Atherosclerosis Flashcards
Epidemiology
Known that atherosclerosis is present to some degree in all adults
Consequences of atherosclerosis including ischaemic heart disease, peripheral vascular disease and cerebrovascular disease estimated to account for around 50% of deaths in Western societies.
What are the risk factors for coronary artery disease?
Age
gender
Family history
Smoking
Hypertension
Diabetes mellitus
Hyperlipidaemia
Sedentary lifestyle
Obesity
Homocysteine more chance
Homoarginine less chance
Molecular Markers of Atherosclerotic Risk
*lipid markers
hyperlipidemia
hypercholesteremia
high LDL cholesterol; low HDL
high oxidised LDL cholesterol
*inflammatory markers
C-reactive protein (not specific)
soluble CD40 ligand
Lipoprotein (a)
interleukin 18 (IL18)
matrix metallo- proteinase 9 (MMP9)
we can put different biomarkers together and start to get a picture.
Describe a normal arterial wall?
three layers
The innermost layer, the tunica intima is simple squamous epithelium surrounded by a connective tissue basement membrane with elastic fibers. The middle layer, the tunica media, is primarily smooth muscle and is usually the thickest layer and tunica externa ( and serosa)
Endothelial Cells
Impermeable to large molecules
Anti-inflammatory (not many cytokines)
Resist leukocyte adhesion (few receptor sites)
Promote vasodilation (they have nitric oxide)
Resist thrombosis (stop blood clots forming)
What are Activated Endothelial Cells
Increased permeability
Increased inflammatory cytokines (TGF beta)
Increased leukocyte adhesion molecules
Decreased vasodilatory molecules (decrease in nitric oxide)
Decreased antithrombotic molecules (heparin sulfate goes down)
express tissue factor that triggers certain pathway
could be shear stress hypertension
repeated infections
increased in cigarette smoke
in the tunica media
Vascular Smooth Muscle Cells
Normal contractile function
Maintain ECM
Contained in medial layer
synthetic side is that they make extracellular matrix?
What does Activated Smooth Muscle Cells cause?
Increased inflammatory cytokines
Increased Extracellular matrix synthesis
Increased migration and proliferation into the subintima
they then become more of a synthetics phenotype so more extracellular matrix
Extracellular Matrix
The ECM contains 3 classes of molecules
*structural proteins (collagens and elastins)
*protein-polysaccharide complexes to embed the structural proteins (proteoglycans)
*Adhesive glycoproteins to attach cells to matrix (fibronectins and laminins)
Describe the Evolution of Atherosclerotic Plaque
Something has activated those endothelial cells which have allowed LDL cholesterol to move below the endothelial cells into sub intima.
Within the sub intima they become modified either by glycation or by reactive oxygen species. They then become modified LDL which then sends off an inflammatory chain reaction.
It sets off monocyte chemoattractant protein 1 (ncp 1) this causes monocytes to attach to endothelial cells as they have increased leukocyte binding.
In sub intima under the influence of something like a stimulating factor, they change into macrophages and under the influence of various cytokines they express scavenger receptors which allows the macrophages to ingest large amounts of cholesterol. They become foam cells.
Foam cells are also responsible for inflammatory cytokines and growth factors so increased expression of growth factors encourages smooth muscle cells to move into sub intima which develops the plaque. They then proliferate and make lots of extracellular matrix. In doing so the plaque now becomes Fibrofatty plaque. In the heart of the plaque it is very anoxic so not very much oxygen so these foam cells start to die. There can also be calcification of the plaque
What are the Consequences of Hyperglycaemia?
(poorly controlled diabetes)
Cell will take up glucose under normal conditions
glycokinase because it has a low Km and a high affinity, glucose will go through glycolytic pathway normally.
HOWEVER
A huge increase in glucose concentration,
Some of that glucose will go through into aldose reductase and enter into polyol pathway.
What is the The Polyol Pathway?
glucose being catalysed by aldose reductase involved NADPH into NADP.
after glucose gets converted to sorbitol which is relatively impermeable so it sticks within the cell and it can be further catalysed by sorbitol dehydrogenase to fructose using NAD+ and converting it to NADH. The more concerning side of polyol pathways is that glucose can be transformed to methylglyoxal, which can be catalysed by aldose reductase into acetol, the combination of these two things can give advanced glycation end product.
Increased NADH/NAD+ Causes
Activation of protein kinase C causes Increased permeability of endothelial cells, increased basement membrane synthesis and increased vasoactive hormones which can lead to blood flow changes.
Formation of Advanced Glycation End-Products (AGEs)
How are they made?
they are caused by a non enzymatic reaction between glucose and free protein amino acids. This will lead onto something called a schiff base. These aren’t indestructible but with further modification they will become an amadori product e.g HbA1c - this is a good blood biomarker for how well someone’s diabetes is controlled or if someone has developed it.
amadori product will then form AGE’s
You can also get a reaction between glucose and lipids to produce a reactive intermediate and eventually an AGE.
What is RAGE
This is the consequence of having to many ACG’s
Receptor for Advanced Glycation End products
AGE binds to RAGE receptor which gives an increase in reactive oxygen species which will give an increase in NF-kB (an inflammatory cytokine). It can also give you increased inflammatory cytokines within the endothelial cell. So both outside and inside of the vessel.
Leads to increase permeability to let in LDL.
lead tp;
increased procoagulant protein expression so more tissue factor and others.
more inflammatory cell adhesion so more VCAM-1
more VEGF (growth factor ) this increases permeability.
What is Cholesterol?
What are its roles?
sterol based on steroid nucleus
*regulation of membrane fluidity (important in terms of regulation of membrane fluidity).
More cholesterol more stiff so harder for things to diffuse
*biosynthesis of;
-steroid hormones (sex hormones), bile acids (important in emulsification and absorption of cholesterol) and vitamin D(important in calcium control)
Tighter packing leads to a stiffer, thicker membrane
What are Sources of Cholesterol?
*Diet (Saturated fatty acids)
*de novo synthesis
-cytosol and ER
liver (10%)
intestine (15%)
rest in endothelial reticulum and cytosol
*plasma cholesterol
-150-200 mg/100 ml
-controlled by de novo synthesis
how is cholesterol made?
What are the 4 statins we can use?
What other things could you use instead of statins?
Two beginning precursors in cholesterol are acetyl CoA and acetoacetyl CoA they come together via the enzyme hmg-CoA synthase to produce 3 hydroxy three methyl ( HMG-CoA).
In the mitochondria it can actually be used to produce ketone bodies in the liver.
In the cytosol it can actually undergo a process by the enzyme HMG CoA-reductase and produce mevalonate.
two NADPH needed and it is the rate limiting step so its
heavily regulated. This is where statins are used as cholesterol regulating drugs to reduce cholesterol levels in our bodies
lots of other steps and products to finally get to cholesterol.
Atorvastatin
Fluvastatin
simvastatin
Lovastatin
you can also use;
-Bile Acid Binding Resins
-Inhibitor of Cholesterol Absorption
Lipoproteins
what do they do?
What do they contain?
Describe them more?
*They transport cholesterol and triacylglycerols
-particles containing…
*inside: hydrophobic lipids
*outside: proteins and more polar lipids (hydrophilic
*increasing density (decreasing size)
*chylomicrons and their remnants (from intestine)
*Very Low Density Lipoproteins (VLDL) (from liver)
-Intermediate Density Lipoproteins (IDL)
Low Density Lipoproteins (LDL)
High Density Lipoproteins (HDL)
important to note that LDL has the highest percentage of cholesterol and cholesterol ester.
Lipoprotein Structure
It is like a malteser
cholesterol
phospholipid
core of triacylglycerols and cholesterol esters
apolipoprotein important because allows LDL cholesterol to bind to different things
5-1000 nm diameter
chylomicrons=biggest
HDL=smallest lipoprotein
The Lipoprotein Transport System
chylomicrons being taken up by the intestines, you then have the addition of various apolipoprotein including from HDL. Then have a first passthrough by enzyme called lipoprotein lipase which will strip out some fatty acids and triacylglycerols which can then be stored in adipose tissue or used as energy in muscles. Heart likes fatty acids. what’s left goes to the liver, here it is repackaged into VLDL from HDL then goes through same enzyme etc as above.
This then forms an intermediate density lipoprotein (IDL) and by lipoprotein lipase then ends up as LDL. LDL will go back to liver. In the liver it can be secreted as bile acids and cholesterol back into the intestine. So bile acids bind cholesterol to help get rid of cholesterol and help in emulsification.
Cholesterol Esters
cholesterol +acyl CoA and catalysed by enzyme ACAT–> cholesterol ester the significance of that is we can now form reactive oxygen species.
Lipid Peroxidation
unsaturated lipid binds with a hydroxyl radical, water comes off and what forms is a lipid radical, this undergoes further oxidation to become lipid peroxyl radical. this then elongates and you end up with lipid peroxide which is a good marker of someone with coronary artery disease.
LDL Receptor Versus Scavenger Receptor
LDL has to receptors
*LDL receptor
-endocytosis of LDL
-‘normal’ route of cholesterol uptake recognises apoB100
*scavenger receptor
-recognises oxidised LDL
-expressed by macrophages
→ foam cells
Plaque Progression
*SMC migration into the intima dominates early plaque progression.
*Early plaque growth shows a compensatory outward remodelling of the arterial wall that preserves the diameter of the lumen. (No impedance to flow).
plaques can come in two types
-a vulnerable plaque (thin fibrous cap)
-the stable plaque (which has a thick cap)
*Later plaque growth outstrips the compensation and begins to restrict the vessel lumen.
*During decades of development, the typical atherosclerotic plaque acquires a distinct thrombogenic lipid core that underlies a protective fibrous cap.
Foam cells in fatty streak
Foam cells in fatty streaks
there are;
-inflammatory cytokines such as TNF-a, IL-1 and TGF-b
-growth factors such as more PDGF (platelet derived growth factor)
-endothelial dysfunction such as less NO (vasodilation) and less PGI2
-increased expression of tissue factor leading to thrombosis and platelet activation
-heparinase that decreases concentration of endothelial heparin sulfate which helps breaks down a blood clot.
Extracellular Matrix Metabolism
It is constantly being made and broken down
MMPS (matrix metalloproteinases) break it down
MMPS are produced by foam cells
What are some complications of Atherosclerosis
Calcification
Rupture or ulceration
Haemorrhage (leaks from plaque)
Embolisation
Weakening of the vessel wall
Microvessel growth within plaques (straining)
‘Approaches’ to Limiting Atherosclerosis
limit LDL cholesterol
-limit oxidised LDL
limit extravasation of immune cells
-limit endothelial dysfunction
Phytochemicals
another way to limit atherosclerosis
DIET
steroids and sterols
e.g sitosterol
*decrease in cholesterol absorption
polyphenols
-wide variety
*antioxidants?
*anti platelet aggregation and adhesion
sulphur compounds
-Alium spp. (garlic, onion etc)
-short-term reduction of serum cholesterol?
Benecol
*hypocholesterolaemic effect
need a lot tho
*2-3 g/d PSE →
-serum LDL
cholesterol decrease by 10-15%
compensatory increase in synthesis
a statin would give you 30-40% reduction.
ROS/RNS
*reactive oxygen and nitrogen species
*ROS: partial reduction of oxygen
O2 + e- –>O2- (superoxide radical)
O2- + e- + 2 H+ –> H2O2 (hydrogen peroxide)
H2O2 + e- + H+ –> OH* (hydroxyl radical) + H2O
OH* + e- + H+ –>H2O
*other ROS
-hypochlorous acid (HOCl)
RNS
-nitric oxide (NO)
-peroxynitrite (NO + O2- → ONOO-) reduce conc of nitric oxide, it’s important because it would then change vasodilation and vasoconstriction properties (more vasoconstriction).
vasoconstriction could be bad as you already have a plaque there so it could be too much constriction.
Oxidative stress
*oxidative stress
-imbalance between pro-oxidants and antioxidants in favour of the former
increased ROS/RNS production
impaired antioxidant defences
*oxidative stress → oxidative damage
-lipids
lipid peroxidation
-proteins
chemical modification, cross-linking
-DNA
strand breaks
affect on gene expression
too many ROS leads to oxidative damage.
proteins change in tertiary structure which can lead to a change in activity. Damage to DNA
Name Dietary antioxidants and properties
vitamin E (tocopherols)
-lipid soluble
-chain terminating
vitamin C (ascorbate)
-water soluble
-regeneration of vitamin E
What happened when using dietary antioxidants and AS
prospective clinical trials
-alpha tocopherol (AT)
-ascorbate (AA)
-AA + AT
-beta carotene
disappointing results
Oestrogens and Atherosclerosis
*‘knock-out’ mice studies
Apoe-/- or Ldlr-/-
-lack apoE and LDL receptor, respectively
-develop Atherosclerosis
*protection by E2 (estradiol)
-initiation and progression
oestrogen receptor alpha (ERalpha)
Note clinical trials targeting oestrogen/progesterone replacement in menopausal women had to be ceased because of adverse CVS events
Phytoestrogens instead of natural oestrogen
*non-steroidal but structure resembles steroids
*agonists or antagonists of steroids
include non-flavonoids, e.g. lignans
soy bean (Glycine max)
positive results
The ‘French Paradox’ and the ‘Blue Zones’
epidemiology
France
relatively low CHD
diet relatively high in saturated fats
demographics
Sardinia
zone of relatively high
longevity
Nicoya peninsula,
Costa Rica
Polyphenols
include phytoestrogens
trans-resveratrol
oligomeric procyanidins (condensed tannins)
catechin
flavonoids
quercetin
Oligomeric procyanidins (OPC)
inhibition of endothelin-1 synthesis
Corder et al. (2006) Nature 444, 566
Possible Mechanisms
antioxidants?
signalling?
-inhibition of NF-kB
→ improved endothelial function
Inhibition of NF-kB
transcription factor
inhibition → decrease expression
-pro-inflammatory cytokines
TNFα, IL-1β, IL-6
-adhesion molecules
-iNOS (inducible nitrate oxide synthase is going to give nitric oxide) if you turn this down it will give you more nitric oxide.
so increased vasodilation.
