*What is Atherosclerosis?

Atherosclerosis is a form of arteriolosclerosis which is defined as the 'hardening' of arteries. An example of a cause of this event is atherosclerosis, which is the formation of atheromatous plaque on arteries leading to inelasticity of arterial walls [4]. When macrophage white blood cells (that intake oxidized LDLs) containing lipids, calcium, connective tissue and cell debris accumulate within the endothelium lining, atheromatous plaque will form [6]. The process of the thickening of atheromatous plaque is called atherogenesis. The collection of oxidized LDLs under the endothelium stimulates a NFB-like transcription factor that expresses a specific gene which contains NFB receptors [4]. These genes produce proteins that cause inflammatory responses leading to what is known as 'fatty streaks', in other words the deposition of monocyte-derived macrophages. This oxidation causes damage to the artery and stimulates an immune response. Monocytes which are a specific type of WBC will intake these oxidized LDLs and form foam cells [2].  The inner portion of the atheromatous plaque will now continue to build while the outer portion of the atheromatous plaque becomes even more rigid and calcific than before [6]. The atheromatous plaque consists of: a soft flaky substance at the center of the plaque composed of macrophages, a primary layer of cholesterol crystals and a hard calcified outer layer which is the oldest and most advanced layer. Atheromatous plaques can lead to clots (also known as thrombus) and ruptures (heart attack or stroke) inside the lumen of the artery as a result of uneven collection of macrophages. These clots may eventually self-heal, however, it will cause narrowing of the artery which leads to insufficient blood flow to organs [2]. This narrowing process is called stenosis and it results from the repeated process of ruptures and repairs [3]. When there is stenosis leading to the heart, heart attacks, hypertension and angina (chest pain) will occur [6]. Aneurysms are caused when atheromas produce enzymes that enlarge the artery into a circular shape.

In addition to stimulating harmful immune responses, LDL oxidation will decrease the levels of nitric oxide which relaxes blood vessels and allows for free blood flow. When foam cells die, the LDL contents are released causing more macrophages to accumulate.

Diagram description:

LDL enters the blood through endocytosis into the endothelial cells. LDLs react with ROS and become oxidized within the endothelial lining. Receptors such as CD36 and SR-A of macrophages take up the LDL and transform into foam cells. These cells then generate proinflammatory cytokines and matrix metalloproteinases. This will lead to proinflammatory milieu and atherogenesis. Myeloperoxidase will also be produced- this enzyme produces ROS and oxidizes LDL (creating a dangerous cycle).

*What does Oxidation mean? [11, 12, 22]

Oxidation directly refers to the loss of electrons or increase in oxidation number by an atom, molecule or ion. Oxidants or oxidizing agents have high oxidation numbers and high electronegativity so that they can remove electrons from other atoms and gain electrons themselves. Examples of oxidizing agents with high oxidation numbers include hydrogen peroxide, chromium trioxide, permanganate, and osmium (VIII) oxide.

The process of oxidation and reduction is extremely important in living organisms. In human cellular respiration, for example, there is reduction of oxygen to water, and oxidation of glucose to carbon dioxide.

C₆H₁₂O₆ + 6 O₂ → 6 CO₂ + 6 H₂O

Similarly, in photosynthesis of plants, there is reduction of carbon dioxide into sugars and oxidation of water into oxygen.

6 CO₂ + 6 H₂O + light energy → C₆H₁₂O₆ + 6 O₂

*Biological oxidation? [5, 7]

When oxidation occurs in the human body, oxygen is metabolized and it forms 'free radicals'. Free radicals are defined as atoms with more than one unpaired electron in the outermost valence shell. And because free radicals have at least one unpaired electron, they are very reactive. Free radicals associated with oxygen are referred as ROS (reactive oxygen species); these specific free radicals contain two or more unpaired electrons in the outermost shell. Free radicals in the human body can be both beneficial and detrimental. In the human immune system, free radicals are used as markers for damaged tissue and foreign bodies. With markers, the immune system is able to remove or repair the foreign substances or damaged tissue. In addition, oxidation provides for a main source of biological energy. An excess of ROS or of Free radicals can also harm the human body. In low-density lipoproteins and in cell membranes for example, there are large amounts of polyunsaturated fatty acids; PUFAs maintain the membrane fluidity of the cells. Free radicals steal electrons from this lipid layer of the cell membrane causing a process called lipid peroxidation. ROS will first attack the carbon-carbon double bond of the PUFA; the free radical will steal an electron from the hydrogen at the double bond of carbon. The carbon will then become a free radical, as it now has an unpaired electron. This molecule will rearrange in efforts to become more stable and as a result it forms into a structure called 'conjugated diene' (or CD). CD will then react with oxygen to form a proxy radical; in turn this proxy radical steals an electron from another lipid molecule by a process known as propogation. From this point, the whole process will cycle continuously in a 'chain reaction'.  Lipid peroxidation and propogation is extremely harmful if not terminated by antioxidants or enzymes such as superoxide dismutase, catalase, and peroxidase. Lipid peroxidation can be mutagenic--cause of gene mutation, carcinogenic--cause of cancer, and can cause damage to the cell membrane. 

*High oxidant foods and chemicals:[10]

*Free radicals and human diseases:[1]

Free radicals in general can cause degenerative illnesses such as deterioration of the eye lens (causes blindness), inflammation of the joints, nerve cell damage (causes Parkinson's or Alzheimer's), accelerated aging, increase in risk of coronary heart disease (atherosclerosis), cancers caused by damage to cell DNA.

*What is an Antioxidant?

Antioxidants are substances which neutralize and scavenge free radicals so that they become less reactive and detrimental to the body. Because free radicals can also be helpful for the body, having an overabundance of antioxidants in the body is not always beneficial, as there would be no free radicals if they are all neutralized. It is essential however, to remove a healthy level of oxidants so that processes such as lipid peroxidaton do not occur.  Antioxidants are able to give electrons to free radicals so they have no unpaired electrons in their valence shells. Once this occurs, the antioxidant is missing an electron; however, it does not become a free radical. This reason is although this antioxidant has an unpaired electron, it does not become reactive and has the ability to remain stable.

In the human cell, there are two sections of antioxidants. The first is found in the 'fat soluble' part of the cell membrane. Here antioxidants such as, vitamin E, beta-carotene, and coenzyme Q are found. Inside the cell, the antioxidants are water soluble. And they include vitamin C, glutathione peroxidase, superoxide dismutase, and catalase.

*High antioxidant capacities in foods:[1]

*How antioxidants protects the body: [8,13]

Vitamin C (ascorbate): protects the human body from free radicals called “free hydroxyl radicals”; this particular vitamin also reacts in solutions such as blood. Before free radical oxidants cause damage to lipids in cell membranes or lipoproteins, vitamin C reacts and “carries” the antioxidized radicals out of the body.

Vitamin E: helps with removing lipid free radicals and preventing membrane damage which leads to atherosclerosis. This antioxidant is fat soluble and not only prevents thrombus in the arteries but also allows blood to flow more easily even in the presence of plaque.

Niacin (B3): is a type of vitamin that reacts with other nutrients inducing them to stimulate their antioxidant capacities.

Carotenoids (beta-carotene, lycopene, etc.): react with free-radicals and inactivate them in the blood or in the cells.

*Antioxidants produced in the body: [17]

Superoxide dismutase (SOD): is a type of enzyme in the body that repairs the damage done by superoxide (which is a free radical in the human body). SOD produces fibroblasts which builds skin cells and is found in the dermis and the epidermis. SOD neutralizes superoxides and other free radicals that give us wrinkles and precancerous cell changes. SOD levels drop as we age and as a result, our free radical levels increase as we age.

L- Glutathione: is a water soluble enzyme with a very high antioxidant capacity. L-Glutathione can be found in the liver. L- Glutathione is essential for maintaining good health as it plays an important role in neutralizing many free radicals.

Catalase: neutralizes hydrogen peroxide which is an extremely detrimental free radical produced in many metabolic events. Catalase converts hydrogen peroxide into gaseous oxygen and water molecules.

*images are directly taken from (respectively):

http://www.nature.com/nm/journal/v9/n6/fig_tab/nm0603-641_F1.html

http://dakappa.com/health/reduction/reduction.html

Alan Stevens and James Lowe, Pathology. 2^nd. Edition.1999

http://www.nlm.nih.gov/MEDLINEPLUS/ency/imagepages/18020.htm

Back to: Virtual Science Fair - Expo-sciences virtuelle                             Creator: Janine Hsu