Team:ITESM-CEM/Project/Details

From 2014.igem.org

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<h2>Atherosclerosis</h2>
<h2>Atherosclerosis</h2>
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<p style="text-align: justify; text-justify: inter-word;"> Atherosclerosis is a cardiovascular disease where arteries are occluded due to the enlargement of their walls and subsequent reduction of the internal diameter. This disease has been recently identified to be one of the major causes of death. Only in the United States, it is estimated that approximately 36.3% of annual deaths are caused by this condition, whereas in Mexico, atherosclerosis is now considered the first cause of death.8
<p style="text-align: justify; text-justify: inter-word;"> Atherosclerosis is a cardiovascular disease where arteries are occluded due to the enlargement of their walls and subsequent reduction of the internal diameter. This disease has been recently identified to be one of the major causes of death. Only in the United States, it is estimated that approximately 36.3% of annual deaths are caused by this condition, whereas in Mexico, atherosclerosis is now considered the first cause of death.8
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<h2>LDL Theory</h2>
<h2>LDL Theory</h2>
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<p style="text-align: justify; text-justify: inter-word;"> Atherosclerosis is a cardiovascular disease where arteries are occluded due to the enlargement of their walls and subsequLDLs trigger the development of atheroma due to their oxidation; this biochemical transformation occurs in response to the highly oxidative environment of the extracellular liquid, and can occur through a variety of mechanisms, the most important of which is the interaction of lipoproteins with Reactive Oxygen Species (ROS) in the bloodstream.6 Even though this reaction can potentially occur either within fatty acids or sterols, the current project will only focus on the oxidation of cholesterol, specifically in the oxidized product 7-ketocholesterol, one of the most common reaction products.6
<p style="text-align: justify; text-justify: inter-word;"> Atherosclerosis is a cardiovascular disease where arteries are occluded due to the enlargement of their walls and subsequLDLs trigger the development of atheroma due to their oxidation; this biochemical transformation occurs in response to the highly oxidative environment of the extracellular liquid, and can occur through a variety of mechanisms, the most important of which is the interaction of lipoproteins with Reactive Oxygen Species (ROS) in the bloodstream.6 Even though this reaction can potentially occur either within fatty acids or sterols, the current project will only focus on the oxidation of cholesterol, specifically in the oxidized product 7-ketocholesterol, one of the most common reaction products.6
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<h2>Chemically altered Cholesterol</h2>
<h2>Chemically altered Cholesterol</h2>
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<p style="text-align: justify; text-justify: inter-word;"> This chemical alteration of cholesterol structure does not only modify its chemical behaviour, but also its metabolism. Among all possible modifications, the following have already been described:6 <br><br>
<p style="text-align: justify; text-justify: inter-word;"> This chemical alteration of cholesterol structure does not only modify its chemical behaviour, but also its metabolism. Among all possible modifications, the following have already been described:6 <br><br>

Revision as of 22:08, 17 October 2014

TEC-CEM | Project

ITESM-CEM | Enzy7-K me

Project 3014

 

Background

Atherosclerosis

Atherosclerosis is a cardiovascular disease where arteries are occluded due to the enlargement of their walls and subsequent reduction of the internal diameter. This disease has been recently identified to be one of the major causes of death. Only in the United States, it is estimated that approximately 36.3% of annual deaths are caused by this condition, whereas in Mexico, atherosclerosis is now considered the first cause of death.8 Even though atherosclerosis isn’t itself mortal, it has been identified as a condition which enhances other health problems such as cardiac arrest, myocardial stroke or even sudden death. The biochemical development of atherosclerosis is complex and involves a variety of factors like hypercholesterolemia, smoking, obesity, diabetes miellitus or even hereditary factors. One of the most accepted theories explaining its origin suggests that it is triggered by the chemical modifications of Low Density Lipoproteins (LDL), which are susceptible to oxdiations; it is believed that these oxidized products accumulate on the artery walls (tunica intima), generating an inflammatory process that will ultimately cause the development of atheroma plaques. “LDLs must be oxidized before being internalized by the macrophages; these cells are then transformed into foam cells, which form the atheroma plaque”7. This hypothesis will be analyzed, and is the basis of the current project.

LDL Theory

Atherosclerosis is a cardiovascular disease where arteries are occluded due to the enlargement of their walls and subsequLDLs trigger the development of atheroma due to their oxidation; this biochemical transformation occurs in response to the highly oxidative environment of the extracellular liquid, and can occur through a variety of mechanisms, the most important of which is the interaction of lipoproteins with Reactive Oxygen Species (ROS) in the bloodstream.6 Even though this reaction can potentially occur either within fatty acids or sterols, the current project will only focus on the oxidation of cholesterol, specifically in the oxidized product 7-ketocholesterol, one of the most common reaction products.6


Chemically altered Cholesterol

This chemical alteration of cholesterol structure does not only modify its chemical behaviour, but also its metabolism. Among all possible modifications, the following have already been described:6

1. Modification of the lipidic membrane structures: These membranes (found in a variety of organelles) are commonly stabilized by the presence of sterols.6 After oxidation, the physicochemical nature of sterols becomes slightly more polar; this change triggers cholesterol migration out of the membrane, towards the polar environment of extra and intracellular fluids.6 This destabilization does not only affect the outer membrane, but also a variety of organelles like the lysosome or the mitochondria. This causes the accumulation of metabolic products that are able to induce cell death.6

2. Incapability of human cells to metabolize the oxidized lipoproteins (oxLDL): This is due to two independent events: the internalization of LDL into the macrophage is commonly regulated, at the genetic level, by the internal concentration of sterols; this level of regulation does not work with oxidized sterols, which enter the cell through other type of receptors, modifying the normal functions.6 Secondly, the enzymes that normally regulate cholesterol degradation are quite inefficient when metabolizing oxidized sterols: this is the most widely accepted explanation of the incapability of macrophages to stop the growth of atheroma plaques.6

3. Developement of atherosclerotic plaque: This is caused by the accumulation of oxLDL in the bloodstream and, consequently, in the vascular endothelium, triggering the process of monocyte recruitment.7 These monocytes differentiate then into macrophages, which try to digest the oxidized lipids. The incapability of macrophages to degrade oxidized cholesterol (as previously explained) causes their transformation into Foam Cells, characterized by their morphology at the microscope, where an abnormally high amount of vesicles and fragmented lysosomes, as well as high lipid content, can be observed.7 These events start an inflammatory reaction, and ultimately cause the migration of muscle cells from the tunica media to the tunica intima; these cells proliferate, creating a muscular layer that covers the lesion and reduces the internal diameter of the artery.