What are the different stages of LDL oxidation?

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The process of LDL oxidation occurs in many steps and is the modification of LDL particles by oxidative stress, which may be the cause of many cardiovascular and metabolic diseases, particularly atherosclerosis. The following are the most significant steps in LDL oxidation:

1. Initiation of LDL Oxidation
Oxidative stress begins when free radicals or reactive oxygen species (ROS) attack the polyunsaturated fatty acids of the phospholipid and triglyceride lipids of the surface of the LDL particle.

The oxidation of the polyunsaturated fatty acids, which are primarily the linoleic acid of the LDL, is the first step of LDL oxidation that forms lipid hydroperoxides.

This process may occur through various pathways, including exposure to free radicals generated by enzymes like myeloperoxidase (MPO) or enzymatic oxidation by lipoxygenase and cyclooxygenase.

2. Lipid Hydroperoxide Formation
The oxidative attack on the double bonds of polyunsaturated fatty acids leads to the generation of lipid hydroperoxides.

Lipid hydroperoxides are reactive intermediates that degrade to yield a variety of aldehydes and other reactive compounds such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), which are generally found in oxidized LDL particles.

These compounds can also react with other molecules, resulting in advanced oxidation products that modify the structure of LDL.

3. Modification of ApoB-100 (Apolipoprotein B-100)
Apolipoprotein B-100 (apoB-100), the protein component of LDL, is also oxidized during LDL oxidation.

The oxidation of amino acids like methionine and tyrosine in apoB-100 alters the protein conformation such that it binds less to liver and other cell LDL receptors.

This change decreases the binding by the LDL receptor of oxidized LDL particles, which otherwise would remove native LDL from the circulation. Oxidized LDL thus becomes sequestered in the circulation.

4. Formation of Oxidized LDL (oxLDL).
When lipid hydroperoxides and modified proteins build up, oxidized LDL (oxLDL) particles are formed.

These particles have chemically altered structures that include oxidized phospholipids, oxidized cholesteryl esters, and oxidized fatty acids.

oxLDL has structural changes in the lipid and protein components, and the modified LDL can now cause deleterious effects on the cardiovascular system.

5. Recognition by Scavenger Receptors
Whereas native LDL is taken up by LDL receptor, oxidized LDL is recognized by scavenger receptors such as CD36 and SR-A1, mainly present on macrophages and other immune cells.

This binding leads to macrophage accumulation of oxidized LDL, with the consequence of the development of foam cells, one of the characteristics of the atherosclerotic plaque in the arterial walls.

Foam cells could be the cause of chronic inflammation of the arteries, also stimulating the development and growth of atherosclerosis.

6. Advanced Oxidation Products (AOPs) Formation
With continued LDL oxidation, advanced oxidation products (AOPs) are formed. They include products such as malondialdehyde (MDA) and carboxymethyl lysine (CML), formed by oxidative degradation of lipids and proteins.

AOPs can further increase inflammatory responses and adhesion of immune cells to endothelium of blood vessels. They also augment the formation of foam cells and atherosclerotic plaque growth.

7. Inflammation and Endothelial Dysfunction
The oxidized LDL gets deposited within the walls of arteries, leading to a cascade of inflammatory events. The endothelial cells (blood vessel lining) respond to oxidized LDL by releasing cytokines and chemokines that attract more immune cells such as monocytes and neutrophils.

These cells contribute to vascular inflammation, which leads to endothelial dysfunction, a state in which blood vessels fail to dilate normally, a prelude to atherosclerosis and cardiovascular diseases.

8. Plaque Formation and Progression
As foam cells accumulate and inflammation persists, the involved area of the artery becomes a site for the development of atherosclerotic plaques. The plaques are made up of lipids, immune cells, and collagen and have the ability to narrow the arteries in the long term.

Oxidized LDL makes the plaques prone to formation and is possibly more likely to destabilize plaques, which can lead to rupture and result in heart attack or stroke.

Conclusion
The oxidation of LDL is a sequential process beginning with the formation of lipid hydroperoxides, followed by apolipoprotein B-100 modification and formation of oxidized LDL (oxLDL) particles. The modified particles are then taken up by macrophages via scavenger receptors, forming foam cells and promoting the pathogenesis of atherosclerosis. Thus, oxidized LDL is implicated at the core of cardiovascular disease by perpetuating inflammation, endothelial dysfunction, and plaque formation.

Would you like to learn more about how to reduce LDL oxidation or its function in disease prevention?
Small dense LDL (sdLDL) is a subpopulation of low-density lipoprotein (LDL) particles that are denser and smaller than the typical, larger LDL particles. Small, dense LDL particles are considered more atherogenic (more likely to result in the development of atherosclerosis) than larger, less dense LDL particles. One of the major features of sdLDL is that it is more liable to oxidation, which is also a major factor in its cardiotoxicity.

Small Dense LDL Function in Cholesterol Oxidation:
Increased Susceptibility to Oxidation: Small dense LDL particles have a higher likelihood of being oxidized than the large LDL particles. This is due to their compact nature and small size, which render them prone to getting entrapped within artery walls, where they get exposed to oxidative stress. Once sdLDL is oxidized, it also undergoes chemical changes that compromise its structure, making it more hazardous.

Faster Passing Through the Arterial Wall: Because denser, smaller LDL particles are also smaller in diameter, they will experience lesser resistance to pass into the wall space of an artery. When they find their way into an artery wall, sdLDL is more likely to be oxidized because the oxygen-rich environment utilized by cells does exist within arteries, particularly on the arterial locations where hypertension and inflammation can occur.

Oxidized sdLDL Causes Inflammation: Like oxidized LDL (oxLDL), oxidized small dense LDL particles cause inflammation. The body’s immune system recognizes oxidized sdLDL as toxic, and macrophages and other immune cells become activated. These immune cells phagocytose the oxidized particles and become foam cells. Foam cells are deposited in the walls of the arteries, creating atherosclerotic plaques, and lead to the hardening and narrowing of the arteries, causing cardiovascular diseases like heart attack and stroke.

Increased Foam Cell Formation: Following oxidation, sdLDL is more readily ingested by macrophages, which can be foam cells. Foam cells are lipid-laden immune cells that accumulate in the arterial wall and contribute to the fatty streaks and plaques of atherosclerosis. Since sdLDL is more readily oxidized and more efficiently becomes foam cells than larger LDL particles, it supports plaque formation.

Impaired Clearance and Prolonged Circulation Time: Small dense LDL particles are also cleared less efficiently from the circulation than larger LDL particles. This means that they circulate longer, giving them more time to oxidize. The longer that sdLDL circulates in the blood, the greater the likelihood that it will oxidize and be a participant in the formation of atherosclerotic plaque.

Endothelial Dysfunction Promotion: Oxidized sdLDL can cause endothelial dysfunction, which is an early first step towards atherosclerosis. Oxidation modification of sdLDL causes injury of the endothelium lining within the blood vessel, weakening their function to regulate blood flow as well as discourage other inflammatory cells from binding. This promotes a pro-inflammatory state with a propensity for lipid accumulation as well as augmented plaque formation.

Overall Impact on Cardiovascular Disease:
The oxidation of small dense LDL contributes to cardiovascular disease in different ways:

Increased plaque development: As oxidized sdLDL causes foam cells to develop, it accelerates the formation of fatty streaks and plaques in artery walls, causing atherosclerosis.

Plaque instability: Inflammatory processes initiated by oxidized sdLDL may destabilize atherosclerotic plaques, risking rupture and formation of blood clots, resulting in heart attack or stroke.

Chronic inflammation: Oxidized sdLDL continues to enhance chronic inflammation, which is the major driving force behind cardiovascular disease progression.

Summary:
Small dense LDL is more susceptible to oxidation than large LDL particles due to its reduced size and dense structure. Oxidized sdLDL particles play a central role in initiating atherosclerosis through the induction of inflammation activation, foam cell formation induction, endothelial dysfunction, and intimal plaque accumulation in the arteries. These routes later increase the threat of cardiovascular conditions such as heart attack, stroke, and peripheral artery disease. Reducing small dense LDL in the blood, using either drugs or life modification, can lower the risk of these conditions.