Flashcards in Atherogenesis Deck (21)
Loading flashcards...
1
Q

What are atherogenic plaques composed of?

A

Cells (smooth muscle cells, macrophages (foam cells), T cells)
Matrix components (collagen, proteoglycans, elastic fibres)
Intracellular and extracellular lipid (cholesterol and cholesterol esters)

2
Q

Describe the normal role of the endothelium

A

Normal endothelium has anti-coagulant and anti-adhesion properties

3
Q

Describe early dysfunction of the endothelium in the context of atherogenesis

A

Increased permeability to lipoproteins
Allows inflammatory cells into vascular wall
Loss of cell-repellent quality

4
Q

How are monocytes attracted to developing plaques?

A

Attracted to developing plaques by MCP-1/CCL2

5
Q

What happens to the monocytes when they are attracted to the developing plaques?

A

Transform into macrophages under influence of cytokines (IFN-γ, TNF-α, GM-CSF, M-CSF) secreted by endothelium and vascular smooth muscle cells (VSMC)

Generate Reactive Oxygen Species (ROS) which can oxidise LDL in intima

Produce pro-inflammatory cytokines

Express scavenger receptors

6
Q

Which type of lipid is the most atherogenic?

A

LDL

7
Q

What is the problem with oxidised LDL?

A

Stimulates expression of VCAM-1 and MCP-1; directs macrophages to sites of lesions

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

No feedback regulation via cholesterol concentration

Generation of foam cells (visible in arterial walls as fatty streaks)

8
Q

What happens when you upregulate VCAM-1?

A

Increased migration of monocytes from blood into the artery

9
Q

What does non-oxidised LDL bind to?

A

LDL receptors

10
Q

What are foam cells?

A

Macrophages filled with lipids

11
Q

What do foamy macrophages do?

A

Drive the inflammatory process

12
Q

Describe how endothelial cells and macrophages affect the vascular smooth muscle cells

A

Endothelial cells and macrophages secrete: PDGF and TGF-β

Effect on VSMCs: proliferation and migration into the intima

13
Q

What do the activated VSMCs do>

A

Activated VSMCs also synthesise ECM (collagen in particular) which deposits in the plaque

14
Q

Summarise the process of atherogenesis

A

Hyperlipidemia, hypertension, smoking, high LDL, toxins and haemodynamics cause endothelial injury/dysfunction
Monocytes recruited from the blood and enter the artery wall
Lots of LDL in the macrophages forming foam cells
Release of pro-inflammatory cytokines
Foam cells form fatty streak.
Growth factors from foam cells cause migration and proliferation disrupting the structure of the artery wall
ECM synthesis causing a fibrous plaque to form

15
Q

Describe the differences between a smooth plaque and a ruptured plaque

A

Stable plaques have a thick fibrous cap whereas ruptured plaques have a thin fibrous cap
Stable plaques have a high VSMC content whereas ruptured plaques have a low VSMC content
Stable plaques have a small lipid pool and low number of inflammatory cells whereas the opposite is present in ruptured plques

16
Q

Describe the lipid oxidation hypothesis of atherogenesis

A
LDL enters vascular wall and become oxidised
Oxidised LDL phagocytosed by macrophages
Generation of foam cells
Recruitment of macrophages
Generation of plaques
17
Q

Describe the response to injury hypothesis

A
Endothelial dysfunction
Accumulation of lipoproteins 
Monocyte and platelet adhesion
Smooth muscle proliferation 
Lipid accumulation
18
Q

List the risk factors for endothelial injury

A

raised LDL
‘toxins’ eg cigarette smoke
hypertension
haemodynamic stress

19
Q

What does endothelial injury cause?

A

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

20
Q

What do stimulated VSMC and foam cells DO?

A

Stimulated VSMC produce matrix material

Foam cells secrete cytokines causing
further VSMC stimulation
recruitment of other inflammatory cells

21
Q

Early dysfunction of the endothelium is… rather then …

A

Functional

Structural