Atherosclerosis/CHD Flashcards
What are the modifiable risk factors for CHD?
Smoking, Lipid intake, BP, Diabetes, Obesity and sedentary lifestyle
What are the non-modifiable risk factors for CHD?
Age, Sex, Genetic background
How has intervention modified the epidemiology of CHD?
Reduced population levels of hyperlipidaemia due to statins, and reduced hypertension due to antihypertensives means that plaques now primarily driven by obesity
What are LDLs?
Bad cholesterol - synthesised in liver, carried from liver to arteries (needed for normal function, so shows J-curve)
What are HDLs?
Good cholesterol - carrying from peripheral tissues to the liver
What is the structure of LDLs?
Has lipid monolayer and a docking molecule (apolipoproteins), with cargo fat (triglycerides and cholesterol esters) for fuel
Where are atheroscleroses most often found?
At branching where there is disturbed flow and branching
What is LDL deposition?
LDLs deposit in subintimal space - binding to matrix proteoglycans
What is the modification of subendothelially trapped LDLs?
Bind to sticky matrix carbohydrates (proteoglycans), becoming susceptible to modification and are oxidised (partial burning) by free radicals; phagocytosed by macrophages to lead to chronic inflammation/foam cell formation
What are the two types of Macrophage Scavenger Receptors?
MSR A
MSR B
What does MSR A do?
CD204, bind oxLDL, dead cells and gram positive bacteria to cause inflammation and destruction
What does MSR B do?
CD36, bind oxLDL, malaria parasites and dead cells for safe clearance and reverse cholesterol transport
What are the five actions of macrophages?
Generate free radicals
Phagocytose modified lipoproteins
Express cytokine mediators to recruit monocytes
Express chemo-attractants and growth factors
Express metalloproteinases
Describe the action of macrophage free radicals:
NADPH oxidase and myeloperoxidase (hypochlorous acid from ROS + Cl-) - bleach secreted to walls to oxidise LDLs
What happens when macrophages engulf modified lipoproteins?
Accumulate modified LDLs and become enlarged foam cells
What do the chemokines expressed by macrophages do?
Chemokines attract monocytes (MCP1 binding to GPCR CCR2 attracts monocyte, so if deficient then atherosclerosis reduced) and cytokines activate endothelial cell adhesion molecules (IL1 upregulates VSMC VCAM-1 that mediates tight monocyte binding - reduced IL1/VCAM-1 expression reduces atherosclerosis)
What do the chemo-attractants and growth factors expressed by Macrophages do?
Platelet derived growth factor and transforming growth factor beta for “wound healing” role - release complementary protein growth factors to recruit VSMCs and stimulate to proliferate (in atherosclerosis then reduced contractile filaments and increased matrix deposition genes)
What do the metalloproteinases expressed by macrophages do?
Family of 28 homologous enzymes that activate each other by proteolysis to degrade collagen (catalytic mechanism based on Zn); blood coagulation at site of rupture may lead to occlusive thrombus and cessation of flow - DEGRADE WALL OF PLAQUE SO RUPTURES AND CAUSES THROMBUS
What are ruptured plaques?
Macrophages mean fibrous cap becomes so thin that will break and rupture, allowing necrotic core to contact blood and cause thrombus formation
What are vulnerable plaque characteristics?
Large, soft, eccentric lipid-rich necrotic core with increased VSMC apoptosis, reduced VSMC/collagen content, thin fibrous cap and infiltrate of activate macrophages expressing metalloproteinases
What is macrophage apoptosis?
OxLDL derived metabolites (e.g. 7-keto-cholesterol) toxic to macrophages, and while foam cells have protective systems to survive, when overwhelmed they will die via apoptosis; release macrophage tissue factors and toxic lipids to lipid necrotic core, so that thrombogenic and toxic material accumulates and is walled off until plaque ruptures, so meets blood
What is Nuclear Factor Kappa B (NFkB)?
Master regulator of inflammation, activated by scavenger/toll-like/cytokine receptors, switching on inflammatory genes (e.g. Matrix metalloproteinases and inducible nitric oxide synthase) - can be activated by many stimuli and coregulate multiple genes
