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ATHEROSCLEROSIS
Jon Yap
John A. Burns School of Medicine
Department of Cell and Molecular Biology
Atherosclerosis by the Numbers
• Cardiovascular diseases are the leading global cause of
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death ~18 million deaths per year
Heart disease is the number one cause of death in the
United States >375,000 people/year
Heart disease strikes someone in the US ~every 43
seconds
Heart disease is the leading cause of death among
women, more than all forms of cancer combined
~735,000 heart attacks/year in the US killing ~120,000
people
Risk Factors
• Preventable
• Type II diabetes/blood sugar
• High fat, high cholesterol diet
• Tobacco smoking
• Sedentary lifestyle
• High blood-preassure
• Obesity
• Non-preventable
• Advanced age
• Heredity
• Male
Atherosclerosis
1. Circulating LDL infiltrate endothelial cell layer
2. LDL is modified (i.e. oxidation; ox-LDL)
3. Accumulation of ox-LDL elicits an immune response
4.
5.
6.
7.
(recruitment of macrophages)
Activated macrophages release pro-inflammatory
signaling molecules (cytokines)
Macrophages uptake ox-LDL via phagocytosis but are
unable to digest the modified LDL
Lipid laden macrophages are characterized as foam
cells
Foam cells accumulate forming the atherosclerotic
plaque
Lipoproteins
• Lipoproteins are a biochemical complex of proteins and
bound lipids
• Allow fats to move throughout the body
• Low-density Lipoproteins
• Capable of entering arterial intima (sub-endothelial space)
• High-density Lipoproteins
• Facilitate removal of cholesterol from the vasculature and to the
liver (digestion and absorption of dietary fats)
LDL vs. HDL…
• High serum levels of
free cholesterol result
in elevated LDL in the
vasculature
• LDL interacts with the
ECM where it is
retained
• LDL is modified (oxLDL)
and taken up by
macrophages
LDL vs. HDL…
Reverse Cholesterol Transport: Free cholesterol is removed from the
circulation by macrophages and is transferred back to the liver for digestion
and biosynthesis of steroid hormones (i.e. androgens, estrogens, and
glucocorticoids).
Macrophages and Atherosclerosis
• Monocytes transmigrate
through the endothelium in
response to accumulating
modified LDL and
differentiate into
macrophages
• Mature macrophages are
activated by modified LDL and
secrete inflammatory
mediators
• Phagocytosis of modified LDL
results in foam cell formation
Foam Cells
Foam cells are unable to metabolize and efflux
the cholesterol that they have accumulated. As
a result, they die which exacerbates the
inflammatory conditions in and around the
atherosclerotic lesion.
Atherosclerotic Plaque
Necrotic core
Thrombosis (Plaque Rupture)
Vascular Occlusion
Hemodynamic pathologies
associated with
atherosclerotic plaque: Aside
from plaque rupture, stable
plaques can completely
occlude vessels. The resulting
lack of blood flow can have
profound implications
• Coronary artery disease
leading to myocardio
infarction
• Ischemic stroke due to lack
of adequate bloodflow to
the brain
Atherosclerotic Plaque
A. Plaque rupture without thrombus
B. Acute coronary thrombosis with disruption of fiberous cap  fatal
myocardial infarction
C. Massive plaque rupture with resulting thrombus  fatal myocardial
infarction
Summary
• Atherosclerosis is an inflammatory disease, the
progression of which can be attributed to a prolonged
immune response that ultimately compromises the
structural integrity of the entire vascular system.
• Treaments
• Statins (cholesterol lowering drugs)
• Diet (decrease blood presure, cholesterol/fat intake)
• Exercise (metabolic attenuation of caloric intake, loose weight)
• Surgery (angioplasty, stent, bypass graft)
Questions?