15-atherosclerosis Flashcards
What are risk factors for atherosclerosis
• Potentially Modifiable: Smoking Lipids Blood Pressure Diabetes Obesity Lack of Exercise • Not Modifiable: Age Sex Genetic Background
Where does atherosclerosis tend to arise
At junctions with turbulent glow
E.g. bifurcation of the common carotid artery
Describe atherosclerosis progression
The lesion begins small and then LDLs accumulate which brings in macrophages which eat up the endothelial fat and become FOAM CELLS and remove themselves from the viscinity
• As fat deposition continues, the lesion accumulates pools of extracellular lipids (outside the macrophages) and the macrophages can no longer cope
• The fat builds up further and you get a core of extracellular lipid - the pool of fats coalesce and forms a large mass of fat
• The inflammation irritates the interior of the plaque to form a fibrous thickening
• The macrophages produce growth factors that stimulate smooth muscle cells to grow, divide and make more collagen
• Eventually the plaque will RUPTURE which allows the lipid core (which is thrombogenic) to communicate with the lumen and stimulate clot formation within the lumen
What are 4 epidemiological changes related to atherosclerosis
Reduced hyperlipidemia (statin treatment)
•Reduced hypertension (antihypertensive treatment)
•Increased obesity
• Increased diabetes
What are the 5 important cells in atherosclerosis
Vascular endothelial cells –Barrier function (eg to lipoproteins) –Leukocyte recruitment •Platelets –Thrombus generation –Cytokine and growth factor release •Monocyte-macrophages –Foam cell formation –Cytokine and growth factor release –Major source of free radicals –Metalloproteinases •Vascular smooth muscle cells –Migration and proliferation –Collagen synthesis –Remodelling and fibrous cap formation •T lymphocytes –Macrophage activation
How do LDLs stimulate chronic inflammation
LDL deposit In subendothelial space
LDL becomes oxidatively modified by free radicals
•Oxidised LDL is phagocytosed by macrophages (become foam cells) and stimulates chronic inflammation
How are macrophages involved in atherosclerosis
Macrophages can injure host tissue if they are activated excessively or inappropriately
• Macrophages are the MAIN INFLAMMATORY CELLS IN ATHEROSCLEROSIS
What is familial hyperlipidaemia
Autosomal recessive genetic disease
• People with FH have a massively elevated choleterol (20 mmol/L)
• There is failure to clear LDL from the blood
• Patients’ skin and their arteries
contain deposits of fat with the
accumulations of foam cells (when this happens in the skin it is called a xanthoma)
What are scavenger receptors on macrophages
pathogen receptors that accidentally bind to oxidised LDLs
What are the 2 types of scavenger receptor
Macrophage scavenger receptor A •CD204 •Binds to oxidised LDL •Binds to Gram-positive bacteria like Staphylococci and Streptococci •Binds to dead cells
Macrophage scavenger receptor B •CD36 •Binds to oxidised LDL •Binds to malaria parasites •Binds to dead cells
How can macrophages Generate free radicals that further oxidise lipoproteins
NADPH Oxidase Takes oxygen and reduces it (adds an electron) forming
extremely reactive SUPEROXIDE (O2-)
Myeloperoxidase firms
–HOCl hypochlorous acid (bleach) from ROS + Cl-
–HONOO Peroxynitrite
Describe how macrophages Phagocytose/scavenge modified lipoproteins, and become foam cells
When macrophages enter the subendothelial layer they start off small but as they get further and further in they get bigger and bigger
• They become so bloated with fat that the fat comes out of solution forming fat
globules within the macrophage which eventually kills it
When macrophages Become activated by modified lipoproteins/free intracellular cholesterol/oxidised cholesterol was do they produce
Cytokine mediators (eg IL-1, MCP-1) that recruit more monocytes
–Chemoattractants and growth factors for VSMC
–Proteinases that degrade tissue (eg the fibrous cap)
–Tissue factor that stimulates coagulation upon contact with blood
Describe 2 growth factors macrophages release in atherosclerosis
Platelet derived growth factor
–Vascular smooth muscle cell chemotaxis, survival and mitosis
•Transforming growth factor beta
–Increased collagen synthesis
–Matrix deposition
Describe how proteases from macrophages degrade ECM
Metalloproteinases (=MMPs)
–Family of ~28 homologous enzymes
–Activate each other by proteolysis
–Degrade collagen
