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
