LDL Oxidation

The Smoking Gun Behind Heart Disease?

By Tim Guilford, MD

Cholesterol, which is known to be associated with the formation of atherosclerosis and plaque in arteries, is actually an important component of the structure of our cells¹ and even contributes to the formation of many hormones in the body. While it is clear that cholesterol provides a critical component to many tissues, high cholesterol\'s link to atherosclerosis indicates cholesterol levels that are too high may pose a problem. The medical literature is now suggesting, however, that elevated cholesterol is not the sole link to formation of atherosclerosis and artery blocking plaque.²

Most of us are familiar with HDL, known as “good” cholesterol and LDL, known as “bad” cholesterol. Part of the reason that HDL is known as “good” cholesterol is that it carries an antioxidant enzyme (HDL-PON), which helps in cell repair and preventing the oxidation of cholesterol.³ While research shows that LDL cholesterol is a major risk factor for developing atherosclerosis, there is new information that suggests it is the oxidized form of LDL (oxLDL) that appears to be a significant trigger in the chain of events that accelerates atherosclerosis and plaques in the arteries.^4-6

How LDL Becomes Oxidized

Cholesterol is formed primarily in the liver, although some cholesterol is derived from the intestine from the ingested dietary fats, proteins and carbohydrate food sources. Cholesterol is then transported through the blood to different tissues. As cholesterol is a form of fat, it does not dissolve in water, so for transport in the blood to occur cholesterol needs to be coated with a thin lipid and protein coat, called a lipoprotein, to allow it to be transported. There are 5 major classes of lipoproteins, such as the low density lipoprotein (LDL) and high density lipoprotein (HDL), both of which carry cholesterol through the blood. The LDL and HDL carriers of cholesterol are the most commonly monitored components of cholesterol in regard to health.

LDL is associated with bringing cholesterol to cells that need cholesterol for repair and maintenance of cell membranes. HDL carries cholesterol away from the cells and back to the liver. Inside the arteries, it turns out that the scavenger cells known as monocytes and macrophages play an important role in carrying the cholesterol from the cells lining the arteries and turning it over to the HDL for the return trip to the liver. Because both HDL and LDL contain lipids in addition to their protein components, both are susceptible to free radical damage that causes oxidation of the lipoprotein cover of both HDL and LDL. The HDL enzyme, paraoxinase (PON), helps protect it from oxidation,⁷ so the LDL molecule is more susceptible to oxidation than HDL. This oxidation can occur in areas of the artery where there is physical damage from high blood flow, inflammation or an accumulation of metals including iron or copper, which can be found normally in the body.⁷

Antioxidant protection of LDL helps prevent oxidative changes. It has been known for some time that HDL and LDL carry vitamin E as an antioxidant. However, vitamin E is a fat-soluble vitamin and it has limitations in terms of its ability to prevent oxidation.⁸ Recent information shows that an enzyme called glutathione peroxidase is also carried in both HDL and LDL cholesterol.⁹ This study, done in a laboratory that is well known for research in lipid metabolism and vascular disease, used the dietary supplement liposomal glutathione to demonstrate that supplying a steady supply of the reduced (non-oxidized) form of glutathione is able to prevent the oxidation of LDL cholesterol.⁹

Oxidation\'s Devastating Effects

The role of oxidation stress has been debated in regard to the formation of atherosclerosis.¹⁰ Artery blockage by fatty plaques was initially thought to be due to a simple overload of cholesterol. It turns out that the turnover of cholesterol and the ability to remove damaged or oxidized cholesterol plays a critical role in avoiding the collection of lipids in arteries and the formation of plaque. The scavenger cells called macrophages play a critical role in converting the “waste” or oxidized low density lipoprotein (oxLDL) containing cholesterol into a form that can be handed off to HDL and transported back to the liver.¹¹

Oxidized LDL cholesterol needs some special handling by the scavenger cells used to “clean up” the lining of arteries called macrophages. Even in the macrophage cells, an excess of oxLDL can become toxic.^12-15 While most cells can regulate the amount of LDL they ingest, the macrophages and the smooth muscle cells lining arteries cannot limit the amount of oxLDL they take in. The unlimited ingestion of oxLDL results in a large collection of cholesterol inside both macrophages and smooth muscle cells to the point that they look foamy under the microscope. These cholesterol laden cells then become toxic, pile up and create the foundation for the formation of plaque. The toxicity of oxLDL can lead to damage to the endothelial lining and will cause the adhesion of platelets and the local release of growth factors¹⁶ and inflammatory factors that are associated with artery narrowing or clots.¹⁷

Oxidized LDL can be measured in blood and increased levels of oxLDL correlate with the progression of coronary artery disease.¹⁸ The role of oxLDL in promoting atherosclerosis is demonstrated in a study of mice that have a gene defect leading to high levels of LDL and atherosclerosis. In these mice, if the oxLDL was removed by increasing the liver absorption of oxLDL they did not develop as much atherosclerosis even though the LDL level was very high.¹⁹

Elevated levels of oxLDL are also found in other metabolic conditions related to vascular disease including stroke.²⁰ Abnormalities related to oxidized LDL are found in the early stages of metabolic diseases that are associated with atherosclerosis such as metabolic syndrome,²¹ diabetes and obesity.²²

The importance of oxLDL is illustrated by the increased number of research papers identified by the library of medicine search engine PubMed in regard to the phrase “oxidized LDL.” In 1989, there were only 25 papers corresponding to oxidized LDL. In 1999 the number was 324. The number has now (early 2010) grown to over 5,600.

Conclusion

OxLDL is now recognized as both a biomarker and also a cause of atherosclerosis.²³ The study with liposomal glutathione, which shows that a steady supply of glutathione can help delay the oxidation of LDL and slow the development of atherosclerotic plaque in the mouse model of atherosclerosis, should encourage more research.⁹ Monitoring the levels of oxLDL through a newly offered test that is now available here may also provide an early indicator of the early changes in the metabolism related to metabolic syndrome, diabetes and progression of atherosclerosis.

It is now understood that the progression of atherosclerosis is multifaceted; there are many players involved including oxLDL, fibrinogen, homocysteine, C-reactive protein and other lipid constituents that can now be tested far beyond even these factors. Remaining expansive on one\'s thinking about cardiovascular disease will be essential as knowledge continues to grow rapidly.

References

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