Atherosclerosis Flashcards
what are the modifiable risk factors of artherosclerosis?
- smoking
- lipid intake
- blood pressure
- diabetes
- obesity
- sedentary lifestyle
what are the non-modifiable risk factors of atherosclerosis?
- age
- sex
- genetic background
How much does hypertension alone increase your risk of developing atherosclerosis?
x 3
How much does high cholesterol alone increase your risk of developing atherosclerosis?
x 4
How much does smoking alone increase your risk of developing atherosclerosis?
x 1.6
How much does both hypertension and smoking increase your risk of developing atherosclerosis?
x 4.5
How much does both hypertension and high cholesterol increase your risk of developing aetherosclerosis?
x 9
How much does both smoking and high cholesterol increase your risk of developing atherosclerosis?
x 6
How much does smoking, hypertension and high cholesterol increase your risk of developing atherosclerosis?
x 16
Where does atherosclerosis tend occur?
at branches, bends and bifurcations
Why does atherosclerosis occur at branches and bends?
turbulent blood flow causes damage to artery and inflammation
What does the endothelium do?
- controls contraction
- maintain the blood pressure
What happens in atherosclerosis?
LDLs deposit in the subintimal space of artery walls and binds to matrix proteoglycans
What are the main cell types involved in the inflammation of the arteries and the progression of atherosclerosis?
- vascular endothelial cells
- monocyte-macrophages
- vascular smooth muscle cells
- T lymphocytes
- Platelets
What are the roles of vascular endothelial cells?
- barrier function (lipoproteins)
- leukocyte recruitment
What are the roles of platelets?
- thrombus generation
- secrete cytokines and growth factor
What are the role of monocyte-macrophages?
- foam cell formation
- cytokine and growth factor release
- major source of free radicals
- metalloproteinases
What are the role of vascular smooth muscle cells?
- Migration and proliferation
- Collagen synthesis
- Remodelling & fibrous cap formation
What are the role of T-lymphocytes?
- macrophage actication - CD4 Th1
- macrophage deactivation - CD4 Treg
- VSMC death - CD8 CTL
- B-cell help - CD4 Th2
What is the relationship between macrophages and the T lymphocytes?
both activate each other
What are the 2 main types of macrophages?
- inflammatory macrophages
- resident macrophages
What do inflammatory macrophages do?
adapted to kill microorganisms
What do resident macrophages do?
- suppress anti-inflammatory activity for homeostasis
- alveolar resident macrophages contribute to lipid surfactant homeostasis
- some are osteoclasts involved in calcium and phosphate homeostasis
- iron haemostasis in spleen
What characterises atherosclerosis?
macrophages causing inflammation in artery walls
What do LDLs do?
carries cholesterol from the liver to the rest of the body (including arteries)
What do HDLs do?
carries cholesterol from peripheral tissues (including arteries) back to the liver
What are oxidised/modified LDLs?
- highly inflammatory and toxic forms of LDLs found in vessel walls
- caused by the action of free radicals on LDLs
How are LDLs modified?
- LDLs leak through the endothelial barrier
- LDLs are trapped by binding to the sticky matrix proteoglycans in the sub-endothelial layer
- LDL becomes oxidatively modified by free radicals
How can oxidised LDLs cause chronic inflammation?
- phagocytosed by macrophages making them foam cells
- stimulates chronic inflammation
What is familial hyperlipidemia?
- massively elevated cholesterol (>20mmol/L)
- autosomal genetic disease (dominant)
What causes familial hyperlipidemia?
failure to clear LDL from the blood
What the effects of familial hyperlipidemia?
- xanthomas
- early atherosclerosis
- fatal MI <20 if untreated
What gene causes familial hyperlipidemia?
- LDLR gene absent
- causes macrophages to accumulate cholesterol
- scavenger receptors bind to OxLDL
What does macrophage scavenger receptor A (CD204) do?
- binds to oxidised LDL
- binds to gram positive bacteria
- binds to dead cells
What does macrophage scavenger receptor B (CD36) do?
- binds to oxidised LDL
- binds to malaria parasites
- binds to dead cells
What oxidative enzymes activated by macrophages can modify LDL?
NADPH oxidase (superoxide) Myeloperoxidase (hypochlorous acid)
What are the negative impacts of macrophages
- generate free radicals that further oxidise lipoproteins
- phagocytose modified lipoproteins and become foam cells
- express cytokine mediators that recruit monocytes
- express chemoattractants and growth factors
- express proteinases that degrade tissue
What are cytokines?
protein immune hormones that activate endothelial cell adhesion molecules
What are chemokines?
small proteins chemoattractant to monocytes
What cytokines are released by macrophages?
- IL-1 stimulates intracellular cholesterol crystals and NFkB
- coordiantes cell death and proliferation
What happens if IL-1 isn’t present?
atherosclerosis is reduced (seen in mice)
What chemokines are released by macrophages and what do they do?
MCP-1 binds to G protein coupled receptor CCR2
What happens if MCP-1 or CCR2 aren’t present?
atherosclerosis is reduced (in mice)
What is the wound healing role of macrophages?
release growth factors that recruit VSMC and stimulate them to proliferate and deposit matrix
What is the impact of platelet derived growth factor (PDGF)?
Chemotaxis, survival and mitosis of VSMCs
What is the impact of transforming growth factor beta (TGF-b)?
- increased collagen synthesis
- matrix deposition
What are the main 2 types of growth factors released?
- platelet derived growth factor
- transforming growth factor beta
What happens in atherosclerotic vascular smooth muscle cells?
- reduced contractile filaments
- increased matrix deposition genes
Which proteinases are expressed by macrophages?
metalloproteinases (MMPs)
What are Metalloproteinases?
- family of 28 homologous enzymes
- zinc based enzymes
What do Metalloproteinases do?
- activate eachother via proteolysis
- degrade collagen
- catalytic mechanism based on zinc
What happens when MMPs breakdown collagen?
- plaque erosion/rupture
(no longer trapped in smooth muscle) - blood coagulation may cause an occlusive thrombus
What are the characteristics of vulnerable and stable plaques?
- lipid-rich necrotic core
- increased VSMC apoptosis
- reduced VSMC and collagen content
- thin fibrous cap
- infiltrate of activated macrophages expressing MMPs
What happens in macrophage apoptosis?
- Ox LDLs are toxic
- Macrophage foam cells have protective systems that maintain survival when toxic lipid loading
- when overwhelmed, apoptosis
- then release tissue factors and toxic lipids forming a lipid necrotic core
- thrombogenic and toxic material accumulates until plaque rupture
What is Nuclear Factor kappa B (NFkB)?
transcription factor that regulates inflammation
What activates NFkB?
- scavenger receptors
- toll-like receptors
- cytokine receptors (IL-1)
What does NFkB activate?
- matrix metalloproteinases
- inducible nitric oxide synthase
- IL-1
What happens in atherosclerotic inflammation?
- LDLs are converted into OxLDLs that activate macrophages
- activated macrophages damage artery walls
- all regulated by NFkB
What are statins?
- HMG-CoA reductase inhibitors
- lower plasma cholesterol
What is PCSK9?
an enzyme which degrades LDLRs
How are PCSK9 inhibitors used?
- to supplement statins
- in severe or statin-resistant hyperlipidaemia
What are ABCA1 ABCG1 Cholesterol export pumps?
- transport pumps for reverse cholesterol transport
- export cholesterol to HDL when ApoA is found on HDL
- removes cholesterol from arteries and initiates return to the liver
What are the macrophage functions in atherosclerosis?
- Secrete inflammatory cytokines and chemokines
- Reverse cholesterol transport
- Secrete oxidants that damage cells and LDL
- Accumulate cholesterol and become activated by cholesterol overload
- secrete matrix metalloproteinases which degrade fibrous cap collagen
- inititate death of vascular smooth muscle cells
What are the signs and symptoms of atherosclerosis?
- death of downstream tissue (heart and brain)
- one-sided loss of function (major ischaemic stroke)
- severe central crushing chest pain with fear, dizziness and nausea (MI)
- angina
- plaque rupture
What can a plaque rupture lead to?
stroke or myocardial infarction
