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Flashcards in Pathogenesis of Atherosclerosis Deck (27):
1

development of atherosclerosis

chronic inflammatory response in the subintima of elastic and muscular arteries

accumulation of macrophage-derived "foam cells"

migration and proliferation of vascular smooth muscle cells

cellular buildup outgrows its supply of oxygen and nutrients at its center

resulting necrosis stimulates more inflammation and the lesion grows

mature lesions have a fibrow cap of caollagen and smooth muscle cells overlying a necrotic core of cellular debris

2

results of a ruptured atherosclerotic lesion

myocardial infarct

cerebral infarct

gangrene of extremities

abdominal aortic aneurysm

3

fatty streak

a subintimal accumulation of lipid-laden macrophages called foam cells

may progress into mature atherosclerotic lesions, but they often regress

4

mature atherosclerotic lesion

consists of a fibrous cap of proliferating vascular smooth muscle cells that produce collagen overlying a necrotic core of cellular debris

5

contents of the necrotic core

cell debris from macrophage- and later on in the progression of the lesion, smooth muscle cell-derived foam cells

free cholesterol can crystallize in this region as well

calcium is also present

6

contents of the fibrous cap

smooth muscle cells

macrophages

foam cells

lymphocytes

collagen

elastin

proteoglycans

7

How do atherosclarotic lesions grow and heal?

from the edges, so the oldest part of the lesion with the most advanced changes will be toward the center

more recent damage will be at the interface with the normal tissue

8

Why does atherosclerosis begin at branch points and ostea?

due to changes in laminar flow, which allows leukocytes to slow down

instead of being swept along with the current, leukocytes are being activated

9

complications of atherosclerosis

calcification

fissuring/ulceration/plaque hemorrhage

atheroembolism

aneurysm formation

10

atherosclerosis and chronic inflammation process

• Monocytes migrate into subintima in response to inflammatory stimuli

• T Lymphocytes migrate into subintima

• Release of cytokines and vascular smooth muscle cell (SMC) mitogens

• Recruitment of mesenchymal cells (SMC)

• Proliferation of mesenchymal cells (SMC)

• Production of extracellular matrix (collagen) by SMC

• Macrophages digest debris

• High levels of matrix metalloproteinases (at edges)

• Inflammatory cells secrete angiogenic factors

• Angiogenesis

• Attempts to restore healthy tissue 

11

Why does cholesterol build up in atherosclerotic lesions when the LDL receptor and its regulation are not designed to accumulate it?

macrophage scavenger receptors recognize modified LDL (oxidized, aggregated, acylated) and are NOT down-regulated

scavenger receptors keep taking in cholesterol, even after it has accumulated to toxic levels

12

Describe the oxidized LDL control pathway.

LXRs suppress inflammation and and promote lipid efflux, preventing inflammation

13

foam cells

macrophages that have tried to clear the altered lipoproteins but took in too much and their catabolic activity got overwhelmed

if conditions continue unabated, they will die by apoptosis

the inability of newly-recruited macrophages to clear the apoptotic cells cause foam cells to die by secondary necorsis, forming the necrotic core

14

factors that promote atherosclerosis

LDL modification

infection

unknwon "endothelial cell dysfunction"

trauma

immunity (prevents atherosclerosis)

15

modifying enzymes from endothelial cells, macrophages, and smooth muscle cells involved in atherosclerosis

oxidases

proteases

sphingomyelinase

phospholipase A2

cholesterol esterase

16

toxic/proinflammatory products of LDL

oxidized lipids

aggregated LDL

ceramide

lysoPC

free cholesterol

17

experimental evidence for the role of innate and adaptive immunity in the pathogenesis of atherosclerosis

patients taking statins (which have anti-inflammatory effects as well as lipid-lowering effects) were
protected from atherosclerosis out of proportion to the degree of cholesterol and LDL reduction

SLE and genetic polymorphisms in TLR4 are associated with higher incidence of atherosclerosis

in mice, inflammation and immunity have been shown to be critical for the development of atherosclerosis, and interference with the inflammatory or immune process significantly blocks atherosclerosis despite continued high circulating cholesterol and LDL levels

18

C-reactive protein (CRP)

an acute phase protein released by the liver in response to acute systemic inflammation

elevated in people with coronary artery disease, 4x increased in people in MI

found in atherosclerotic lesions

binds LDL and allows uptake of unmodified LDL

activates endothelial cells and stimulates secretion of IL6 and MCP-1

19

additional risk factors for atherosclerosis

chlamidia pneumoniae and cytomegalovirus infections

circulation of endotoxin (LPS)

D299G polymorphism in TLR-4

systemic lupus erythematosus

20

op mutation

no monocytes/macrophages

smaller lesion size

21

MCP-1 mutation

no monocyte chemoattractant

smaller lesion size

22

CCR2 mutation

no MCP-1 receptor

smaller lesion size

23

VCAM-1 mutation

very low VCAM-1 levels

smaller lesion size

24

Tbet mutation

no helper T cells

smaller lesion size

25

Rag-1 mutation

no T or B cells

similar or smaller lesion size

26

Class I mutation

no cytotoxic T cells

increased lesion size

27

IFN=gamma mutation

no T helper cells

smaller lesion size