Atherosclerosis

Question 1

3 major factors contributing of CVD

Answer 1

Hypertension
Smoking
Cholesterol

Question 2

Where do LDLs depsit and bind?

Answer 2

Deposit: subintimal space
Bind: Matrix proteoglycans

Question 3

Main inflammatory cells in atherosclerosis?

Answer 3

Macrophages

Question 4

2 main classes of macrophages and functions?

Answer 4

Resident (normally homeostatic)

Inflammtory (kill microorganisms)

Question 5

How are macrophage subtypes regulated?

Answer 5

By combinations of transcription factors binding to regulatory sequences on DNA

Question 6

What is reverse cholesterol transport

Answer 6

When HDL carries cholesterol from “peripheral tissues” incl arteries back to the liver

Question 7

What are oxidised/modified LDLs and how are they produced?

Answer 7

Family of highly inflammatory and toxic forms of LDL found in vessel walls

Produced due to the action of free radicals on LDL
note one single substance

Question 8

Type of membrane in LDL

Answer 8

Lipid monolayer

Question 9

LDL membrane what does it include

Answer 9

Phospholipids, cholesterol, apoproteins, cargo (fat for fuel)

Question 10

How do LDLs become trapped

Answer 10

Leak through the endothelial barrier by uncertain mechanisms

LDL trapped by binding to sticky matrix carbohydrates (proteoglycans) in the sub-endothelial layer

Question 11

What happens to LDLs after they become trapped in the subendothelial layer

Answer 11

Modification

Oxidation by free radicals

Question 12

Significance of modified LDL

Answer 12

Oxdised LDL is phagocytosed by macrophages and stimulates chronic inflammation

Question 13

Familial hyperlipidemia
Inheritance 
Characteristics (2)
Physical signs (2)
Consequences if left untreated

Answer 13

Autosomal genetic disease
Massively elevated cholesterol(20mm/L)
Failure to clear LDL from blood
Xanthomas
Early athersclerosis
Fatal myocardial infarction before the age of 20

Question 14

What is the cause of familial hyperlipidemia

Answer 14

No LDL receptor

Question 15

Mechanism of familial hyperlipidemia

Answer 15

No LDL receptor, macrophages accumulate cholesterol
Second LDL receptor deduced in atherosclerotic lesions, not under feedback control
removes oxLDL

Question 16

What are scavanger receptors?

Answer 16

Family of pathogen receptors that accidentally bind to oxLDL and remove it by reverse cholesterol transport

Question 17

Macrophage scavenger receptor A

Answer 17

CD204
Binds to
oxLDL
gram +
dead cells

Question 18

Macrophage scavenger receptor B

Answer 18

CD36
Binds to:
oxLDL
malaria parasites
dead cells

Question 19

What is the function of macrophages within plaques (4)

Answer 19

Generate free radicals (further ox of LDL)
Phagocytose oxLDL –> foam cells
Become activated by oxLDL/free intracellular chol to secrete substances
Die by apoptosis - contributing to the lipid - rich core of the plaque

Question 20

What kind of substances do macrophages secrete when they become activated by oxLDL/free intracellular cholesterol (4)

Answer 20

Cytokine mediators that recruit more monocytes
Chemoattractants an growth factors for vascular smooth muscle cells
Proteinases that degrade tissue
Tissue factor that stimulates coagulation upon contact with blood

Question 21

Give 2 examples of oxidative enzymes that macrphages have

Answer 21

NADPH oxdase

Myeloperoxidase (HOCL, HONOO)

Question 22

Definition of chemokines released by macrophages

and 1 example

Answer 22

small proteins chemoattractant to monocytes

MCP-1

Question 23

Definition of cytokines released by macrophages

and 1 example

Answer 23

Protein immune hormones that activate endothelial cell adhesion molecules IL-1

Question 24

Give two examples of growth factors released by macrophages

Answer 24

Platelet derived growth factor

Transforming growth factor beta

Question 25

Function of Platelet derived growth factor

Answer 25

VSMC chemotaxis VSMC survival VSMC mitosis

Question 26

What does VSMC mean

Answer 26

Vascular smooth muscle cell

Question 27

Function of Transforming growth factor beta

Answer 27

Increased collagen synthesis Matrix deposition This strengthens the plaque works on VSMC

Question 28

Difference between normal and atherosclerotic VSMC

Answer 28

Normal: Increased contractile filaments, decreased matrix deposition Atherosclerotic: Decreased contractile filaments, increased matrix deposition

Question 29

Give a general example of proteinases that degrade tissue and function

Answer 29

Metalloproteinases (MMPs) Family of 28 homologous enzymes activate each other by proteolysis degrade collagen

Question 30

What is the catalytic mechanism of metalloproteinases based on?

Answer 30

Zinc

Question 31

Give 5 characteristics of vulnerable and stable palques

Answer 31

Large soft eccentric lipid-rich necrotic core (non-cellular material) Thin fibrous cap Reduced VSMC and collagen content Increased VSMC apoptosis Infiltrate of activated macrophages expressing MMPs

Question 32

How do macrophages die by apoptosis?

Answer 32

oxLDL derived metabolites are toxic Macrophage form cells have protective systems that maintain survival in face of toxic lipid loathing Macrophages can be overwhelmed and die by apoptosis

Question 33

What does macrophage apoptosis result to

Answer 33

Release of macrophage tissue factor and toxic lipids into the central death zone called lipid necrotic core Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood

Question 34

What is NFkB

Answer 34

Transcription factor

Question 35

What is the function of NFkB

Answer 35

Maser regulator of inflammation, switches on numerous inflammatory genes e.g. matrix metalloproteinases inducible NO synthase

Question 36

What is NFkB activated by

Answer 36

Numerous inflammatory stimuli such as Scavenger receptors Toll-like receptors Cytokine receptors

Question 37

5 factors that predispose to atherosclerosis

Answer 37

``` Smoking Hyperlipidaemia Location - disturbed flow Diabetes Hypertension ```

Question 38

other name for Scavenger receptor

Answer 38

pathogen recognition receptor

Question 39

What happens when collagen gets destroyed

Answer 39

Collagen keeps things together, if it is digested this creates a hole/weakening that then allows the fat in the vessel (which is intensely pro-coagulant and intensely toxic) to touch the lumen of the artery  immediate clot formation, thrombosis

Question 40

What are endothelial erosion lesions

Answer 40

You have an area where the endothelial cells -possibly because of the macrophages- are lost/dying, this stimulates a thrombus directly on the collagen in the fibrous cap

Question 41

General function of growth factors

Answer 41

Generates more smooth muscle cells that are going to be able to switch on to generate more collagen, makes the arteriole stronger and rupture resistant