inflammation and atherogenesis

Question 1

step 1 of atherogenesis

endothelial activation

Answer 1

1) LDL enters intima

2) oxidized and stim endothelial cell to express adhesion molec

Question 2

step 2 of atherogenesis

monocyte localization

Answer 2

3) monocytes adhere to endothelial cells expression VCAM-1

4) monocytes respond to chemokines (MCP-1) and migrate into intima

Question 3

step 3 of atherogensis

macrophage activation

Answer 3

5) monocytes –> foam cell via mCSF
6) macrophages express scavenger receptor for uptake of oxid LDL

7) foam cells interact with inflammatory molec
- further macrophage apoptosis
- pro-inflamm mediators

Question 4

why is inflammation involved with atherogenesis

Answer 4

host response to bacterial infection –> incr risk of sterile inflammation (no bacteria in subintima)

oxidized LDL and cholesterol are DAMPs recog by innate immune system assoc with potential infection –> sterile inflamm

Question 5

role of dendritic cells in ather

Answer 5

present antigens –> activ T cells

Question 6

what if you have no monocytes

Answer 6

no atherosclerosis (b/c nothing to respond to oxid LDL)

Question 7

monocytes are ___ leukocytes

Answer 7

innate immune system leukocytes

Question 8

___ accumulation in mouse atherogenesis proportional to extent of disease

Answer 8

monocyte accumulation

Question 9

monocyte adhesion to activated endothelium is ___ in atherogenesis

Answer 9

obligate step

monocytes interact with VCAM-1 via integrins (VLA-4)
arrests monocyte against endothelium
so monocytes can diapadese into subendothelial space

Question 10

____ is an obligate step in atherogenesis

Answer 10

monocyte adhesion

Question 11

what happens when you inhib monocyte adhesion

Answer 11

decr atherosclerosis initiation

Question 12

what are key molec that when knocked out decr atherosclerosis initiation?

Answer 12

adhesion molecules –> nothing for monocytes to stick to endothelium

1) VLA-4 (monocyte tight adhesion to VCAM-1)
2) B2 integrins (all 4 CD18) and CD11c

Question 13

atherosclerosis is a ___ type response

Answer 13

Th1 response with IL-1 and IL-6

Question 14

role of adaptive immunity in atherogensis

Answer 14

1) after dendritic cell presents antigen, activ T cells
2) incr IFN-gamma nd atherosclerosis
3) Th17 –> promote plaque instability and neoangiogenesis

Question 15

blockage of what Th17 component decr atheroslcerosis

Answer 15

block IL-17, decr atherosclerosis

Question 16

Th1 response in atherogenesis

Answer 16

1) T cells patrol endothelium
2) T cells interact with APC (presenting oxidized LDL) to initiate T cell response for atherogenesis
3) Th1 response

4) further endothelial activ, foam cells
incr lesion formation/plaque vulnerability

Question 17

Treg response in atherogenesis

Answer 17

Treg incr collagen formation, decr plaque vulnerability and lesion formation

Question 18

overall role of inflammation in atherogenesis

*******KNOW

Answer 18

1) immune response to injury initiate atherogenesis
2) innate immune cell interact with endothelium –> initial plaque formation
3) T cells promote further expansion of lesion and plaque vulnerability

Question 19

after establishing fatty streak, ___ drives additional plaque expansion to form unstable plaque

Answer 19

inflammatory mediators

Question 20

after establishing fatty streak, inflammatory mediators ___

Answer 20

drive additional plaque expansion

Question 21

plaque expansion is a ___ process

Answer 21

Th1 process with macrophage apoptosis

Question 22

5 steps in inflammation driving plaque instability

Answer 22

1) basal inflammation
2) endothelial activation
3) oxid stress
4) neoangiogenesis
5) plaque instability

Question 23

step 1
inflammatory cells in

basal inflammation

Answer 23

cytokines

acute phase reactants

Question 24

step 2
inflammatory cells in

endothelial activ

Answer 24

monocyte adhesion

leukocyte diapadesis

Question 25

step 3 inflammatory cells in oxid stress

Answer 25

LDL oxid | foam cells

Question 26

step 4 inflammatory cells in neoangiogenesis

Answer 26

blood vessel form intraplaque hemorrhage activ MMP

Question 27

step 5 inflammatory cells in plaque instability

Answer 27

rupture/erosis | platelet activ

Question 28

what are major drivers of plaque instability (3)

Answer 28

1) macrophage apoptosis + necrosis --> "necrotic core" 2) MMP degrade fibrous cap 3) intraplaque hemorrhage weaken core

Question 29

role of MMPs in atherosclerosis

Answer 29

MMPs destablize plaque Breakdown of type 1 collagen

Question 30

what is necessary for atherosclerotic plaque to become MI

Answer 30

1) lesion expansion 2) macrophage apoptosis/necrosis 3) weaken fibrotic cap 4) plaque rupture

Question 31

how is CRP produced?

Answer 31

by hepatocytes and macrophages and smooth muscle cell

Question 32

what does CRP bind to?

Answer 32

1) modified membranes 2) apoptotic cells 3) lipoproteins

Question 33

what pathway is CRP in?

Answer 33

classical complement

Question 34

fxn of CRP in therapy

Answer 34

1) CRP predict incr CV risk | 2) statin lower cholest and CRP

Question 35

JUPITER trial | pt either receive placebo or statin

Answer 35

after 4 yrs, patients with elev CRP and normal LDL had benefit with taking statin, support inflamm in CV disease

Question 36

why would statins be used in people with normal cholesterol

Answer 36

because can also lower inflammatory biomarkers (CRP)

Question 37

why does autoimmune disease have accelerated atherogenesis

Answer 37

1) incr monocyte/macrophage activ 2) decr endothelial vasodilator fxn (in RA) 3) proinflamm HDL --> incr LDL oxid (RA, psoriasis) 4) plaque instability (RA)

Question 38

how does inflammation affect HDL fxn

Answer 38

1) endotoxemia/inflamm changes HDL size, decr reverse cholesterol transport 2) HDL becomes pro-atherogenic

Question 39

HDL cholesterol efflux inversely assoc with (2)

Answer 39

1) carotid intima-media thickness (plaque thickness) | 2) risk of CAD

Question 40

impaired HDL efflux assoc with ____

Answer 40

more severe psoriasis

Question 41

____ assoc with more severe psoriasis

Answer 41

impaired HDL efflux

Question 42

what happens if you treat psoriasis? how does that affect HDL

Answer 42

incr macrophage efflux capacity and incr HDL FUNCTION!!! TREATING DID NOT CHANGE HDL LVL

Question 43

how does plaque morphology change in RA?

Answer 43

RA patient had more vulnerable plaque in LAD

Question 44

confounding factors when looking at psoriasis with CV events

Answer 44

obesity, HTN, smoking, diabetes which are also assoc with CV disease

Question 45

if you have RA at younger age, then you have ____ CV disease

Answer 45

more severe and earlier

Question 46

treatment of ___ may lower risk of CV events

Answer 46

autoimmune disease

Question 47

what is currently being done to control CV risk in RA and psoriasis patients?

Answer 47

using TNF alpha inhibitors

Question 48

effect of prednisone on CV risk

Answer 48

prednisone incr CV risks despite being an anti-inflamm drug HTN incr salt retention