L10 Dyslipidaemia and Atherosclerosis: Identifying drug targets

what carries the highest risk for cardiovascular diseases

LDL (low-density lipoprotein)

low-density lipoprotein is more full of

cholesterol

high-density lipoprotein is less full of

cholesterol

dyslipidaemia has high risk of

CVD

what is ApoA1

High-density lipoprotein

• ApoA1 reduces risk of CVD

whats a chylomicron

large, triglyceride-rich lipoprotein particles synthesized in the small intestine that transport dietary lipids (fats) from the gut to adipose, cardiac, and skeletal muscle tissues for energy or storage

what is VLDL

very low-density lipoprotein

apolipoprotein A1 structure

major Apo of the non-atherogenic HDL particles

• ApoA1 concentrations correlate with HDL-C

apolipoprotein B

each of the atherogenic lipoproteins LDL, IDL and VLDL contain one copy of Apo B100

lipoprotein (a)

a highly atherogenic modified form of LDL

Apolipoproteins can be used to assess risk and

as treatment targets

A- endothelial cells (single layer of cells in contact with the blood)

B- internal elastic lamina

C-smooth muscle

D-external elastic lamina

E-mast cell (WBC)

space between endothelium and internal elastic lamina

sub-intimal space

adventitia

mast cell

endothelium and sub intimal space

intima

media

internal elastic lamina, smooth muscle cells, external elastic lamina

A- coronary artery

B-fatty streak

C-adipose tissue

what is fatty streak

buildup of cholesterol in the wall of the artery

how early can you start to see fatty streaks in the walls of arteries

10-12 years old

aorta with an atheromatous plaque

A-fatty streak

B-thrombus (dark red) or adipose tissue (lots of cholesterol deposits)

1-LDL

2-Oxidised

3-Cytokines IL-1 and MCP-1 attract myocytes

4-macrophages

5-foam cells

6-smooth muscle cells

7-plaque

8-plaque with fibrous capsule

A- LDL cholesterol

describe thrombus formation in a blood vessel

• circulating LDL gains access to endothelial space where it is oxidised

• cytokines IL-1 and MCP-1 attract circulating monocytes

• monocytes cross intima to become macrophages

• macrophages phagocytose LDL to form foam cells

• Smooth muscle cells migrate and proliferate under the influence of smooth muscle mitogens

• a primitive plaque is formed of foam cells, smooth muscle, lipid, and necrotic cells

• the plaque enlarges, develops a fibrous capsule and protrudes in vessel lumen

LDL being a lipoprotein can

navigate past endothelial cells and gets underneath endothelial cells and accumulates between the internal elastic lamina and endothelial cells

• fatty things find it easy to move across tissues (membrane permeable)

what is the cause of primary dyslipidaemia

familial hypercholesterolaemia (too much cholesterol in the blood) - genetic predisposition

what is primary dyslipidaemia

an inherited genetic disorder causing abnormally high cholesterol or triglycerides, independent of lifestyle factors, often leading to premature cardiovascular disease

what are the causes of secondary dyslipidaemia

• alcoholism

• diabetes

• renal disease

• thyroid disease

what percentage of males with familial hypercholesterolaemia will have symptomatic heart disease by the age of 50?

50%

build up of cholesterol examples

• tendon xanthomata

• lipaemia retinalis

• serum in chylomicronaemia