Pathogenesis of Atherosclerosis
Remember: Atherosclerosis is an inflammatory, immune system-mediated process.
Words to use for blanks (some can be used more than once)
thrombus
lipid core
stroke
monocytes
foam cells
fibrous cap
thrombogenic
oxidized
collagen
heart attack
plaque
reactive oxygen species
pro-atherogenic
rupture
matrix metalloproteinases
smooth muscle cells
intima
adhesion molecules
macrophages
endothelium
oxidized LDL
nitric oxide (NO)
endothelial dysfunction
1.
2.
3.
4.
5.
6.
7.
8.
intima
High blood levels of LDL lead to accumulation of LDL in the _______________ of the artery wall. The lining
endothelium
(_____________________
) of the blood vessel is naturally permeable to LDL, but high LDL levels and decreased levels of
nitric__________
oxide
endothelium
___________
may loosen intercellular junctions in the ___________________,
causing it to be more
permeable to LDL particles.
oxidized
Retained LDL in the intima becomes _________________
, and this causes chemical changes that lead to inflammation
and ____________________
__________________.
endothelial
dysfunction
endothelial dysfunciton
nitric oxide
The ____________________
___________________ in step 2 leads to reduced levels of ___________
__________ and
oxygen species
higher levels of a _______________reactive
______________
______________ called superoxide, and this leads to the
adhesion molecules
expression of ___________________
_________________ (like VCAM-1) on the endothelium.
adhesion_________________
molecules
monocytes
__________________—a
type of white blood cell—attach to the ___________________
on the
endothelium and are taken up into the intima.
It is important to note that endothelial dysfunction can also be caused by disturbed blood flow, high blood pressure,
adhesion molecules
hyperglycemia, or smoking, but again, the outcome is inflammation and the expression of ___________________
___________________ on the endothelium.
The inflammatory response (mediated by molecules such as TNF-α, IL-1, and others)--which was initiated by
oxidized LDL
macrophages
________________
________--causes monocytes to transform into ___________________.
These cells engulf (swallow)
oxidized LDL and become _________
foam _________.
cells
macrophages
The ____________________ that engulfed oxidized LDL also produce the chemokine IL-1β, which leads to the recruitment
pro-atherogenic
of certain T-cells (T-helper cells) that secrete inflammatory _______________________
cytokines like interferon γ and
tumor necrosis factor.
lipid core
Foam cells die (go through apoptosis) and build up, contributing to a necrotic ______________
_________.
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9.
10.
11.
12.
13.
In addition to engulfing LDL, macrophages release a factor (platelet-derived growth factor) that draws ____________
smooth muscle
cells into the intima, probably to “wall-off” or form a “scab” or cap over the lesion. These cells
____________
_________
collagen
produce the protein __________________
, which helps to strengthen and stabilize the cap.
Macrophages also produce tissue factor (TF), a clot-forming substance that makes the necrotic core
thrombogenic
_______________________.
plaque
The lesion evolves into a fibrotic, collagenous (and sometimes calcified) _______________.
As mentioned above, T-cells release a cytokine called interferon- γ (INF-γ). This molecule promotes plaque growth and
matrix metalloproteinase
inflammation and also stimulates the expression of __________________
____________________ , which degrade the
_________________
in
the
______________
________
over
the
lesion,
which
weakens it.
collagen
fibrous cap
matrix________________________
metalloproteinase
collagen
Macrophages also express _______________
that degrade _______________
in the
______________
fibrous________.
cap
Below: Cross-sectional photomicrograph of a coronary
artery showing plaque rupture
Thr = thrombus (blood clot), NC = necrotic core
fibrous ______
cap
14. A large plaque can result in completely obstructed blood flow, or if the _______________
weakens enough, it can
rupture
thrombus
___________________
, leading to formation of a __________________.
Both of these processes can occlude (block) an
artery in the heart and cause a ___________
(myocardial infarction [MI]). The _________________
can also
heart___________
attack
thrombus
stroke
break off and travel to the brain and block blood flow, which leads to a ________________.
Top figure on page 1 taken from “The immunology of atherosclerosis,” Nature Reviews Nephrology, 2017. Cartoon images taken from: “Progresses and
challenges in translating the biology of atherosclerosis,” Nature, 2011. Image A taken from “Pathophysiology of atherosclerosis plaque progression,” Heart,
Lung and Circulation, 2013.
Additional references: “The pathogenesis of atherosclerosis,” Medicine, 2014; “Oxidized LDL and anti-oxidized LDL antibodies in atherosclerosis – Novel
insights and future directions in diagnosis and therapy,” Trends in Cardiovascular Medicine, 2019; Atherosclerosis: Beyond the lipid storage hypothesis. The
role of autoimmunity,” European Journal of Clinical Investigation, 2020; “Critical roles of inflammation in atherosclerosis,” Journal of Cardiology, 2018;
“Upregulated LOX-1 Receptor: Key Player of the Pathogenesis of Atherosclerosis,” Current Atherosclerosis Reports, 2019.
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