> BACKGROUND KNOWLEDGE

Atherosclerosis

Role of macrophages

Macrophages are always present within tissues and differentiate from cell types called monocytes. They have got the same functions as macrophages but circulate within the blood. Atherosclerosis causes a narrowing in the arteries and therefore disturbs the normal blood flow.

Blood is slowed down, which allows circulating monocytes to roll over the endothelium by using its adhesion molecule VCAM-1. This adhesion molecule causes the monocyte to stick to the endothelium. However, the bond between the monocyte and the arterial wall is weak, therefore the monocytes roll over the endothelium only.

The next step is the penetration of the monocyte into the intima by using the molecule MCP-1. After this penetration, monocytes are activated. They differentiate into macrophages (as they are within a tissue) by M-CSF. Macrophages try to digest the fat deposits behind the arterial wall, but as cholesterol is insoluble and hard to digest, they cannot break it down and cholesterol accumulates within the macrophage. Due to their new appearance, they are now called foam cells. They then form fatty streaks.

Lipoproteins

Cholesterol and triglycerides are lipids, which are transported in the blood by lipoproteins. Lipoproteins consists of two layers, a hydrophobic lipid core, composed of cholesterol and triglycerides, and an outer hydrophilic coat, made up of phospholipids, free cholesterol, and apolipoproteins. There are different types of lipoproteins:

HDL: High Density Lipoprotein LDL: Low Density Lipoprotein vLDL: Very Low Density Lipoprotein Chylomicrons They are all determined by the proportion of triglyceride and cholesterol in the inner lipid core, by the type of lipoprotein, and by the size and density, which is determined by ultracentrifugation.

Triglycerides are absorbed from the gastrointestinal tract and transported to the tissues. This is called the exogenous pathway. The endogenous pathway is the route away from the liver to the tissues. Therefore, lipids are transported to tissues by using two sources, the liver and the gastrointestinal tract.

The Exogenous Pathway

Chylomicrons are used to transport triglycerides and cholesterol from the the gastrointestinal tract to tissues where they are split by an enzyme called lipoprotein lipase in the designated tissues. This releases free fatty acids which is taken up, either to be stored (adipose/fat tissue) or to be used for energy metabolism (muscle tissues). As most of the triglycerides have been taken up, cholesterol remains in the chylomicrons and are transported to the liver. Cholesterol is then stored, used to make bile acids, or released into vLDL.

The Endogenous Pathway

vLDL take up cholesterol and synthesized triglycerides from the liver to transport them, in the blood, to the tissues. There, using the same procedure as in the exogenous pathway, triglycerides are split by lipoprotein lipase and the resulting free fatty acids are taken up. This leaves LDL and HDL carriers.

LDLs contain a large amount of cholesterol, which is taken up by the liver and tissues. HDLs absorb cholesterol from the tissues and either transfer this cholesterol to LDLs and vLDLs, or transfer it back to the liver. As HDLs are the "good lipoproteins", they are also able to pick up cholesterol from the arteries.

Treatment

There are several factors responsible for atherosclerosis. Not all of them might be present in a patient. The most important factors are:

• Hypertension
• Diabetes
• Smoking
• Dyslipidaemia (high lipid levels, including cholesterol)

Hypertension used to be and might still be treated by diuretics (drugs increasing urine output) and beta blockers (atenolol). A new way of treatment involves ACE and AT1 antagonists.