inflammation and atherogenesis Flashcards
step 1 of atherogenesis
endothelial activation
1) LDL enters intima
2) oxidized and stim endothelial cell to express adhesion molec
step 2 of atherogenesis
monocyte localization
3) monocytes adhere to endothelial cells expression VCAM-1
4) monocytes respond to chemokines (MCP-1) and migrate into intima
step 3 of atherogensis
macrophage activation
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
why is inflammation involved with atherogenesis
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
role of dendritic cells in ather
present antigens –> activ T cells
what if you have no monocytes
no atherosclerosis (b/c nothing to respond to oxid LDL)
monocytes are ___ leukocytes
innate immune system leukocytes
___ accumulation in mouse atherogenesis proportional to extent of disease
monocyte accumulation
monocyte adhesion to activated endothelium is ___ in atherogenesis
obligate step
monocytes interact with VCAM-1 via integrins (VLA-4)
arrests monocyte against endothelium
so monocytes can diapadese into subendothelial space
____ is an obligate step in atherogenesis
monocyte adhesion
what happens when you inhib monocyte adhesion
decr atherosclerosis initiation
what are key molec that when knocked out decr atherosclerosis initiation?
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
atherosclerosis is a ___ type response
Th1 response with IL-1 and IL-6
role of adaptive immunity in atherogensis
1) after dendritic cell presents antigen, activ T cells
2) incr IFN-gamma nd atherosclerosis
3) Th17 –> promote plaque instability and neoangiogenesis
blockage of what Th17 component decr atheroslcerosis
block IL-17, decr atherosclerosis
Th1 response in atherogenesis
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
Treg response in atherogenesis
Treg incr collagen formation, decr plaque vulnerability and lesion formation
overall role of inflammation in atherogenesis
*******KNOW
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
after establishing fatty streak, ___ drives additional plaque expansion to form unstable plaque
inflammatory mediators
after establishing fatty streak, inflammatory mediators ___
drive additional plaque expansion
plaque expansion is a ___ process
Th1 process with macrophage apoptosis
5 steps in inflammation driving plaque instability
1) basal inflammation
2) endothelial activation
3) oxid stress
4) neoangiogenesis
5) plaque instability
step 1
inflammatory cells in
basal inflammation
cytokines
acute phase reactants
step 2
inflammatory cells in
endothelial activ
monocyte adhesion
leukocyte diapadesis
step 3
inflammatory cells in
oxid stress
LDL oxid
foam cells
step 4
inflammatory cells in
neoangiogenesis
blood vessel form
intraplaque hemorrhage
activ MMP
step 5
inflammatory cells in
plaque instability
rupture/erosis
platelet activ
what are major drivers of plaque instability (3)
1) macrophage apoptosis + necrosis –> “necrotic core”
2) MMP degrade fibrous cap
3) intraplaque hemorrhage weaken core
role of MMPs in atherosclerosis
MMPs destablize plaque
Breakdown of type 1 collagen
what is necessary for atherosclerotic plaque to become MI
1) lesion expansion
2) macrophage apoptosis/necrosis
3) weaken fibrotic cap
4) plaque rupture
how is CRP produced?
by hepatocytes
and macrophages and smooth muscle cell
what does CRP bind to?
1) modified membranes
2) apoptotic cells
3) lipoproteins
what pathway is CRP in?
classical complement
fxn of CRP in therapy
1) CRP predict incr CV risk
2) statin lower cholest and CRP
JUPITER trial
pt either receive placebo or statin
after 4 yrs, patients with elev CRP and normal LDL had benefit with taking statin, support inflamm in CV disease
why would statins be used in people with normal cholesterol
because can also lower inflammatory biomarkers (CRP)
why does autoimmune disease have accelerated atherogenesis
1) incr monocyte/macrophage activ
2) decr endothelial vasodilator fxn (in RA)
3) proinflamm HDL –> incr LDL oxid (RA, psoriasis)
4) plaque instability (RA)
how does inflammation affect HDL fxn
1) endotoxemia/inflamm changes HDL size, decr reverse cholesterol transport
2) HDL becomes pro-atherogenic
HDL cholesterol efflux inversely assoc with (2)
1) carotid intima-media thickness (plaque thickness)
2) risk of CAD
impaired HDL efflux assoc with ____
more severe psoriasis
____ assoc with more severe psoriasis
impaired HDL efflux
what happens if you treat psoriasis? how does that affect HDL
incr macrophage efflux capacity and incr HDL FUNCTION!!!
TREATING DID NOT CHANGE HDL LVL
how does plaque morphology change in RA?
RA patient had more vulnerable plaque in LAD
confounding factors when looking at psoriasis with CV events
obesity, HTN, smoking, diabetes which are also assoc with CV disease
if you have RA at younger age, then you have ____ CV disease
more severe and earlier
treatment of ___ may lower risk of CV events
autoimmune disease
what is currently being done to control CV risk in RA and psoriasis patients?
using TNF alpha inhibitors
effect of prednisone on CV risk
prednisone incr CV risks despite being an anti-inflamm drug
HTN
incr salt retention
