1. Is atherosclerosis a metabolic disease?

2. METABOLIC ASPECTS OF ATHEROSCLEROSIS
biochemical changes turn physiological, benign LDL into an atherogenic agent

3. Atherosclerosis
The term atherosclerosis, which comes from the Greek words atheros (meaning “gruel” or “paste”) and sclerosis (meaning “hardness”), denotes the formation of fibrofatty lesions in the intimal lining of the large and medium-size arteries such as the aorta and its branches, the coronary arteries, and the large vessels that supply the brain.
Atherosclerosis contributes to more mortality and more serious morbidity than any other disorder in the western world.

4. “Should I get my cholesterol checked?”

5. The development of atherosclerosis
The key event – damage to the endothelium caused by excess of lipoproteins, hypertension, diabetes, components of cigarette smoke.
Endothelium becomes more permeable to lipoproteins.
Lipoproteins move below the endothelial layer (to intima).
Endothelium loses its cell-repelent quality.
Inflammatory cells move itno the vascular wall.

6. TWO MODES OF UPTAKE OF CHOLESTEROL INTO MACROPHAGES
LDL - cholesterol
The scavenger cells, such as the monocytes and macrophages, have receptors that bind LDL that has been oxidized or chemically modified.
The amount of LDL that is removed by the “scavenger pathway” is directly related to the plasma cholesterol level. When there is a decrease in LDL receptors or when LDL levels exceed receptor availability, the amount of LDL that is removed by scavenger cells is greatly increased.
TWO MODES OF UPTAKE OF CHOLESTEROL INTO MACROPHAGES

7. The Scavenger Receptor (SR-A1 receptor)
How macrophages deal with oxidized or modified LDL
The scavenger receptor recognizes modified and/or oxidized LDL and internalizes the modified LDL.
Accumulation of these modified LDL in the cell leads to the accumulation of cholesterol droplets in the macrophage and the formation of foam cells.

9. Macroscopic appearance of atherosclerotic lesions
© Michael Palmer 2014

10. Mechanisms
One of the earliest responses to elevated cholesterol levels is the attachment of monocytes to the endothelium.
The monocytes emigrate through the cell-to-cell attachments of the endothelial layer into the subendothelial spaces, where they are transformed into macrophages.
Activated macrophages release free radicals that oxidize LDL.
Oxidized LDL is not recognized at the cell receptor level and so, it can not be internalized and it longer remains into the blood stream.
Oxidized LDL is toxic to the endothelium, causing endothelial loss and exposure of the subendothelial tissue to blood components:
It stimulates specific immune system (production of antibodies against oxidized LDL).

11. Mechanisms
Endothelial disruption leads to platelet adhesion and aggregation and fibrin deposition.
Platelets and activated macrophages release various factors that are thought to promote growth factors that modulate the proliferation of smooth muscle cells and deposition of extracellular matrix in the lesions: elastin, collagen, proteoglycans.
Activated macrophages also ingest oxidized LDL to become foam cells, which are present in all stages of atherosclerotic plaque formation.
Lipids released from necrotic foam cells accumulate to form the lipid core of unstable plaques.

12. Development of an atherosclerotic lesion
© Michael Palmer 2014

13. Which modifications of LDL are significant in vivo?
© Michael Palmer 2014

14. How does LDL become oxidized?
Transition metals (Fe, Cu) convert O2 to reactive oxygen species: hydrogen peroxide (H2O2), superoxide (•O–O−)
Lipoxygenases produce lipid hydroperoxy-radicals that can bind to LDL and induce lipid peroxidation