LDL

HDL

ApoA1-Milano
in
atherosclerosis
By Padminee Krishnan
3 rd year BDS
ApoA1
mutation

ApoA1Milano

ATHEROSCLEROSIS
Atherosclerosis is a specific form of

arteriosclerosis in which an artery wall

thickens as a result of invasion and
accumulation of foam cells.

It is characterized by intimal lesions called

atheromas
An atheromatous plaque consists of a raised

lesion with a soft yellow grumous core of lipid

covered by firm white fibrous cap

STAGES OF
ATHEROSCLEOSIS

Oxidation of ldl and formation

of foam cells
LDL

FREE
RADICALS
(NO, ROS,etc)

Lipid laden
monocytes
FOAM CELLS

oxidation
Monocyte

Ox-LDL
Scavenger
receptors

The
monocyte
engulfs the
lipid particles

ROLE OF hdl AND LDL

Lethally Dangerous Lipoprotein versus

Highly Desirable Lipoprotein !!

HDL- transports cholesterol from peripheries to liver

anti-atherogenic
Normal value -30 to 60 mg/dl
LDL- transports cholesterol from liver to peripheral tissues
oxidized LDL is responsible for formation of foam cells
normal value - 80 t0 175mg/dl

HDL STRUCTURE- apoa1

Lipids complexed with
proteins are lipoproteins.
The protein part of the
lipoprotein is known as the
apolipoprotein.
The apolipoprotein
present in HDL is ApoA1

Protective role of HDL

Endothelial
Deposition
Up-regulation
Recognition
HDL
Increase
transports
binds
into
cholesterol
of
HDL
damage
ofreceptors
cholesterol
of
up-regulation
ABCA1
to liverby ApoA1

Patient with
TG

low HDL,
high triglycerides
but no signs of pathology?!?!

ApoA1- Milano
ApoA1-Milano is a naturally occurring mutant
variant of ApoA1 of human HDL
The ApoA1-Milano mutation was found by
University of Milan
It was discovered that this mutant variant was
present in 3.5% of the local population of
Limone, a small village in Northern Italy

The amino acid arginine is replaced by

cysteine at position 173 in ApoA1Milano

aa

ApoA
1

aa

Point

aa
aa

173
aa

ApoA1Milano

Argi
nine

aa

Cyst
eine

173

mutation
In ApoA1
peptide

aa
aa

of
Human
HDL

The amino acid cysteine has a sulfhydryl group

The 70% of Milano proteins occur in pairs by disulfide

bridge formation
This restricts the size and growth of HDL attributing to

low HDL levels.

30% of Milano mutation proteins do not form

dimers and they remain monomeric.

The free sulfhydryl form of the Milano

mutation is a powerful anti-oxidant.

They act as free radical scavengers and

prevent oxidation of LDL

LDL

Prevents
oxidation of
LDL

mops up
unpaired
electrons

Free
radica
ls

ApoA1Milano
in
HDL

This in turn results in prevention of plaque formation

because only oxidized LDL are detected and taken up by

the monocytes to form the foam cells.
The mutated protein also targets the same receptor ABCA1

just like the normal ApoA1 proteins

This ensures that the antioxidant powers concentrate where

oxidation and cholesterol deposition occur thus preventing

atherosclerosis at its earliest stage!!

FUTURE SCOPE
Having known the new activity associated

with the Milano protein that suggests how it

protects against heart disease, this knowledge
can be used to evolve better therapies!!
Combining the conventional HDL therapy with

the Milano mutation protein will provide a

more efficient treatment!!

CONCLUSION
Study of literature says that the carriers of

this Milano protein are free from

cardiovascular disorders for more than
20years now after its discovery.
It has stood the test of time, promising

new therapies to combat the worlds

leading cause of death!!

THANK YOU