Atherogenesis

Question 1

Atherogenic plaque components

Answer 1

SM, Macrophage - foam and T cells

Matrix components (collagen, proteoglycans, elastic fibres)
Intracellular and extracellular lipid (cholesterol + their esters)

Question 2

Endothelium dysfunction is

Answer 2

Functional rather than structural

Question 3

Endothelium dysfunction leads to

Answer 3

Loss of cell repellent quality

Allows inflammatory cells into vascular wall

Increased permeability to lipoproteins

Question 4

Monocyte role

Answer 4

Attracted to developing plaque by MCP-1 and CCl2

Transform into macrophage (cytokine influence - IFN-γ, TNF-α, GM-CSF, M-CSF) and secreted by endothelium & VSMC

Generate ROS - oxidise LDL in intima

Produce pro-inflammatory cytokines

Express scavenger receptors

Question 5

IFN-γ, TNF-α, GM-CSF, M-CSF

Answer 5

Transform monocyte into macrophage

Cytokines

Question 6

Cytokines which transform monocyte into macrophage

Answer 6

IFN-γ, TNF-α, GM-CSF, M-CSF

Question 7

Lipid involvement atherogenesis

Answer 7

Smaller lipoproteins enter vascular wall easier

Can be oxidised in intimate

Question 8

Oxidised LDL can

Answer 8

Stimulate VCAM-1 and MCP-1 expression - directs macrophage to sites of lesions

Oxidised B-100 binds to scavenger receptors on macrophage and is phagocytosed

No feedback regulation via cholesterol concentration

Generate foam cells

Question 9

Foamy Macrophage

Answer 9

Stimulus: OxLDL

Increase lipid uptake and ROS

Question 10

VSMC migration

Answer 10

Endothelial cells and macrophage secrete PDGF and TGF-B

Effect VSMC: proliferation and migration into intima
Activated VSMCs also synthesise ECM material - deposits in plaque

Question 11

Activated VSMCs

Answer 11

Synthesise ECM material - deposits in plaque

Question 12

PDGF and TGF-B

Answer 12

Secreted by endothelial cells and macrophage

proliferation and migration into intima

Question 13

Stable Plaque

Answer 13

Thick fibrous cap
High collagen content 
High VSMC content 
Small lipid pool 
Few inflammatory cells

Question 14

Atherogenesis causes: Lipid oxidation hypothesis

Answer 14

LDL enters vascular wall + oxidised -> OxLDL phagocytose (macrophage) -> generate foam cells -> recruit macrophage -> generate plaque

Question 15

Atherogenesis causes: Response to injury hypothesis

Answer 15

Endothelial injury/dysfunction -> Accumulate lipoproteins in vessel walls -> monocyte adhesion -> platelet adhesion -> smooth muscle proliferation -> lipid accumulation -plaques

Question 16

Endothelial injury due to

Answer 16

◦ raised LDL
◦ ‘toxins’ eg cigarette smoke
◦ hypertension
◦ haemodynamic stress

Question 17

Endothelial injury causes

Answer 17

◦ platelet adhesion, PDGF release, VSMC proliferation and migration
◦ insudation of lipid, LDL oxidation, uptake of lipid by VSMC and macrophages
◦ migration of monocytes into intima