ATHEROSCLEROSIS

REPORTER:

COLLERA, CHARISSA
CONSTANTINO, VENICE
CLEMENA, ADNAN
CORONEL, ROMEO
CORDOVA, KARLA
 LEARNING OBJECTIVES
• After the report, the class will:
• Be able to define atherosclerosis and define an atheroma and site its
contents.
• Trace and explain how atherosclerosis develops.
• Be able to determine the theories that explain atherogenesis
• Be able to determine the association between cholesterol, saturated fat
and atherosclerosis
• Be able to explain the transport of cholesterol in the blood
• Be able to explain the direct and indirect association of LDL and HDL with
atherosclerosis
• Be able to identify the risk factors for atherosclerosis, explain how each
factor increases the risk of having atherosclerosis and distinguish whether
they are modifiable or non-modifiabl, as well as explain its significance
• Be able to determine and discuss the possible complications of
atherosclerosis
• Be able to explain the role of increased homocysteine levels in the
development of atherosclerosis.
 How are Cholesterol and Saturated
Fat associated with Atherosclerosis?

Reporter: CHARISSA COLLERA

ARE YOU HUNGRY?
DO YOU WANT SOME MORE?
DO YOU ALSO WANT THIS?
 CHOLESTEROL AND SATURATED FAT
• Saturated Fatty Acids does not have a double
bond; it is found mostly in animal fats like
Palmitic Acid and Stearic Acid.
• is fat that consists of triglycerides containing
only saturated fatty acid radicals.
 CHOLESTEROL AND SATURATED FAT
• Cholesterol is a lipid with a unique structure consisting
of four linked hydrocarbon rings forming the bulky
steroid structure. There is a hydrocarbon tail linked to
one end of the steroid and a hydroxyl group linked to
the other end. The hydroxyl group is able to form
hydrogen bonds with nearby carbonyl oxygen of
phospholipid and sphingolipid head groups.
• Cholesterol is known as a "sterol" because it is made
out of a alcohol and steroid. Cholesterol is present in
most animal membranes with varying amounts but is
absent in prokaryotes and intracellular membrane.
 Two forms of Cholesterol
• Free Cholesterol – not attached to any fatty
Acid; the biologically active form of
Cholesterol.
• Cholesteryl Ester – cholesterol attached to an
unsaturated fatty acid in C3 of a ring A
– It is a storage form of cholesterol
– A kind of cholesterol deposited in atherosclerotic
plaques
Structure of Cholesterol showing site of attachment of
Fatty Acid in Cholesteryl esters.
 ATHEROSCLEROSIS, CHOLESTEROL
AND SATURATED FAT
• Atherosclerosis (also known
as arteriosclerotic vascular disease or ASVD)
is a condition in which an artery wall thickens
as the result of a build-up of fatty materials
such as cholesterol.
• Local buildup of cholesterol in arteries is the
process that produces atherosclerotic
plaques, the cause of most coronary artery
disease and strokes.
Damage to the arterial wall due to factors such as
hypertension or smoking, allows cholesterol in the
blood to enter the artery wall. This starts a chain of
events that leads to a narrowing within the artery
wall due to cholesterol accumulation, known as a
‘plaque’.
 HOW IS
CHOLESTEROL
TRANSPORTED
IN THE BLOOD?
• Lipoproteins are molecular complexes of lipid
and specific proteins called
APOLIPOPROTEINS.
• They serve as vehicles for transport of lipid in
the blood.
• They keep lipid soluble as they are
transported in the blood.
• They also provide an efficient mechanism for
delivering lipids to tissues.
 PRIMARY PRODUCTS

1. TRIACYLGLYCEROL PL 2, monoacylglycerol +
2FFA

2. CHOLESTERYL ESTER
cholesterylesterase

Fcholesterol + FFA
 PRIMARY PRODUCTS

3. PHOSPHOLIPID + CHOLINE
= PHOSPHATIDYL CHOLINE
phospholipase A2
LYSOPHOSPHATIDYLCHOLINE + FFA
lysophospholipase
GLYCEROPHOSPHORYLCHOLINE
 PRIMARY PRODUCTS
1. 2, monoacylglycerol
2. Free Fatty Acids (FFA)
3. Glycerophosphorylcholine
4. Free Cholesterol
 Free Fatty Acid
Fattyacyl CoA sythetase/ thiokinase

Fatty Acyl CoA

Acyltransferase
joins 2, monoacylglycerol

= TAG
• Resynthesis of the primary products happen in the ER of the
enterocyte.
• Chylomicron formation happens in the GA of the enterocyte.
• Primary products contained in the Micelle enter the
enterocyte via Simple Diffusion through the Brush Borders.
• Chylomicrons exit the enterocyte through Exocytosis.
FROM THE LYMPHATICS
WHERE DOES THE
CHYLOMICRON GO?
Exogenous and endogenous pathways
• EXOGENOUS PATHWAY – most of the
cholesterol comes from the food we eat
(dietary cholesterol)

• ENDOGENOUS PATHWAY – most of the

cholesterol comes from the liver (hepatic
cholesterol)
 Exogenous Pathway
1. Fat & Cholesterol absorbed in
the GI tract are assembled to form Chylomicrons
2. The Chylomicrons head into the blood stream
3. In the peripheral
tissues (e.g.adipose) chylomicrons release their fats w
hen they meet tissues….expressing Lipoprotein
Lipase, which allows fats to be absorbed in the form
of fatty acids &….glycerol (it breaks down triglycerides)
4. The Chylomicrons are now smaller &
called Chylomicron Remnants
5. Empty HDL is produced as a bi-product of this process
6. They then travel to the liver & are removed by the
binding of apoE to their Remnant Receptor.
 Endogenous Pathway
1. Fat & Cholesterol arriving at the Liver or newly synthesised is
repackaged into VLDL’s
2. VLDL’s enter the bloodstream between meals & head out to
the peripheral tissues
3. VLDL’s meet tissues expressing LPL (muscle & adipose)
& release glycerol & fatty acids
4. After the VLDL has lost most of it’s fats it becomes smaller & is
known as an IDL
5. Empty HDL is produced as a bi-product – can collect LDL from
periphery
6. IDL’s are absorbed from the blood by the liver
7. They are then broken down by Hepatic
Lipase into LDL’s (triglycerides removed)
8. LDL’s have a relatively high cholesterol content with little fatty
acids or glycerol
9. LDL circulates & is absorbed by various tissues via binding
to LDL receptors
10. Any excess LDL is taken up by the liver via LDL receptors
• Exogenous Pathway
• The exogenous pathway starts with the intestinal absorption of triglycerides and cholesterol from
dietary sources. Its end result is the transfer of triglycerides to adipose and muscle tissue and of
cholesterol to the liver. After absorption, triglycerides and cholesterol are re-esterified in the
intestinal mucosal cells and then coupled with various apoproteins, phospholipids, and unesterified
cholesterol into lipoprotein particles called chylomicrons. The chylomicrons in turn are secreted
into intestinal lymph, enter the bloodstream through the thoracic: duct, and bind to the wall of
capillaries in adipose and skeletal muscle tissue. At these binding sites the chylomicrons interact
with the enzyme lipoprotein lipase, which causes hydrolysis of the triglyceride core and liberation
of free fatty acids. These fatty acids then pass through the capillary endothelial cells and reach the
adipocytes and skeletal muscle cells for storage or oxidation, respectively.
• After removal of the triglyceride core, remnant chylomicron particles are formed. These are high in
cholesterol esters and characterized by the presence of apoproteins B, CIII, and E. These remnants
are cleared from the circulation by binding of their E apoprotein to a receptor present only on the
surface of hepatic cells. Subsequently, the bound remnants are taken to the inside of hepatic cells
by endocytosis and then catabolized by lysosomes. This process liberates cholesterol, which is then
either converted into bile acids, excreted in bile, or incorporated into lipoproteins originated in the
liver (VLDL).
• Under normal physiologic conditions, chylomicrons are present in plasma for 1 to 5 hours after a
meal and may give it a milky appearance. They are usually cleared from the circulation after a 12-
hour fast.
• Endogenous Pathway
• The liver constantly synthesizes triglycerides by utilizing as substrates free fatty acids and carbohydrates; these
endogenous triglycerides are secreted into the circulation in the core of very-low-density lipoprotein particles
(VLDL). The synthesis and secretion of VLDL at cellular level occur in a process similar to that of chylomicrons,
except that a different B apoprotein (B-100 instead of B-48) together with apoproteins C and E intervene in their
secretion. Subsequent interaction of the VLDL particles with lipoprotein lipase in tissue capillaries leads to
hydrolysis of the core triglycerides and production of smaller remnant VLDL particles rich in cholesterol esters
(intermediate-density lipoproteins, IDL) and liberation of free fatty acids. Around half of these remnant particles
are removed from the circulation in 2 to 6 hours as they bind tightly to hepatic cells. The rest undergo
modifications with detachment of the remaining triglycerides and its substitution by cholesterol esters and
removal of all the apoproteins except apoprotein B. This process results in transformation of the remnant VLDL
particles into low-density lipoprotein particles (LDL) rich in cholesterol. In fact, these last particles contain around
three-fourths of the total cholesterol in human plasma, although they constitute only some 7% of the total
cholesterol pool. Their predominant function is to supply cholesterol to cells with LDL receptors, like those in the
adrenal glands, skeletal muscle, lymphocytes, gonads, and kidneys. The quantity of cholesterol freed from LDL is
said to control cholesterol metabolism in the cell through the following mechanisms: (1) increased LDL cholesterol
in the cell decreases synthesis of the enzyme 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, which
modulates the intracellular synthesis of cholesterol; (2) increased LDL cholesterol may enhance the storage of
cholesterol within the cell by activation of another enzyme; and (3) increased cholesterol within the cell diminishes
the synthesis of LDL receptors through a negative feedback process.
• Besides the above described route for LDL degradation in extrahepatic sites, a so-called scavenger cell pathway has
been described. This consists of cells in the reticuloendothelial system which, by phagocytosis, dispose of the
excess concentrations of this lipoprotein in plasma.
• Reverse Cholesterol Transport Pathway
• 1. When there is too much cholesterol
in peripheral tissue the ABCA1 receptor
becomes activated2. HDL then interacts with
this receptor & collects cholesterol returning
it to the liver3. This can help
prevent ATHEROSCELROSIS.
ASSOCIATION OF LDL AND
HDL IN ATHEROSCLEROSIS

REPORTER: CLEMENA, ADNAN

• Atherosclerosis develops from low-density lipoprotein molecules (LDL)
becoming oxidized (ldl-ox) by free radicals, particularly reactive oxygen
species (ROS).

M ECHANISM:
1. When oxidized LDL comes in contact with an artery wall, a series of
reactions occur to repair the damage to the artery wall caused by oxidized
LDL. The LDL molecule is globular shaped with a hollow core to carry
cholesterol throughout the body.

2. Cholesterol can move in the bloodstream only by being transported by

lipoproteins

3. The body's immune system responds to the damage to the artery wall
caused by oxidized LDL by sending specialized white blood cells
(macrophages and T-lymphocytes)
4. To absorb the oxidized-LDL forming specialized foam cells. These white
blood cells are not able to process the oxidized-LDL.

5. It ultimately grow then rupture, depositing a greater amount of oxidized

cholesterol into the artery wall. This triggers more white blood cells,
continuing the cycle.

6. Eventually, the artery becomes inflamed. The cholesterol plaque causes

the muscle cells to enlarge and form a hard cover over the affected area.

7. This hard cover is what causes a narrowing of the artery, reduces the
blood flow and increases blood pressure.
8. LDL that does not get taken up into cells tends to oxidize. The
polyunsaturated fatty acids (PUFA) in its membrane get damaged by free
radicals, and then they proceed to damage the protein in the surface, and
finally the fatty acids and cholesterol in the core.

9. Once LDL oxidizes, it can invade the arterial wall in areas that experience
disturbed blood flow, like the points were arteries curve or branch. These
areas, especially in people who do not exercise enough, are permeable to
large molecules. Oxidized lipids cause them to attract white blood cells
and initiate an inflammatory cascade that produces arterial plaque.
• The liver also secretes HDL particles that contain ApoA-I. When they first
leave the liver, they consist of the apoprotein and some phospholipids, but
no fatty core.

• HDL particles can extract free cholesterol from cell membranes and attach
it to fatty acids, producing cholesterol esters.

• HDL generally pass this off to LDL and other apoB-containing proteins in
exchange for fats, also called triglycerides, and fat-soluble vitamins such as
vitamin E.

• The result is that, over time, HDL tends to be rich in fats and vitamin E,
while the other lipoproteins, especially LDL, are rich in cholesterol.

• The cholesterol HDL extracts from plaques and other tissues tends to be
passed off to LDL rather than to the liver directly.
Risk Factors of Atherosclerosis

Reporter:
Romeo Coronel, Jr.
 Risk Factors of Atherosclerosis
Non-Modifiable
– Age
– Gender
– Family history of heart desease
– Genetic abnormalities

Modifiable
– Cigarette smoking
– Alcohol Drinking
– Hypertension (BP 140/90 mmHg or on antihypertensive medication)
– Low HDL cholesterola [<1.0 mmol/L (<40 mg/dL)]
– Diabetes mellitus
– Obesity (BMI 30 kg/m2) and Metabolic syndrome
– Physical Inactivity
Non-Modifiable
Risk Factors
 Non-Modifiable Risk Factors
Age
– Age is a dominant influence.  
– The arteries become less elastic and more
susceptible to arteriosclerosis.
– Genetic or lifestyle factors cause plaque to build in
your arteries as you age.
– In men, the risk increases after age 45. In women,
the risk increases after age 55.
 Non-Modifiable Risk Factors
Gender
– Male > Female
– After menopause, however, the risk accelerates in
women. Premenopausal women derives from
their relatively higher HDL levels compared with
those of men. After menopause, HDL values fall in
concert with increased coronary risk.
 Non-Modifiable Risk Factors
Family History of Heart Disease.
– Individuals with a family history of heart diseases
have an increased risk of heart attack.
– The risk is higher if there is a family history of
developing atherosclerosis, including a heart
attack or sudden death before age 55 in the father
or other first-degree male relative, or before age
65 in the mother or other female first-degree
female relative.
 Non-Modifiable Risk Factors
Genetic Abnormalities
• The genetic propensity relates to familial
clustering of other risk factors, such as
hypertension or diabetes
• involves well-defined hereditary genetic
derangements in lipoprotein metabolism that
result in excessively high blood lipid levels, such
as familial hypercholesterolemia.
• mutations in the LDLR gene that encodes the LDL receptor 
protein.
Modifiable Risk Factors
 Modifiable Risk Factors
Smoking
– Cause elevated blood pressure, worsen lipids, and
make platelets very sticky, raising the risk of clots.
– Heavy cigarette smokers are at greatest risk,
people who smoke as few as three cigarettes a
day are at higher.
– Regular exposure to passive smoke also increases
the risk of heart disease in nonsmokers.
 Modifiable Risk Factors
Alcohol
– Moderate alcohol consumption (one or two drinks
a day; 5 ounces wine, 12 ounces beer, or 1.5
ounces hard liquor is one drink) can help boost
HDL “good” cholesterol levels. Alcohol may also
prevent blood clots and inflammation.
– By contrast, heavy drinking harms the heart.
 Modifiable Risk Factors
Hypertension
– Angiotensinogen, renin, and angiotensin II are
synthesized locally in many tissues, including the
brain, pituitary, aorta, arteries, heart, ect.
– tissue angiotensin II is a mitogen that stimulates
growth and contributes to modeling and repair.
– Excess tissue angiotensin II may contribute to
atherosclerosis.
– Blood vessels may be a target organ for
atherosclerotic disease secondary to long-standing
elevated blood pressure.
 Modifiable Risk Factors
Hyperlipidemia
– Most of the evidence specifically implicates
hypercholesterolemia.
– stimulate lesion development, even if other risk
factors are absent.
– increased risk high levels of low-density
lipoprotein (LDL) cholesterol which has an
essential physiologic role as a vehicle for the
delivery of cholesterol to peripheral tissues(PVD).
 Modifiable Risk Factors
Obesity
– BMI 30 kg/m2
– Obesity increases the risk for other conditions
(high blood pressure, diabetes)
 Modifiable Risk Factors
Diabetes Mellitus, Insulin Resistance
– diabetic patients often have LDL cholesterol levels
near average, the LDL particles tend to be smaller
and denser, and, therefore, more atherogenic.
– Diabetes mellitus induces hypercholesterolemia
and a markedly increased predisposition to
atherosclerosis.
 Modifiable Risk Factors
Physical Inactivity
– Exercise has a number of effects that benefit the
heart and circulation, including improving
cholesterol and lipid levels and maintaining weight
control. People who are sedentary are almost
twice as likely to suffer heart attacks as are people
who exercise regularly.
Complications
of
Atherosclerosis
 Complications of Atherosclerosis
Angina Pectoris
– When blood flow to your heart muscle is reduced
or blocked, it can lead to angina (chest pain) and a
heart attack.
 Complications of Atherosclerosis
Aneurysm
– in long compensation of artery enlargement,
eventually lead to plaque raptures and clots inside
the artery lumen over the ruptures. The clots heal
and usually shrink but leave
behind stenosis (narrowing) of the artery.
– Due to long excessive compensation of artery
enlargement, it results to aneurysm.
 Complications of Atherosclerosis
• Thrombus Formation
– Most commonly, soft plaque suddenly ruptures
(vulnerable plaques), causing the formation of
a thrombus.
– most common recognized scenarios is
called coronary thrombosis of a coronary artery,
causing myocardial infarction.
– worse is the same process in an artery to the
brain, commonly called stroke (CVA).
 Complications of Atherosclerosis
• Claudication
– Occlusive aortic disease caused by atherosclerosis
is usually confined to the distal abdominal aorta
below the renal arteries.
– involves the buttocks, thighs, and calves and may
be associated with impotence in males
– complete occlusion of the abdominal aorta may
occur without the development of ischemic
symptoms
 Atherosclerosis-Related Diseases
• Atherosclerosis can affect any artery in the
body, including arteries in the heart, brain,
arms, legs, and pelvis. As a result, different
diseases may develop based on which arteries
are affected.
– Coronary Heart Disease
– Carotid Artery Disease
– Peripheral Arterial Disease
 Role of increased homocysteine in
the development of atherosclerosis

Reporter: Cordova, Karla

 Hyperhomocysteinemia (HHcy)

• Deficiency of 5,10-
methylenetetrahydrofolate reductase
(MTHFR)
– can lead to premature atherosclerosis and
thrombotic disease. (Frosst et al, 1985)
 Hyperhomocysteinemia (HHcy)

• An important, independent risk factor for

atherosclerosis and thrombotic disease in 5 to
7% of the general population.
(Koning, 2003)
 Potential cellular mechanisms by which
homocysteine promotes atherosclerosis:

• Inflammatory response
• Oxidative stress
• Endoplasmic reticulum stress
 Inflammatory response
• Expression of Monocyte chemoattractant protein 1 (MCP-
1) and IL-8 through activation of NF-κB.
• In vivo activation of NF-κB and inflammatory marker
expression in atherosclerotic lesions in
hyperhomocysteinemic apolipoprotein E- deficient mice
supports the concept that homocysteine contributes to
the development of atherosclerosis by causing vascular
inflammation. (Hofmann et al, 2001)
 Oxidative stress
• Generation of reactive oxygen species (ROS)
• Hyperhomocysteinemia enhances intracellular
production of superoxide anion (02-).
– Decrease endothelial NO
– React with NO to yield peroxynitrite

• homocysteine sensitizes cells to the cytotoxic

effects of agents or conditions known to
generate ROS.
 Endoplasmic reticulum stress
• Disruption of disulphide bond formation and
causing misfolding of proteins traversing the ER.
• elevated levels of intracellular homocysteine
increase the expression of several ER stress
response genes
• Homocysteine induces the expression of GADD153, a
basic region leucine zipper transcription factor involved
in ER stress-induced cell death
Metabolism of Methionine
• Reference:
Koning, L, Werstuck, G, et al. Hyperhomocysteinemia and its
role in the development of atherosclerosis. Clinical
Biochemistry 2003;431:441-36