Atherosclerosis and peripheral vascular disease Flashcards
What are the non-modifiable risk factors for atherosclerosis?
- age
- sex
- genetics
What are the modifiable risk factors for atherosclerosis?
- smoking
- lipid intake (high LDL=bad, high HDL=protective)
- hypertension
- diabetes
- obesity
- sedentary lifestyle
How does atherosclerosis build up/progress?
- adaptive thickening of intima (smooth muscle)
- infiltrated by macrophage foam cells
- apoptosis and necrosis occurs, producing small pools of extracellular lipid
- core of extracellular lipid forms
- fibrous thickening forms fibrous cap
- in advanced disease, it bursts, releasing toxic lipids into blood
What are the main cell types involved in atherosclerosis and their roles?
- vascular endothelial cells: barrier/keep lipoproteins out of intima (but not when activated), recruit leukocytes when activated
- monocyte-macrophages: foam cell formation, cytokine and GF release, major source of free radicals, metalloproteinases
- platelets: thrombus generation, and cytokine and GF release
- vascular smooth muscle cells: migrate to and proliferate in plaque, secrete collagen, remodelling and fibrous cap formation
- T lymphocytes: macrophage activation
What are the 2 main classes of macrophages?
- inflammatory macrophages: adapted to kill microbes, at the expense of some host damage
- resident macrophages: normally homeostatic and suppress inflammatory activity e.g. alveolar resident macrophages- mediate surfactant homeostasis, osteoclasts- mediate calcium homeostasis, spleen macrophages- mediate iron homeostasis
Which type of lipoprotein is a risk factor for atherosclerotic cardiovascular disease?
LDL
(synthesised in liver, carries cholesterol from liver to rest of body, inc. arteries)
–> more specifically, oxidised/modified LDLs
Why is HDL called ‘good cholesterol’?
formed in vessel walls and carries cholesterol from peripheral tissues inc. arteries BACK to liver- reverse cholesterol transport
What are the 2 main types of modification that sub endothelial trapped LDL undergoes?
oxidation and glycation
What is familial hyperlipidaemia (FH)?
- autosomal genetic disease (mainly dominant)
- massively elevated cholesterol (>20mmol/L)
- failure to clear LDL from blood
- skin xanthomas containing foam cells
- early atherosclerosis (if untreated, fatal MI before 20yrs)
What do macrophage scavenger receptors do?
- known as CD204
- bind to oxidised LDL, dead cells and pathogens (gram +ve bacteria like staph. and strep. - A, malaria parasites- B)
- on the one hand, generate inflammation
- on the other hand, deal with ox.LDL deposits and interacts w/HDL to initiate reverse cholesterol transport (homeostatic/clearing process)
What is macrophage scavenger receptor A known as?
CD204
What is macrophage scavenger receptor B known as?
CD36
What are the 2 main enzymes that macrophages use to oxidise LDL?
- NADPH oxidase
- myeloperoxidase
What inflammatory factors do plaque macrophages express?
- cytokines e.g. IL-1–> which up regulates vascular adhesion molecule 1 (VCAM-1)–> which mediates tight monocyte binding
- chemokines e.g. MCP-1 (monocyte chemotactic protein-1)–> binds to monocyte G-protein coupled receptor CCR2
- positive feedback loop/vicious cycle leading to self-perpetuating inflammation
N.B. atherosclerosis reduced in mice without these factors^
What role do macrophages play in ‘wound healing’ in atherosclerosis?
- they secrete PDGF (platelet derived growth factor)–> drives vascular smooth muscle cell chemotaxis from media into plaque, promotes VSMC survival in the toxic environment, and mitosis
- secrete TGF-beta (transforming growth factor beta)–> acts on smooth muscle cells in plaque to increase collagen synthesis (to make plaque stronger) and matrix deposition
- VSMCs shift from contractile to synthetic phenotype (dec. contractile filaments and inc. matrix deposition genes)
