Summary
Samenvatting Atherosclerosis
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Summary of the BPS Lecture Series Atherosclerosis including all notes and important slides
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Summary AtherosclerosisCollege 1 – Welcome and Introduction
Atherosclerosis is a chronic inflammatory disease
resulting from endothelial damage, cholesterol, and
immune cell accumulation in the arterial wall. The
development of an athferosclerotic plaque leads to
narrowing of the blood vessel.
Complete occlusion of a blood vessel can lead to an acute
cardiovascular event such as myocardial infarction or a
stroke.
Treatment includes statins, betablockers, surgery and
lifestyle changes. Although cardiovascular diseases still
remain the number 1 death cause worldwide.
Research of Division of
Biotherapeutics:
➔ Focus on underlying
mechanism of atherosclerosis:
lipids and immune cells
➔ Identify novel therapeutic
targets
College 2 – Mouse models for
Atherosclerosis
Learning goals:
Students are able to
➔ Describe the most commonly used mouse models for studying
atherosclerosis pathology and understand how metabolic
dysregulations in lipid fluxes underly atherosclerosis pathology in
these models.
➔ Describe the similarities and differences between atherosclerosis
pathology in mice and humans.
➔ Design experimental setups to study a specific aspect of
atherosclerosis pathology or treatment, taking into account the best
mouse model to be used.
➔ Describe statins and PCSK9 inhibitors as therapeutic strategy to
treat atherosclerosis and explain the mechanism of action of these therapies.
Mice are naturally resistant to atherosclerosis. Majority of cholesterol is transported by the
atheroprotective HDL, and largely lack the typical pro-atherogenic lipoprotein LDL. This in contrary to
humans, where there is a significant amount of LDL present.
,Different techniques of separating lipoproteins:
1. Fast-Performance Liquid Chromatography (FPLC) separates lipoproteins based on size. Large
molecules come through first, smaller take longer. From large to small: Chylomicrons → VLDL
→ LDL → HDL
2. Density-gradient ultracentrifugation separates lipoproteins based on density. Lowest density
above, highest density below. From low to high density: Chylomicrons → VLDL → LDL → HDL
→ LPDS
Lipoprotein metabolism
The liver is the metabolic hub of lipoprotein metabolism, which can be separated into endogenous
(internal origin) metabolism and exogenous (external origin) metabolism → See figures.
Endogenous lipoprotein metabolism.
The liver produces Very Low Density Lipoproteins (VLDL) that consist of a high amount of
triglycerides. VLDL is metabolized to the Intermediate Density Lipoprotein (IDL) by lipoprotein lipase
(LPL), which in turn is metabolized to the Low Density Lipoprotein (LDL) by LPL and hepatic lipase
(HL). LDL consists of a high amount of cholesterol, in contrary to the triglyceride consisting VLDL.
The Apolipoproteins E and B (ApoE and ApoB) are present on different lipoproteins and are markers
for the Low Density Lipoprotein Receptor (LDLr) and the Low Density Lipoprotein Receptor-Related
protein (LRP). These receptors are responsible for taking up the respective lipoproteins, thus
lowering their concentrations:
➔ LRP recognizes ApoE
➔ LDLr recognizes ApoE/B.
Endogenous lipoprotein metabolism summary: VLDL (ApoE and ApoB) → IDL (ApoE and ApoB) → LDL
(ApoB)
Exogenous lipoprotein metabolism
Chylomicrons are made in the gastro-intestinal track and are derived from the lipids in our diet.
Chylomicrons are processed to remnants which van be taken up by the liver. Both chylomicrons as
well as remnants contain ApoE and ApoB. ApoB containing lipoproteins are pro-atherogenic.
,Apoliprotein A-I (ApoA-I) is produced in the intestines
and by the liver and is a lipid poor protein. It develops
to the nascent Preβ HDL, which is also lipid poor.
Lecithine-cholesterol-acyltransferase (LCAT) is present
in these nascent HDL particles and is responsible for
taking up lipids, leading to the development of α-HDL,
which can be taken up by the SR-BI receptor in the
liver. In mouse HDL cannot be converted to other
lipoproteins, however in humans HDL can be
metabolized by the Cholesterylestertransferproteïne
(CETP enzyme) to VLDL and IDL, which converts
cholesterol into triglycerides.
Mouse models
Use of diets to induce atherosclerotic lesions:
➔ Paigen diet (1% cholesterol, 0,5% cholic acid and 15% butter fat). Standarized methodology
for quantitating degree of atherosclerosis.
➔ Western Diet (our diet)
➔ CHOW diet (regular mouse diet)
The ApoE knockout mouse
= Mouse that lack ApoE. VLDL uptake by both the LDLr
and the LRP blocked due to the absence of ApoE. Note:
uptake not completely blocked since ApoB is still
present, however LDL cannot efficiently take up VLDL
with only ApoB and no ApoE → Results in very high
levels of VLDL. Mouse develop atherosclerotic lesions
very quickly.
The LDLr knockout mouse
= Mouse that lack the LDLr. So there is no uptake by the
LDL receptor. However, LRP is unaffected so lipoproteins
can be taken up. Results in higher levels of VLDL and LDL.
➔ With a Western-type diet, mouse develop
atherosclerotic lesions very quickly.(CHOW is a
regular diet).
, Pathology mouse VS human
➔ In humans lesions develop over decades
➔ In ApoE and LDLr knockout mice, atherosclerosis progresses through the different lesion
types in weeks to months
➔ Female mice are more susceptible to atherosclerosis, while in humans men are more
suspceptible than woman (pre-menopause).
➔ Major limitation: plaque rupture and superimposed thrombus formation is a rarity in mice.
➔ Like in humans, atherogenesis in mice is multifocal and locates to regions of the vasculature
subjected to low or oscillating shear stress
➔ Sites with high chance of lesions:
- Aortic root
- Lesser curvature of the aortic arch
- Brachiocephalic trunk
➔ In contrast to humans, first branch of all major coronary arteries are protected from disease
➔ In contrast to humans, the normal intima of mice does not contain smooth muscle cells
(SMCs) and connective tissue fiber.
➔ SMCs and connective tissue are important components of human atherosclerosis from
initiation of the disease.
➔ Development of advanced fibroatheromas is similar in mouse and humans
Mice models for studying atherosclerosis
Using loss-of-function and gain-of-function approaches approximately 100 genes have been found to
robustly and significantly affect atherosclerosis in mice. Mouse models have been essential for the
rapid progress in the understanding of the molecular mechanisms of atherosclerosis.
How useful are the current models for testing drugs?
Statins
Statins reduce LDL cholesterol levels in humans and reduce the risk of heart disease by 30%
(estimation). Statins lower LDL cholesterol by acting as an inhibitor on the HMG-CoA reductase that is
responsible for converting acetate into cholesterol, thus lowering cholesterol levels. As internal
cholesterol is lowered, cells upregulate the LDL receptor to take up more LDL that consists of
cholesterol. This results in lower LDL levels.
➔ ApoE knockout mice do not respond to statins with respect to the reduction of (V)LDL-
cholesterol, as due do the lack of ApoE they cannot be seen by LDL receptors.
➔ LDL receptor knockout mice; Since they lack the LDL receptor, they are not able to
upregulate this receptor as a response to statins. Therefore classic atherosclerosis models
are not a good enough to study the effect of statins on atherosclerosis.
➔ ApoE3*Leiden transgenic mouse: ApoE is replaced by ApoE3L so it can be taken up by both
the LDLr and LRP → making the model more human like.
➔ ApoE3*Leiden/CETP transgenic mouse: also consist of CETP and are able to convert HDL to
VLDL. Makes the model even more human like. Effects of statins can now be made visible.
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