Atherosclerosis

Cardiovascular Disease (CVD)

Heart Attack, Stroke, Peripheral Vascular Disease
Number One Killer of Men
and Women
Where Were Going
Inflammatory Response
Normal Blood Vessel
Lipoproteins + Cholesterol
LDL Oxidation
Dysfunctional Endothelium: Early sign
Inflammatory response + Plaque Growth
Thrombosis
Risk FactorsWhat You Can Do
The Inflammatory Response
How are You Protected if the Skin or Mucous
Membranes are Cut?

ouch.
Protective Cells and Chemicals Lie Deep to
the Epithelium to Kill Pathogens
Cells That Defend
i
Granulocytes: phagocytes, secrete histamine, oxidants
Agranulocytes: Macrophages: phagocytes
Lymphocytes: kill infected cells
and control immune response
Activate each other via chemicals
such as chemokines and other cytokines

Defensive Cells Get to Site of Injury
Margination
Diapedesis
(+) Chemotaxis
Ameboid movement
The Inflammatory Response
A response to:
Intense heat, a physical blow, irritating
chemicals, viruses, bacteria, fungi.

Prevents spread, removes cell debris, prepares
for tissue repair

Signs of The Inflammatory Response
1. Redness
2. Swelling
3. Pain
4. Heat
Inflammatory response can occur within
various body organs as well and is
characterized by the presence of
inflammatory cells and chemicals, as
well as those signs above.

The Inflammatory Response
Monocytes Become Macrophages
Macrophages Act in Tissues
The Blood Vessel Wall
3 Concentric Layers Surrounding the
Lumen
Recall Layers of Blood Vessel Wall
Tunica interna =
Endothelium, matrix
Tunica media =
Smooth muscle
Tunica externa =
Collagen
Subendothelial space:
connective tissue,
some smooth muscle
cells
Cholesterol and Other Lipids
An Important Player:
Cholesterol
What is Meant By Cholesterol?
Good Cholesterol
Vs
Bad Cholesterol
Cholesterol
Steroid
Your body needs it, just not lots of it
For: plasma membrane, vitamin D, bile salts,
sex and adrenal cortical hormones
Travels through body complexed to protein
Can pass freely from lumen to subendothelial
space
If too much, will accumulate there




Fatty acids:
Saturated: single bonds between all Cs
palmitic (16C), stearic (18C),
Monounsaturated: 1 double bond between Cs
oleic (18C), palmitoleic (16C)
Polyunsaturated: >1 double bond between Cs
linoleic(18C), arachadonic(20C)
docosahexaenoic (22C)
Lipoproteins: Cholesterol
Phospholipids
Cholesterol
Triglycerides
Protein
Density: low vs high
VLDL: triglycerides
to adipose tissue
LDL: Cholesterol to
tissues
HDL: Cholesterol
scavenger
Bad: VLDL, LDL
Good: HDL
LDL and HDL Cholesterol
3 Layers:
Inner: Cholesterol esters, triglycerides
Middle: Phospholipids and cholesterol
Outer: Apolipoprotein A or B(transport membrane
interaction)

Antioxidants
esp. Vitamin E
(tocopherol)
found in HDL
and LDL protect
from oxidation


Lipid Make-Up Of LDL
Lots of cholesterol
FAs mostly bound
LDL Core:
1600 cholesterol esters
170 triglycerides
Surrounded by:
600 free cholesterol
700 phospholipids
Surface:
Apolipoprotein B
(4500 aas)

Oxidation of LDL Cholesterol
Oxidization of LDL
Lipid Peroxidation: Chain Reaction
PUFA bound to cholesterol, phospholipids and
triglycerides
Initiation:
Free radicals or enzymes (Myeloperoxidase,
lipoxygenase, mitochondrial e- transport
system) extract hydrogen from PUFA
Propagation:
Rearrange double bonds, add O2, etc of PUFA.
(There is oxidation of apolipoprotein and
cholesterol as well by other means)
Polyunsaturated FA Oxidation
Initiation
1. Remove hydrogen



2. Re-arrange double
bond: Bring closer
together, yield trans
configuration

Polyunsaturated FA Oxidation
Propagation

3. Add oxygen


4. Peroxyl radical
is now able to
remove hydrogen
from neighboring
FA, cholesterol,etc.

The Role of Nitric Oxide (NO)
A Vasodilator from Endothelial Cells
An Index of Blood Vessel Health
Assists in Delivery of O
2
to Tissues

Endothelium:
Nitric oxide synthase (NOS)
L-argenine Nitric Oxide (NO)
Smooth Muscle Cell
soluble guanylate cyclase + NO
GTP cGMP
cGMP Reduces available Ca++
VASODILATION
Normal Blood Flow in Lumen Leads to Basal NO secretion
Hi Shear Stress, Ach, Bradykinins s:
NO:
Responsible for endothelial-dependent
vasodilation to help control blood flow and shear
stress
Attenuates platelet adhesion
Reduces smooth muscle growth
Reduces endothelin production
Overall, reduces likelihood of plaque formation and
vasoconstriction
Normal Endothelium
Secretes NO
Is coated with inhibitors of coagulation: tPA
and inhibitors of thrombin
Secretes inhibitors of platelet aggregation:
prostacyclin and NO
Does not display factors which promote
margination, so leucocytes do not adhere to
endothelial surface


Now Lets Look at The
Development of the Disease
1. Reactive Lesion
Not visible
NO release
3. Hardened Lesion
Collagen-muscle
fibrotic core, thick
cap
30% CV events
2. Soft Lesion
Fragile cap over
lipid-dense core
Grows away
from lumen
70% CV events
Three Types of Vessel Impairment
Big Picture
1. Hi [LDL] in blood Hi [LDL] in
subendothelial space
2. LDL becomes oxidized irritant
3. Inflammatory chemicals from muscle and
endolthelium increase, NO secretion falls
4. Chemicals stimulate increase in macrophages
and LDL-filled foam cells in subendothelial
space more
Big Picture (cont.)
5. Foam cells accumulate, display TF
proteins fatty streak
6. Smooth muscle-collagen cap forms
over lipid core of foam cells
7. Cap thins and bursts exposing lipid
core to procoagulant chemicals in
blood clot, thrombus

Lets Follow How LDL
Contributes to Atherosclerosis
Reduces availability of nitric oxide
Promotes secretion of chemicals which
activate the inflammatory response and
blood coagulation


LDL and Nitric Oxide
Oxidized LDL Decreases production
increases inactivation of NOHow?
1. s NO production via
A. Free radical production which
interferes with NOS activity
B. s transcription (mRNA) for NOS
2. Oxidation of LDL produces superoxide
ion which directly inactivates NO.


Reduced Nitric Oxide-Dependent
Vasodilation
Irritants Dysfunctional endothelium
Early sign of atherosclerosis

Reactive Lesions not seen on angiogram

Progression of the Disease

Oxidized LDL Stimulates Secretion of
Chemicals From
Endothelial and Smooth Muscle Cells

VCAM-1= Vessel cell adhesion molecules
MCP-1 = Monocyte chemoattractant protein 1
MCSF = Macrophage colony stimulating factor

These Chemicals Increase
1. Monocyte adhesion to endothelium and
their movement into subendothelial space
VCAM and MCP-1
2. Conversion of monocytemacrophage
and macrophage cell division MCSF
3. Appearance of scavenger receptors (SRA)
on macrophages and muscle cells MCSF
4. Inhibition of macrophage motility MCSF
5. Monocyte migration to area of OxLDL
MCP-1


LDL Stimulates Inflammatory
Response in Intima
LDL enters intima
LDL lipids and protein are oxidized
1. Basal levels of NO drop
2. Chemical secreted from muscle and endothelial cells
Proteins are oxidized and sugars are added
These are Endothelial irritants:
Adhesion molecules appear on endothelial cells
(MCP-1 from endothelial cells)
Monocytes and t-lymphocytes marginate(VCAM-1)
Chemoattractants (MCP-1 and OxLDL) draw these cells
into intima

In Subendothelial Space
Endothelial cells, smooth muscle cells
secrete factors which:
Monocytes Macrophages
Macrophages display scavenger receptors
which help them engulf oxidized LDL
Macrophages and T-lymphocytes secrete
MCSF which stimulates mitosis of same
Macrophages Secrete and Engulf

Macrophages Foam Cells
Macrophages laden with LDL appear
foamy and are called Foam Cells
Chemical secreted which inhibits
macrophage movement so they remain in
intima
Form a fatty streak:
Earliest form of observable plaque

Formation of Fibrous Cap
Macrophages, endothelial cells, smooth
muscle cells secrete chemicals which
Stimulate smooth muscle from media to
migrate to luminal surface covering foam
cells
Smooth muscle cells proliferate and secrete
collagen creating a cap. Protrudes into
lumen, but forms a stable covering

Macrophages,
endothelial
cells, smooth
muscle cells
Secrete factors
Stimulate
muscle to
migrate to
luminal surface:
form cap
Proliferation of
smooth muscle,
collagen
Thinning of The Fibrous Cap

1. Foam cells secretes interferon and
metalloproteinases which
A. s Enzyme breakdown of collagen
B. s collagen synthesis by musclethus
Cap thins, weakens, and can easily rupture
2. s Tissue Factor displayed by foam cells
Rupture of Thin Fibrous Cap
A ruptured cap can expose Tissue Factor to
other procoagulants in blood large clot

This is aggravated by low Nitric Oxide
which promotes platelet aggregation and
contributes to clot

Foam cells
secrete:
metalloproteinases
that weaken cap
Cap thins, and can
rupture
Tissue factor (TF)
displayed on foam
cells(via
interferon)
Ruptured cap can
expose TF to
procoagulants in
blood clot
Cap is Repaired, but Thickens
Cap reforms over clotted blood
In early stages, this lesion grows away from
lumen toward tunica media
Repeated thinning of cap, thrombus
formation, re-healing results in stable
hardened lesion
It is when the thin cap ruptures and is not
repaired quickly that the clot and lipid-rich
core fill and occlude the vessel heart
attack, stroke, etc
HDL Helps Protect You
1. Promotes cholesterol efflux from foam cells
2. Inhibits oxidation of LDL
3. Inhibits release of cell adhesion molecules
from endothelial cells
4. Removes excess cholesterol from blood and
takes it to liver for destruction
Major Risk Factors for Cardiovascular
Disease (CVD)
Family History of CVD
Age men > 45, women >55
Obesity
Sedentary Lifestyle
Diabetes
Smoking
High LDL Cholesterol
Hypertension > 140 / 90
(Homocysteine)



Lower Your LDL, Raise HDL
Targets:
LDL < 100 mg / dl blood
HDL > 60 mg / dl blood
If Total cholesterol < 150, LDL is not a risk
factor
Best overall predictor of degree of risk from
cardiovascular disease is this ratio
Total cholesterol / HDL < 4.0
The lower, the better. Higher than 4.0 need to
adjust diet, exercise, and maybe medicate
What Can Help?
Red wine/Beer (polyphenols, antioxidants)
Exercise (raises HDL)
Diet (15% cholesterol from consumption, 85%
made in body from Acetyl CoA)
Eliminate trans-fatty acids, saturated fats, high
glycemic foods
Increase: salmon, tuna, whole grain carbos,
vegetables, fruits, monounsaturated oils (olive,
canola)
HRT?? Once thought yes, now no--controversial
Statins
Statins: Block the Formation of Cholesterol
in Liver from Acetyl CoA
HMG CoA Reductase inhibitors:
Acetyl CoA from fatty acids
HMG CoA Reductase
3-hydroxy,3-methylgluterylCoA Mevalonate
Cholesterol
Atorvostatin, fluvastatin, pravastatin, lovastatin, simvastatin
For a given dosage, LDL is reduce most effectively:
A>S>L>P>F
Oxidized LDL is Not The Only
Endothelial Irritant To Stimulate
Reduced NO Secretion and
Enhance Inflammation
Endothelial Irritants
Oxidized LDL (reduce fats)
Homocysteine (increase folic acid)
Smokingoxidant-production (stop)
Human papilloma virus , Chylamidia pneumonia
Free radicals (antioxidants)
Triglycerides (antioxidants, reduced consumption)
How To Increase HDL-C Levels 1

How To Increase HDL-C Levels 2