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cardio and resp yr 2 > atherosclerosis > Flashcards

atherosclerosis Flashcards

1
Q

where is the most common site of atherosclerosis?/ disease associated with atherosclerosis?

A

coronary arteries: CHD

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2
Q

modifiable RISK factors

A

smoking
high lipid intake
diabetes
sedentary lifestyle
obesity
blood pressure

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3
Q

non mod risk factors

A

age
sex
genetics

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4
Q

how much does each risk factor incr ur risk? how much do all together?

A

most single: high cholesterol
hypertension
then smoking

if you have all three X13 times more likley to get atherosclerosis (its not direct products of single factor risk x)

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5
Q

what has changef in epidemeoology over last decade?

A

hyperlipidaemia and hypertension improved due to statin and antihypertensive treatment respectively

obesity increased
important improvements in diabetes however doubtful impact on macrovascular disease

changing pathology of coronary thrombosis related to altered risk factors

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6
Q

overall is atherosclerosis a greater or lesser global health burdain now>

A

greater

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7
Q

cell types involved in atherosclerosis pahtophysiology

A

blood cells: immune and non immune

-t lymphocytes,
-macrophages/ monocyte
-platelets

vessel cells:
-vascular smooth muscle cells
-vascular endothelial cells

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8
Q

what do vascular endothelial cells do

A

recruit leukocytes
barrier function- to lipoproteins

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9
Q

platelets role

A

thrombus generation
CYTOKINE and growth factor release!!!

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10
Q

T lymphocytes role

A
  • CD4 t1: macrophage activation
  • CD4 reg: macrophage deactivation
  • CD8 killer - endothelial smooth muscle cells killing
  • B-cell/ antibody help- CD4 Th2
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11
Q

macrophage role (overall- general version)

A

foam cell formation
cytokine and growth factor release
major source of free radicals
metalloproteinases

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12
Q

vascular smooth muscle cell role

A

fibrous cap formation + remodelling
collagen synthesis
migration and proliferation

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13
Q

what is a common misconception about the pathophysiology in atherosclerosis? what is the reality? what clinical evidence supports this?

A

-atherosclerosis has an inflammatory basis.
-:MULTIPLE MECHS INcluding cholesterol crystal formation
-ITS NOT passive lipid deposition in vessels. (fatberg).

-This is proven by patients with high risk of atheroscleross complications (stroke and heart attack) having fewer of those after being given antibodies to IL-1

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14
Q

what cell is mucrophage derived form

A

monocyte

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15
Q

how are different macrophage subtypes made/ regulated?

A

by combination of transcription factors binding to regulatory sequences on DNA. However we do not yet understand the regulation.

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16
Q

what are the 2 types of macrophages

A

inflammatory (adapted to kill microorganisms)

non-inflammatory and resident macrophages
-(normally homeostatic functions- parenchymal (=functional not structural))

-alveolar resident macrophages - surfactant lipid homeostasis

  • spleen- iron homeostasis
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17
Q

function of ldls

A

bad cholesterol synthesized in liver
carries cholesterol from liver to rest of body (incl lung and arteries)

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18
Q

function of HDLS

A

good cholesterol, carries cholesterol from peripheral tissues incl arteries back to liver (reverse cholesterol transport!!!)

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19
Q

what shape curve is seen when stroke or myocardial infarction is on y axis and ldl conc on x?

A

LDL- C and J curve: means that stroke chance decr for first few levels of ldl incr ( we need some of it) but incr for further ldld conc incr (we all have too much ldl thats why its bad choletserol)

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20
Q

what are oxidised and modified ldls

A

Chemical and physical modifications of LDL by free radicals, enzymes, aggregation

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

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21
Q

what is the ldl surrounding composed of?

A

lipid monolayer

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22
Q

what is a docking molecule?

A

a molecule that lies embeded in the lipid monolayer of an LDL and acts as an address for where the ldl should be going

some docking molecules also interact with clotting and clotting factors

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23
Q

what parts of the LDL do free radicals attack>

A

lipid monolayer and docking molecule

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24
Q

Describe the process of ldl modification (ex. oxidation)

A

1) LDLs leak through endothelium in areas of -endothelial vortex-: due to endothelial activation in these areas

2) LDL becomes suscesptible to modifications by binding to sticky matrix carbohydrates (proteoglycans) in subendothelial layer

3) LDLs become oxidised after being attacked by free radicals

4) OXIDISED LDLs are phagocytosed by acitvated macrophages that are now called foam cells

this stimulates chronic inflammation

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25
Q

what is familial hyperlipidemia? FH. (nature of illness and main features seen)

A

1) genetic autosomal dominant with gene dosage (meaning if you have 1 allele you do have it but if you have 2 you have more intense)

2) very high levels of cholesterol (>20 mmol/ L vs 1-5mmol/L: normal)

3) xanthomas and early atherosclerosis

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26
Q

what is the risk of leavinf FH untreated?

A

fatal myocardial infarction before 20

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27
Q

what is the pathophysiology of FH (one line answer)

A

failure to clear LDLD from blood

28
Q

what 2 things does cellular cholesterol negatively regulate?

A

LDL receptor expression and
cholesterol synthesis

29
Q

what is the biochem name of statins and what do they do

A

HMG-CoA reductase inhibitors - they inhibit this enzyme which is involved in cholesterol synthesis in the liver

30
Q

the discovery of which homeostatic cellular negative feedback loop helped in the discovery of statins and why?

A

discovery of the loop of: cholesterol synthesis being negatively regulated by cellular cholesterol

(because increased cellular cholesterol inhibits HMG-CoA reductase, thats how they got the idea of making an inhibitor for this enzyme: statins)

31
Q

what happens in patients that are LDLR negative?

A

since ldl cant be scooped up by normal cells, macrophages accumulate cholesterol

32
Q

what is a scavanger receptor? feedback control? location? what binds to it?

A

another type of LDL recepetor discovered after the main one.
1) not under feedback control
2) found in atherosclerotic lesions
3) bind OxLDL
4) later found out that they are pathogenic (not normal)

33
Q

what is an other drug mechanism for lowering LDL levels?

A

PCSK9 inhibitors

PCSK9 is bad, degrades LDL receptors (leads to
1) more ldl in blood,
2) less ldl in cells which would lead to supressed cholesterol synthesis

34
Q

when are PCSK9 inhibitors used?

A

PCSK9 inhibitors are used
1) as supplement to statins for severe hyperlipidemia or
2) for statin resistant hyperlipidemia

35
Q

WHAT Forms can PCSK9 inhibitors be designed in?

A

Antibodies
Antisense
Si-RNA

36
Q

what are ABCA? (ABCA1 and ABCG1)

A

-CHOLESTEROL EXPORT PUMPS:
-in macrophage membranes
- interact with apolipoprotein on HDLs
- removing cholesterol from arteries and initiating return to the liver

37
Q

what cells are scavanger receptors found on?

A

macrophages

38
Q

what is the biochem name of macrophage scavanger receptor A and where does it bind?

A

Known as CD204
-Binds to oxidised LDL

-Binds to Gram-positive bacteria!!!! like Staphylococci & Streptococci
-Binds to dead cells!!!!

39
Q

what is the biochem name of macrophage scavanger receptor B and where does it bind?

A

-Known as CD36
-Binds to oxidised LDL
-Binds to malaria parasites!!!!
-Binds to dead cells

40
Q

what is the response to arterial Ox-LDL deposits when there are scavanger receptors vs when there are not

A

with scavanger receptors LDLs bind on them on the macrophage and the “bug detector “ pathways are activated - infammation

note(:think abt the other things that bind on scavanger rec- pathogens and dead cells: infm responce trigger)

vs without scavanger, theres safe clearance reverse cholesterol transport- HDL production to transport cholesterol back to blood (ABCA pumps)

41
Q

difference of cytokines vs chemokines in general (got it from online for personal clarity)

A

cytokines are signalling molecules in general

chemokines are specifically signalling molecules that help in recruitment of immune cells (get their name from chemotaxis: movement of a cell across a chem gradient)

42
Q

examples of free radicals generated by macrophages to oxidise lipoproteins and the oxidising enzymes that form the radicals

A

1) NADPH Oxidase: enzyme that results in, superoxide O2-. formation

2) Myeloperoxidase : enzyme -catalyzes reaction between (H2O2) and(Cl-) to produce (HOCl) (radical)

or
myeloperoxidase can react with (NO) to form peroxynitrite (ONOO−) (radical)

3) Generation of H2O2

43
Q

what protein is stained to see macrophages (in their foam cell phase) ? (what colour?)

A

macrophage specific protein: CD68: brown dye

44
Q

what is dark brown?

A

foam cells

45
Q

what is the light brown around?

A

foam cell debris- dead toxic stuff

46
Q

what are the little clear circles inside foam cells?

A

fat globules

47
Q

what are the clear random shaped zones around foam cell debris?

A

cholesterol crystals

48
Q

what is the function of cytokines released by macrophages

A

they are protein “immune hormones”(-meaning the equivalent of a hormone for the immune system bc they signal..) that activate endothelial cell adhesion molecules

49
Q

1 example of a macrophage released cytokine and proof that its involved in atherosclerosis pathophysiology

A

Interleukin-1
– triggers intracellular cholesterol crystals and NFkB. (ect.)

-Coordinates cell death and cell proliferation; and elevated CRP (ect.)

-Atherosclerosis is reduced in mice without IL-1 and humans with anti-IL-1 antibodies

50
Q

macrophage derived chemokines role

A

small proteins chemoattractant to monocytes

51
Q

example of chemokine, where it binds on monocyte and proof its involved in atherosclerosis pathophysiology

A

Monocyte chemotactic protein-1 (MCP-1)

binds to a monocyte G-protein coupled receptor CCR2.

Atherosclerosis is reduced in MCP-1 or CCR2 deficient mice.

52
Q

what is 1 bad side effect of cytokine and chemokine release

A

immunosupression (think- monocytes recruited..)

53
Q

what is a problematic feature of cytokine and chemokine recruitment>

A

Positive feedback loop / vicious cycle leading to self-perpetuating inflammation.
(bc monocytes (the recruited cell) are the pre-form of macrophages..)

54
Q

what are teh functions of platelet derived growth factors (one of the 2 types of gf for Vascular smooth muslce cells VSMC)

A

Vascular smooth muscle cell chemotaxis
Vascular smooth muscle cell survival
Vascular smooth muscle cell division (mitosis)

55
Q

what are the functions of transforming growth factor beta factors?

A

Increased collagen synthesis
Matrix deposition

56
Q

what are the effects of PDGF and TGF-b ON A VASCULAR SMOOTH MUSCLE CELL?

A

turns from normal conctractile medial cell
with high contractile filaments and low matrix deposition genes

to

atherosclerotic synthetic VSMC with low contractile filaments and high matrix deposition genes

57
Q

what are metalloproteinases

A

Family of ~28 homologous enzymes.

58
Q

how are metalloproteinases activated

A

Activate each other by proteolysis.

59
Q

what do metalloproteinases do and what chemical element is their mechanism based on

A

Degrade collagen.
Catalytic mechanism based on Zn.

60
Q

what is the effect of plaque errosion/ rupture?

A

Blood coagulation at the site of rupture may lead to an occlusive thrombus and cessation of blood flow.

61
Q

what happens to pacrophages (foam cells) once they are overwhelmed and why

A

even though macrophage foam cells have protective mechanisms that mentain survuval in face of toxic lipid loading, they can become overwhelmed at some point due to oxLDL-derived toxic metabolites such as 7 keto-cholesterol

die via apoptosis

62
Q

what happens when macrophages have nbeen apoptosed

A

Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core

this Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood.

63
Q

what does it mean that NFKb IS A NON REDINDANT NETWORK IN INFLAMMATION

A

it means that NF-κB plays a unique and essential role in regulating the inflammatory response, and its functions are not easily replaced or duplicated by other signaling pathways.

64
Q

WHAT IS NFkB?

A

NUCLEAR FACTOR KAPPA b

A TRANSCRIPTION FACTOR that directs multiple inflammatory genes based on multiple different inflammatory stimuli

65
Q

examples of inflammatory stimuli acting on NFkB and the inflammatory genes regulated

A

Scavenger receptors
Toll-like receptors
Cytokine receptors e.g. IL-1
cholesterol signals

66
Q

examples of inflammatory genes regulated by NFkB

A

Matrix metalloproteinases
Inducible nitric oxide synthase
Interleukin-1

cardio and resp yr 2 (10 decks)

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