atherogenesis

Question 1

where in the artery to plaques develop? 3

Answer 1

• tunica intima of the artery wall
• caused by the migration of cells from the tunica media
• caused by the recruitment of leukocytes and deposition of lipids from the blood

Question 2

what are atherogenic plaques made of? 3

Answer 2

• cells (smooth muscle cells, macrophages (foam cells), T cells)
• matrix components (collagen, proteoglycans, elastic fibres)
• intracellular and extracellular lipid (cholesterol and cholesterol esters)

Question 3

what does a normal endothelium produce?

Answer 3

• nitric oxide which controls vasorelaxation and has anti-adhesive properties

Question 4

what is the role of endothelium in atherogenesis? 6

Answer 4

• normal endothelium has anti-coagulant and anti-adhesion properties
• early dysfunction/damage of the endothelium is functional rather than structural
• loss of cell repellant quality
• allows inflammatory cells into the vascular wall
• increased permeability to lipoproteins
• structural damage is caused by processes above and is observed later in the atherogenic process

Question 5

what is the role of monocytes in atherogenesis? 5

Answer 5

• attracted to developing plaques by chemokine MCOP-1/CCL2
• transform into macrophages under the influence of cytokines secreted by the endothelium and vascular smooth muscle cells
• generate reactive oxygen species (ROS) which can oxidise LDL in intima
• produce pro inflammatory cytokines
• express scavenger receptors

Question 6

explain lipid involvement in atherogenesis? 3

Answer 6

• Smaller lipoproteins (remnants and LDL) enter vascular cell wall more easily than other particles, hence are more atherogenic
• Entry of lipoproteins into the vascular cell wall occurs more easily when present in high concentrations in the blood
• Lipoproteins in the vascular wall can be oxidised in the intima (by oxidases and ROS from macrophages and ROS from VSMCs)

Question 7

describe oxidised LDL? 4

Answer 7

• stimulates the expression of VCAM-1 and MCP-1 which directs monocytes to the sites of the lesions
• oxidised B-100 binds to scavenger receptors on macrophages and is phagcytosed
• no feedback regulation via cholesterol concentration
• generation of foam cells (visible in artery walls as fatty streaks)

Question 8

how do macrophages become foam cells? 5

Answer 8

• Oxidised LDL is not recognised by LDL receptor but by scavenger receptors
• Stored as cholesterol esters in the cell
• Regulation controlling cholesterol export are down-regulated
• Accumulation of lipid in the form of cholesterol esters in the cytosol
• These cells then become foamy macrophages which are pro-inflammatory as they release pro inflammatory cytokines

Question 9

describe the migration of vascular smooth muscle cells? 5

Answer 9

• VSMCs are responsible for the structure of the vessel wall
• endothelial cells and macrophages secrete PDGF and TGF beta which cause proliferation and migration of VSMCs into the intima
• VSMCs can differentiate into macrophage like cells and become foam cells
• activated VSMCs also synthesise ECM (collagen in particular) which deposits in the plaque
• migrating cells and deposits of ECM material all disrupt the structure of the arterial wall

Question 10

what are the 2 types of atherosclerotic plaques and the differences? 8

Answer 10

stable:
thick fibrous cap 
high VSMC and collagen content 
-small lipid pool
-few inflammatory cells

ruptured:

• thin fibrous cap
• low VSMS and collagen content
• large lipid pool
• many inflammatory cells

Question 11

explain the lipid oxidation hypothesis for atherogenesis? 5

Answer 11

• LDL enters vascular wall and becomes oxidised
• Oxidised LDL phagocytosed by macrophages
• Generation of foam cells
• Recruitment of macrophages
• Generation of plaques

Question 12

explain the response to injury hypothesis for atherogenesis? 6

Answer 12

• Endothelial injury/dysfunction
• Accumulation of lipoproteins in the vessel wall
• Monocyte adhesion
• Platelet adhesion
• Smooth muscle proliferation
• Lipid accumulation (plaque)

Question 13

what is familial hypercholesterolaemia? 3

Answer 13

• Genetic disorder
• Autosomal inheritance in genes related to LDL metabolism resulting in lifelong elevation of LDL-C levels
• If untreated, many patients with FH die of MI or other CV event

Question 14

how can endothelial injury be caused? 4

Answer 14

• Raised LDL
• Toxins
• Hypertension
• Haemodynamic stress

Question 15

what can endothelial injury cause? 3

Answer 15

• Platelet adhesion, PDGF release, migration of monocytes into the intima
• Insudation of lipid, LDL oxidation, uptake of lipid by VSMC and macrophages
• VSMC proliferation and migration

Question 16

how do we prevent atherogenesis? 3

Answer 16

• Protection of artery walls (stop smoking, lower blood pressure)
• Reduce plasma lipid levels
• Reduce ROS and inflammation

Question 17

name some treatments to decrease plasma lipids? 2

Answer 17

• statins

- anti-PCSK9 antibodies

Question 18

what do statins do? 3

Answer 18

• competitive inhibitors of HMG-CoA reductase, they are bulky and literally get stuck in the active site
• this prevents the enzyme from binding with its substrate, HMG-CoA
• lower blood cholesterol

Question 19

name 2 classes of statins?

Answer 19

• Natural statins: lovastatin, compactin, pravastatin, simvastatin
• Synthetic statins: atorvastatin, Fluvastatin

Question 20

how do statins inhibit cholesterol synthesis? 3

Answer 20

• HMG-CoA expression increases, but no activity in the presence of a statin
• increased LDLR expression- uptake of LDL from plasma increased
• increased PCSK9 expression- degradation of LDLR promoted