Oxidative Stress in Coronary Artery Disease Development Introduction Coronary artery disease

Oxidative Stress in Coronary Artery Disease Development

Coronary artery disease (CAD) is caused by the narrowing of coronary arteries by the formation of cholesterol complex called plaque builds up intima (endothelium) of the coronary arteries (Figure1). The coronary arteries bring oxygen and nutrient-rich blood to the heart (Ambrose and Singh,2015). Damages of coronary arteries facilitate plaque formation to the inner lining of the arteries, the condition is called atherosclerosis. Hypertension, hypercholesterolemia, diabetes, and smoking are the major risk factors damage inner layer of coronary arteries (Gander et al.,2014).

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Figure1: The buildup of plaque reduces the flow of blood (National heart, lung health institution,2018).
If the plaque buildup over time, plaque can harden or becomes rupture. Hardened plaque narrows the coronary arteries and affect the flow of oxygen-rich blood to the heart. The plaques can also suddenly break open, a blood clot can form in its surface by the help of platelets and completely blocks the coronary blood vessels (Figure2). When the flow of oxygen-rich blood reduced to the cardiac muscle, angina occurs. Angina is a chest pain. A heart attack occurs when the flow of oxygen-rich blood is restricted to the part of cardiac muscle, which can lead to the heart failure and arrhythmias(Burke,2009).

Figure2: Buildup and rupture of plaques inside the coronary arteries (National library of medicine,2018).

The average adult inhales about 10,000L of air daily (Sheng et al., 2014). Oxygen gas makes up about 21% of atmospheric air. Oxygen is necessary for the series of chemical reactions that take place in the body cell and release energy (ATP) from nutrients (Anne and Allison, 2014).
Oxygen-derived free radicals(ROS) are oxygen(O) containing molecules with higher chemical reactivity than molecular oxygen e.g. Hydrogen peroxide(H2O2) hydroxyl radical(OH-) and the superoxide anion(O2-) (Kong and Chandel, 2018). Several primary ROS-producing systems are present in blood vessel wall including xanthine oxidase (XO), enzymes of the mitochondrial respiratory chain, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOXs), lipoxygenase, myeloperoxidase (MPO) and uncoupled endothelial nitric oxide synthase (eNOS) (Koichi and Keaney,2011).

ROS act as an intracellular signaling molecules to promote coronary artery disease. Normally ROS present in all aerobic cells in balance with biochemical antioxidants (Waris and Ahsan, 2014). An antioxidant is a substance that neutralize oxidative injury of tissues from ROS, and inhibits radical linked damage of proteins, DNA, lipid and other cellular components (Mykc-Mbata, Meludu and Dioka,2018).
Oxidative stress is an imbalance between ROS and antioxidants because of excess ROS, antioxidants depletion, or both (Leopold, 2009). Oxidant stress causes endothelial dysfunction, activates inflammation, immune responses, and thrombus formation, oxidizes lipids, and initiates a cascade of vascular events that is permissive for the formation of plaques inner line of the artery vessels (Leopold, 2015).
In order to mitigate from the effects of ROS, antioxidants systems are present in artery blood vessel wall. Antioxidants can be categorized into endogenous antioxidants (enzymatic ROS scavengers – glutathione peroxidase, catalase, superoxide dismutase and non-enzymatic – glutathione, thioredoxin) and exogenous antioxidants. Exogenous antioxidants are dietary antioxidants (vitamins A, C, E, minerals and polyphenolics) and pharmaceutical antioxidants (?-tocopherol, ascorbic acid, ?-carotene, and reduced glutathione (GSH) (Vichova and Motovska,2013). When antioxidant activity is decreased oxidant stress may occur in tissues (Koichi and Keaney,2011).

Table1: Roles of ROS in physiological vs. pathological states (Koichi and Keaney,2011).
Physiological state
Low levels of ROS Pathological state
High levels of ROS
Cell growth Cause apoptosis/cell death
Stress adaptation Killing pathogens(extracellular)
Promote injury response Attenuate cell function
Modify cellular phenotype Promotes tissue injury
Chronic antioxidants not effective or harmful Chronic antioxidants more likely to be effective

Pathologies of coronary artery disease and Oxidative Stress

ROS are produced in low amounts during several kinds of enzymatic and non-enzymatic processes under normal conditions: by proton leakage during oxidative phosphorylation in mitochondria; by various enzymes such as NADH/NADPH oxidase in endothelial cells, vascular smooth muscle cells and neutrophils, xanthine oxidase in endothelium, lipoxygenase pathways, uncoupled nitric oxide synthase (NOS) and myeloperoxidase (MPO) (Vinchova and Motovska,2013).

Typically, these processes are nonpathogenic to the host organism because low levels of ROS are maintained by antioxidants. When ROS produce under oxidative stress condition can pose threat to intima cells by causing peroxidation of lipids, oxidation of proteins, damage to nucleic acids, enzyme inhibition and leading to programmed cell death in vascular structure and function(Sanjay,2015).

Mitochondria are predominant source of ROS in all cells. Superoxide (O2.-) mainly generated by mitochondrial electron transport chain and can be converted to hydrogen peroxide(H2O2) by superoxide dismutase(SOD). In the presence of metal ions such as iron and copper ions, H2O2 can generate the highly reactive hydroxyl radical(HO.). Neutrophils produce many ROS via myeloperoxidase(MPO). MPO dependent formation of hypochlorous acid (HCLO) reacts withO2.- to form peroxynitrite(ONOO-) (Ilaria, Fabio and Ilaria,2017) (Figure3).

Figure3: ROS present in cardiovascular system (Koichi and Keaney,2011).

Oxidative stress of coronary artery disease is a determinant in the onset and progression of endothelial dysfunction and predisposing to artherosclerosis. Endothelium dysfunction is a process allows entry and modification of lipids in the intima of artery. These lipids serve as a pro-inflammatory mediator which initiate leukocyte recruitment and foam cell formation to promote artherosclerosis. Oxidative stress of coronary artery disease is caused by different risk factors of artherosclerosis such as hypercholesterolemia, hypertension, diabetes and smoking. Hypercholesterolemia and smoking are caused coronary artery disease by Oxidative modification of LDL (Sultan and Eric,2005).
Biomarker is a substance or process that can be measured in the body or its products and influence or predict the incidence of disease (Frijhoff et al.,2015). Lipid peroxidation(OX-LDL) act as an oxidative biomarker is related to increased risk for coronary artery diseases(Vassalle,2012).
Oxidized low density lipoprotein (OX-LDL) – An increased concentration of plasma LDL cholesterol plays a major role in the development of atherosclerosis. LDL is composed of a hydrophilic surface layer of phospholipid, free cholesterol, and hepatically derived apoB100. The core of the LDL particles consist of esteri?ed cholesterol and triglyceride together with the fatty acid tails of the phospholipid.
Oxidative modification of LDL by all major cell types of the arterial wall including endothelial cells, Smooth muscle cells, and macrophages via their extracellular release of ROS plays a major role in artherogenesis. Formation of superoxide anion formation in vascular cells promote conversion of LDL to more artherogenic oxidized LDL(ox-LDL) (Jezovnik and Poredos,2007). Also oxidized LDL has a portability to stimulus of vascular oxygen radical formation increasing oxidative stress. Ox-LDL is taken up by macrophages via scavenger receptor pathways such as lectin-like oxidized LDL receptor-1 to form cholesteryl ester-rich foam cells and endothelial cells become dysfunctional, promotes the development of the early fatty-streak lesion.
NAD(P)H oxidases are the major source of ROS in the vasculature. An activity of the phagocytic NAD(P)Hoxidases with a corresponding increase of oxidized LDL (oxLDL) enhances the thickness of intima coronary arteries.

Lipid peroxidation is process which provides a source of secondary free radical; it acts as a second messenger and enhancing the biochemical lesions. The initiation of peroxidation catalyzed by a hydroxyl radical within the LDL molecule gives rise conjugate dienes by removing hydrogen atoms. After the addition of oxygen, lipid hydroperoxy radicals (LOO*). Hydrogen peroxide increase vascular permeability, prostacyclin (Type of prostaglandins stimulates constriction and clotting of platelets) release, and translocation of P-selectin to the endothelial cell surface. Lipid hydroperoxy radicals (LOO*) attacks another fatty acid resulting in the formation of lipid hydro-peroxide (LOOH*) and additional free radical. Lipid peroxides also inhibit the synthesis of prostacyclin. Malondialdehyde (MDA) and lysophosphatides are accumulate in the LDL particle. These products interact with the amino side chain of the apoB100 and modify it to form new epitopes. Changes in apoB100 cause hypercholesterolemia (Randhir, Sushma and Rakesh,2014).
Oxidized LDL also stimulates the release of monocyte derived tumor necrosis factor-?(TNF-?) and IL-1?, facilitate smooth muscle cell proliferation. Oxidized lipids which accumulate in the intima, strongly modulate in?ammation through involvement of various signaling pathways.
Antioxidants in coronary artery disease
Antioxidants as a therapeutic intervention which prevent or repair the coronary artery damage by scavenging oxygen – derived free radicals from the oxidized low -density lipoprotein. By the prevention of oxygen – derived free radicals from the oxidized LDL help lower the risk of heart attacks by inhibiting the formation of plaque in the arteries and the oxidation of LDL cholesterol.
The cardiovascular antioxidant system is highlighted by the array of enzymatic and non-enzymatic antioxidants to reduce cellular ROS to less reactive forms. The major antioxidant are superoxide dismutases, glutathione peroxidases(GPx), and catalase. Catalase serve as to reduce superoxide/hydrogen peroxide (or lipid hydro peroxides) to water (or lipid hydroxides).
There are many important small-molecule antioxidants such as ?-tocopherol, ascorbic acid, ?-carotene, and glutathione reductase (GSH). The enzyme glutathione reductase maintains intracellular levels of GSH by reducing glutathione disulfide in a reaction that requires NADPH, which is supplied by glucose-6-phosphate dehydrogenase.
Dietary antioxidants ?-carotene and related carotenoids, ascorbic acid, and ?-tocopherol play a vital role in the prevention of coronary artery disease. The carotenoids are fat-soluble free radical scavengers that are typically found in yellow-orange fruits and vegetables and leafy green vegetables.

Figure4: Antioxidant signaling and mechanisms of atherosclerosis

Antioxidant activity is decreased or small molecule antioxidant availability is limited, oxidant stress may occur as a result of diminished net antioxidant capacity. Ascorbic acid (vitamin C) is a water-soluble antioxidant in humans that serves as an electron donor and reducing oxidized species. Ascorbic acid typically found in citrus and other fruits and vegetables (leafy greens and tomatoes). The fat-soluble antioxidant ?–tocopherol (vitamin E) that reduce ROS by donating a hydrogen atom. ?–tocopherol is found in vegetable oils, whole grains, nuts and seeds, and green leafy vegetables. Therefore, foods with antioxidant properties are associated with a reduction in inflammatory markers and LDL oxidation, and improved endothelial function.

Apo protein E (apoE) is a protein involve in fat metabolism. It has an anti-oxidant activity and inhibits LDL oxidation, inhibition of platelet aggregation and smooth-muscle-cell migration and proliferation.
All antioxidants are functionally similar but in the clinical trials they have been different threshold effects for cellular effects of atherosclerosis. High dose of antioxidants intake may result in toxicity to human.

Pathophysiology of coronary artery disease

Coronary artery disease mainly occurs due to atherosclerosis which is accelerated by risk factors such as Hypertension, hypercholesterolemia, diabetes, and smoking. Atherosclerosis is a chronic process, characterized by progressive accumulation of lipids, fibrous elements, and inflammatory molecules in the walls of the arteries. Atherosclerosis starts to develop from an injured inner lining of the coronary artery /endothelium. Cholesterol, fats, lipoproteins and other debris start to accumulate at the site of injury in the intima of the artery, where plasma antioxidants are not present. Atherosclerosis starts with the efflux of high concentration of low density lipoprotein (LDL)/ cholesterol to damaged endothelium space, which can be oxidized by various agents.
Oxidized/modified LDL particles are powerful chemotactic molecules that prompt expression of vascular cell adhesion molecules and intercellular adhesion molecules at the surface of endothelium, and stimulate monocyte adhesion and migration to the sub endothelial space. Monocytes transform into macrophages in the intima media. Macrophages engulf oxidized LDL by the help of scavenger receptors such as SRB1, CD36 and TR4. Oxidized LDL–antibody complex is a form of oxidized LDL which can be taken up by the macrophage foam cell receptor and promote to become foam cells and release pro inflammatory cytokines, interleukins and tumor necrosis factor. The foam cells give rise to the earliest visible form of an atheromatous lesion called the fatty streak.

Moreover, in the sub endothelial space accumulate other forms of leukocytes, including lymphocytes and mast cells. The interaction between monocytes, macrophages, foam cells and T-cells induce a cellular and humoral immune response (inflammatory cascade) with the production of several pro inflammatory molecules such as interleukin-6 (IL-6) and tumor necrosis factor (TNF-?).
The smooth muscle cells migrate from the medial layer of the artery into the intima towards fatty streaks, where they multiply and start to produce extracellular matrix comprising of collagen and proteoglycan. Extracellular matrix molecules that are developing a fibrous cap which is covering the initial fatty streak. Inside the fibrous cap the foam cells die, therefore release lipids that collect in the extracellular space, forming a lipid-rich pool. This process results in the formation of the atherosclerotic lesion, the fibrous plaque. The plaque starts bulge into the lumen of the artery generates a limitation of blood flow which is causing ischemia to the tissue and is expressed clinically as stable angina. Increase size of plaque results blood vessels become further narrowed and cause myocardial infarction. Fibrous plaque develops its own small vessels to receive a supply of blood, called as angiogenesis. Thereafter the plaques begin to calcify, calcium starts to deposit.
Moreover, finally fibrous plaques composed of a thin fibrous cap made mostly of type I collagen along with no or few smooth muscle cells, abundant macrophages and pro inflammatory and pro thrombotic molecules leading to atheroma. Two types of plaque can be defined: stable and unstable, based on the balance between formation and degradation of fibrous cap. The vulnerable plaque breaks open which exposes the core lipids and necrotic material to thromogenic factors in the blood. It causes the aggregation of platelets that form a clot across the plaque and

Many different medicines are used to treat coronary artery disease.Antiplatelets (low-dose aspirin,clopidogrel)-prevent clotting, Statins- cholesterol lowering medicine,Beta-blockers-prevent angina and nitrates which are lower blood pressure and relieves heart pain.