Amanda Mckenz Flashcards
What initiates atherosclerosis
Endothelial cell dysfunction
Whats the tunica intima and what is it involved in
It’s the innermost layer of an artery or vein- involved in ATS
Name 3 types of key cells involved in the pathogenesis of ATS
Blood cells
Endothelial cells
Vascular smooth muscle
Where are blood platelets derived from
Megakaryocytes
Define platelet
Anucleate cell fragment
What is atherosclerosis
Thickening if artery wall due to accumulation of fatty material leading to the production of an atheromatous plaque
Name two scavenger receptors on macrophages
CD36 and SRA
How is VCAM-1 involved in ATS
It’s the major adhesion receptor responsible for attachment of monocytes to endothelial cells
What does diapedesis mean
Attachment and migration of monocytes through endothelial layers
In ATS what is responsible for differentiating monocytes into macrophages
Macrophage colony stimulating factor (M-CSF)
What’s the role of cholesterol ester hydrolase in macrophage foam cells
Associates with lipid droplets and releases cholesterol to be picked up by HDL
What is C-reactive protein
Plasma CRP is an acute phase reactant produced by the liver in response to inflammatory cytokines e.g IL-6
When you get plaque erosion what is exposed that’s pro thrombotic?
Collagen
Name a zinc dependent endopeptidase
Matrix metalloproteinases
Give 5 markers of a vulnerable plaque
Large lipid core High density macrophages Low density smooth muscle High tissue factor content Thin and disorganised collagen cap
Name 3 micro vascular damage that can occur in diabetes
Retinal
Kidney
Nervous system
Name three types of macro vascular damage that occurs in diabetes
Coronary
Carotid
Femoral
What is endothelial dysfunction
Imbalance between vasoconstricting and vasorelaxing mediators
What is ADMA?
Asymmetric dimethyl arginine: eNOS inhihitor
What is BH4
Tetrahydrobiopterin
Name two enzymes that phosphorylate eNOS
Akt kinase
Amp kinase
Around 80% of cholesterol is from where?
Endogenous synthesis (HMGcoA reductase pathway)
Rest from diet
What hydrolyses triacylglycerides
Lipoprotein lipase
What is lipoprotein (a)
LDL-like molecule: complex of apolipoprotein (a) bound to LDL molecule via apolipoprotein B-100
Linked by disulphide bonds, inhibits plasminogen
Name three inherited Mendelian disorders
Tangiers disease
Familial hypercholesterolemia
PCSK9 mutations
Name two key symptoms of tangiers disease
Orange coloured tonsils
Clouded corneal
What’s tangiers disease caused by?
Genetic disorder caused by ABCA1 gene mutation on chromosome 9q31 resulting in mutant ABCA1 transporter reducing the ability to transport cholesterol out of cells
What does cholesterol combine with to form HDL
Apolipoprotein A1
Tangiers disease results in decreased levels of circulating what?
HDLs
In tangiers disease why does cholesterol build up inside cells?
Because the ABCA1 transporter stops working
What’s the clinical manifestation of familial hypercholesterolemia (FH)
Elevated plasma LDL
In what Mendelian disorder do you get nodules of cholesterol ‘xanthoma’ in skin and tendons
Familial hypercholesterolemia
What causes familial hypercholesterolemia?
Several loss of function mutations in the LDL receptor- absent or deficient LDL receptor = decreased LDL uptake by liver
Name 3 treatment options for familial hypercholesterolemia
Lipid lowering therapies e.g statins
LDL- lowering apheresis (beads that selectively bind to apoB100 in LDL)
Liver transplant
What does PCSK9 stand for and what is it
Proprotein convertase subtilisin/kexin type 9- is a serine protease mainly expressed in the liver and intestine it controls LDL receptor protein levels
What is evolocumab
Fully human monoclonal antibody against PCSK9 to inhibit activity
What is ezetimibe
Cholesterol absorption inhibitor that targets uptake at the jejunal enterocyte brush border
What’s the primary target of action of ezetimibe
Cholesterol transport protein nieman pick C1 like protein
What is alirocumab?
Monoclonal antibody against PSCK9
How do statins work
Inhibit HMG-CoA reductase preventing build up of pro inflam intermediate products therefore lipid lowering and anti-inflam effects
Do statins work on exogenous or endogenous cholesterol pathway
Endogenous
Name three classes of lipid lowering drugs
Statins
Fibrates
Bile acid binding resins
How do fibrates work
Increase genes for lipoprotein lipase
What are 5 effects of fibrates
1) decrease VLDL
2) increase hepatic LDL uptake
3) reduce C-RP & fibrinogen
4) improve glucose tolerance
5) inhibit smooth muscle inflammation
Cell adhesion molecule expression is increased by statins: T or F?
F is reduced therefore reducing migration and inflammation
What does PPARa stand for and what class of drugs increase it
Peroxisome proliferator-activated receptor alpha
Lipid lowering drugs: FIBRATES
Nike acids are synthesised from what
Cholesterol
Cholesterol 7ahydroxylase
Give three examples of bile acid binding resins
Cholestyramine
Colestipol
Colesevalam
Is clopidogrel a prodrug and how does it work
Yes oxidised by CYP450 to activate- works by inhibiting ADP induced platelet aggregation by blocking P2Y12 receptors
What type of drug is glybera and what is it used to treat
Gene therapy- used to treat familial LPL deficiency
How many genotypes of hepatitis C are there
11
What genotypes are distributed worldwide
1-3
Which genotypes of hepatitis C have more favourable responses to pegylated interferon-a in combination with ribavirin
2 & 3
What three receptors does HCV need to enter cells
CD81
Scavenger receptor B1
Claudin 1
Name two protease inhibitors approved by the FDA in 2011 for the treatment of hepatitis C
Telaprevir
Boceprevir
How is hepatitis A transmitted
Through ingestion of contaminated food and water
How is hepatitis B transmitted
Through contact with blood or other bodily fluids
How is hepatitis E transmitted
Person to person via faecal oral route
