Cardio L24 Athersclerosis Flashcards Preview

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Flashcards in Cardio L24 Athersclerosis Deck (26)
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lipid rich gruel – free/esterified cholesterol, and cell debris


Inflammatory cells

lipid rich gruel – free/esterified cholesterol, and cell debris

Inflammatory cells 1. Macrophages, T cells, mast cells. Macrophages store intracellular lipid as foam cells



connective tissue - smooth muscle cells.


Cholesterol Hypothesis:

1. Lesions contain cholesterol

2. Cholesterol feeding causes atherosclerosis

3. Serum cholesterol (LDL) is a risk factor

4. Familial hypercholestrolaemia predicts later atherosclerosis

5. Lowering LDL cholesterol decreases risk


Cholesterol function

Cholesterol function à is an essential component of cell membranes, it reduces fluidity but lower melting point.


Control of plasma LDL à

Steroid response element binding protein.

If the body is defieinct in cholesterol SREBP will transcrbibe LDL receptors and HMGoA reductase production to allow endogenous production of cholesterol.


Homozygous Familial Hypercholesterolaemia à

The actual gene not the transcription site is defective.

1. Transcription of the genen is fine but a dysfunctionl LDL receptor formed.
2. Therefore no signal sent to say LDL is available.

3. Less cholesterol inside cell

4. SREBP does not translocate to ER.

5. Get an upregulation of HMGCoA to compensate for the ‘lack of’ cholesterol

6. Over synthesis of cholesterol


to reduce cholesterol

1. Reduce intestinal uptake

2. Plant stanols

a. Benecol (yoghurt)- block uptake

3. See below àPathway via HMGCoA reductase à most effective way of altering cholesterol.

* Saturated fat –> increases rate of HMGCoA reductase activity.

* Polyunsaturated fatty acids à decrease HMGCoA reductase activity


Excretion of Cholesterol:

Excreted in faeces. Bile acids are secreted into intestine emulsify food and excreted as faeces.

Reabsorption of bile acids.


Treatment of cholesterol via upregulation of excretion

Treatment: bind bile acids to resin e.g. dietary fibre and can enhance rate of bile acid secretion (modest effect on lowering cholesterol concentration)



* Reduce intestinal uptake à Ezetimibe (reduction by 15%)

* Old: Bile acid sequestrants à cholestyramine

* Reduce HMGCoA reductase inhibitors: STATINS


* Reduce HMGCoA reductase inhibitors: STATINS

o Compactin

o Mevinolin

o Lovostatin

o Simvastatin

o Atorvastatin


Process of atherosclerosis à

LDL trapping by proteoglycans in the artery wall.


Artery structure wall:

* Collagen

* Eleastic fibres

* ECM àproteoglycans which provides a filler and attraction of water (turgor to maintain the size of the tissue) lotsof sulphate groups do this due to their negative charge.


LDL particles carry

LDL particles carry vitamin E to prevent them from oxidising but once it is trapped in the artery wall. Eventually vitamin E store is lost and LDL is oxidised.


How the body deals with stuck LDL

How the body deals with this à macrophages take up LDL via an oxidised LDL receptor (scavenger receptors). The binding causes them to form foam cells with stored LDL in droplets.

LDL receptors are regulated by SREbP. Once the cell has sufficient LDL there receptors switch off.

Scavenger receptors (in macrophages) are not downregulated in response to cholesterol and therefor can continue to uptake LDL = foam cells.


Oxidased LDL causes à

1. Causes endothelial cells to expression adhesion molecules and therefore recruits monocytes.

2. Acts on smooth muscle cells to produce monocyte chemotactant protein 1 – MCP 1


Foam cell

Therefore: Draws in monocytes to damage proteins and oxidised lipids. Monocytes then converted into macrophages express scavenger receptors expressed and ox-LDL uptake = foam cells.


LDL oxidation and inflammation

LDL oxidation and inflammation – summary (therapies in trial which is based on this model) – alternative to statins.

1. Catalysed by Cu, endothelium, macrophages, smooth muscle cells, oxygen radicals, lipxygenase

2. Ox-LDL is present in atheromatous plaques.

3. Accounts for the anti-atherogenic effects of Vitamin E, BHT and probucol

4. Patients have circulating antibodies to oxLDL in plasma

5. Immunisation decreases atherosclerosis in animals (against ox-LDL).


Endothelial nitric oxide production and action

1. Endothelial cells exposed to high sheer

2. Processes in cell membrane activated

3. Elevation of intracellular Calcium

4. Calcium binds to calmodulin (enzymes have this that are calcium modulated)

5. Nitric oxide synthase takes arginine and converts it into citrilline and NO (gas)

6. NO diffuses rapidly around local environment e.g. to SMC surrounding it

7. SMC have receptor for NO à activates soluble guanylate cyclase

8. This converts GTP to cGMP = end result is relaxation, inhibition or proliferation.


NO result

1. regulation of vascular tone

2. Ability of SMC to proliferate e.g. also fibrous cap formation



1. High sheer are the artery is more relaxed and therefore LDL can filter through and less likely to be oxidised. And NO is an antioxidant.

2. Low sheer à less relaxation LDL is less likely to filter through and more likely to get stuck and oxidised.


Anti-oxidant effect of NO

1. Anti-oxidant

2. cGMP is involved in regulating adhesion molecule expression (endothelial cells) and MCP-expression (SMC) à reduction in both due to NO.


Atherosclerosis causes loss of NO:

Main oxidant causing ox-LDL àsuperoxides produced by many enzymes in the body.

* Most potent in the endothelium à NADPH oxidase

* Activity of this enzyme in blood vessel wall is up regulated by

o Hypercholestraemia

o High BP

o Smoking

o High cirucaltion of antiotensin II

o Diabetes


atherosclerosis is an

Atherosclerosis: Interaction between the cholesterol in the blood and the way the artery behaves in particular its ability to produce NO.


NO medication

GTN sprays

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