ingredients obtained from Nigella Sativa volatile oil by High Performance Liquid Chromatography (HPLC) analysis. Thymoquinone is considered the major bioactive component among these active ingredients, as it has been subjected to many studies investigating its variable actions since its first extraction in 1960s (Ragheb, et al., 2009).
Figure 3. Chemical structure of the important Nigella Sativa volatile oil active ingredients (Ragheb, et al., 2009).
Anti-inflammatory activity
Many studies have confirmed the historical knowledge of the anti-inflammatory activity of thymoquinone. The anti-inflammatory properties of thmoquinone are because of its ability to inhibit inflammatory mediators, inhibit B cell-mediated immune response, balance between T helper type 1 and 2 (Th1/Th2 ratio), and enhance T cell and natural killer cell-mediated immune response (Gholamnezhad, Keyhanmanesh, & Boskabady, 2015).
During studying the airway inflammation in mouse and rat models of allergic asthma, thymoquinone showed an effective anti-inflammatory activity. It caused a reduction in prostaglandin D2 production in the airways, and a reduction in lung eosinophilia. Moreover, it decreased the production of T helper type 2 (Th2) cytokines in the broncho-alveolar lavage fluid, and decreased cyclooxygenases (COX-2) protein expression in the lung. Also, it lowered the raised serum levels of IgE and IgG1, and suppressed the allergen-induced lung eosinophilia.
Another experimental procedure was induction of arthritis in rats. Administration of thymoquinone caused marked reduction in both clinical and radiological arthritis scores, and a decline in tumor necrosis factor (TNF-α) and interleukin (IL-1β) as well.
Administration of thymoquinone to female rats with induced gestational diabetes has resulted in improvement of diabetic complications in their offspring. It produced an increase in the IL-2 level and T cell proliferation, improving the T cell immune response (de Cássia da Silveira e Sá, Andrade, & de Sousa, 2013).
Anti-oxidant activity
Reactive oxygen species such as super-oxide anion radical (O2–), hydroxyl radical (OH–), hydrogen peroxide (H2O2), hypo-chlorous acid (HOC1–), and peroxynitrite (ONOO) are normal products of metabolic processes produced by NADPH oxidase enzymes. The high level of these ROS causes tissue damage. The anti-oxidant activity of thymoquinone is summarized in its capability of improving the action of anti-oxidant enzymes such as glutathione peroxidase, glutathione-S-transferase and catalase, and acting as a free radical and superoxide radical scavenger (Gholamnezhad, Keyhanmanesh, & Boskabady, 2015).
In a rat model of acute bacterial prostatitis induced by Escherichia coli (E. coli), thymoquinone exhibited a protective anti-oxidant effect against tissue injury. It produced a reduction in malondialdehyde (MDA) levels, which is regarded as one of the lipid peroxidation markers, and an improvement in the histological damage generated by E.coli (Inci, et al., 2013).
In rats with induced hypercholesterolemia, thymoquinone showed a significant activity in scavenging hydroxyl radicals (OH–) from plasma. Also, it decreased Plasma total cholesterol and low-density-lipoprotein (LDL) levels. In addition, it resulted in an up-regulation of catalase, superoxide dismutase 1 (SOD1) and glutathione peroxidase 2 genes, and an increase in the liver antioxidant enzyme levels (Ismail, Al-Naqeep, & Chan, 2010).
Another experimental procedure was the induction of allergic encephalomyelitis (EAE), which is considered an accepted animal model for human multiple sclerosis, thymoquinone showed anti-oxidant activity by increasing the level of reduced glutathione (GSH) in the spinal cord of animals (Amin & Hosseinzadeh, 2016).
Anti-atherogenic activity
The anti-atherogenic effect of thymoquinone emerges from the fact that it has anti-oxidant properties and it can improve the lipid profile. It causes a decrease in the high levels of LDL, total cholesterol and triglycerides (TG), and causes an increase in high-density lipoproteins (HDL) level. Therefore, it promotes ameliorating oxidative stress-induced atherosclerosis (Farkhondeh, Samarghandian, & Borji, 2017).
In a rabbit model of atherosclerosis, atherosclerosis was induced by hyperlipidemia and aggravated by administration of cyclosporine A (CsA). Thymoquinone exhibited anti-atherogenic properties, and inhibited the formation of atherosclerotic plaque by 50%. This significant result was investigated by many parameters. One of the interesting parameters was studying the intima/media ratio, as thymoquinone caused about 75% reductions in the intimal cross-sectional area and the intima/media ratio (Ragheb, Attia, Elbarbry, Prasad, & Shoker, 2011). Figure 4 shows the different mechanisms of action of anti-atherogenic activity of thymoquinone.
Figure4. A diagrammatic illustration of the beneficial effects of thymoquinone on atherosclerosis (Ragheb, Attia, Elbarbry, Prasad, & Shoker, 2011).
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