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103 Theme 3 - Cardiovascular System > Atherogenesis > Flashcards

Atherogenesis Flashcards

1
Q

What stages of atherogenesis are clinically silent?

A

Normal

Fatty streak

Fibrous plaque

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2
Q

Complete the diagram of the stages of atherosclerosis

A
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3
Q

Where in the artery do plaques develop?

A

Atherogenic plaques develop in the tunica intima of the artery wall

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4
Q

What causes plaques to develop in arteries?

A

Caused by migration of cells from the tunica media

Also caused by recruitment of leucocytes and deposition of lipid from the blood

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5
Q

What are the 3 principal components of an atherogenic plaque?

A
  1. Cells (smooth muscle cells, macrophages (foam cells), T cells)
  2. Matrix components (collagen, proteoglycans, elastic fibres)
  3. Intracellular and extracellular lipid (cholesterol and cholesterol esters)
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6
Q

What is the role of production of NO in healthy endothelium?

A

Controls vasorelaxation and has anti-adhesive properties

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7
Q

Complete the diagram of an atherogenic plaque

A
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8
Q

Normal endothelium has ________ and _________ properties

A

Normal endothelium has anti-coagulant and anti-adhesion properties

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9
Q

What is the role of the endothelium in atherogenesis?

A
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10
Q

What is the role of the monocyte in atherogenesis?

A
  • Attracted to developing plaques by MCP-1/CCL2
  • Transform into macrophages under influence of cytokines (IFN-γ, TNF-α, GM-CSF, M-CSF) secreted by endothelium and vascular smooth muscle cells (VSMC)
  • Generate Reactive Oxygen Species (ROS) which can oxidise LDL in intima
  • Produce pro-inflammatory cytokines
  • Express scavenger receptors
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11
Q

What is the role of lipids in atherogenesis?

A

Lipoproteins in the vascular wall can be oxidised in the intima (by oxidases & ROS from macrophages and ROS from VSMCs)

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12
Q

What 2 factors make it easier for lipids to enter the vascular wall?

A
  • Smaller lipoproteins (remnants and LDL) enter vascular wall more easily than other particles; hence more atherogenic
  • Entry of lipoproteins into the vascular wall occurs more easily when present in high concentrations in the blood
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13
Q

What is the role of oxidised LDL in atherogenesis?

A
  • Stimulates expression of VCAM-1 and MCP-1; directs monocytes to sites of lesions
  • Oxidised B-100 binds to scavenger receptors on macrophages and is phagocytosed
  • No feedback regulation via cholesterol concentration
  • Generation of foam cells (visible in arterial walls as fatty streaks)
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14
Q

What are the differences between macrophages and turning into foam cells?

A

Oxidised LDL NOT recognized by LDL receptor, but by scavenger receptors SR-A1, CD36 (& LOX-1)

Accumulation of lipid in the form of cholesterol esters in the cytosol

Receptors controlling cholesterol export are down-regulated

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15
Q

What are VSMCs responsible for?

A

Structure of the vessel wall

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16
Q

How do VSMCs migrate into the intima?

A

Endothelial cells and macrophages secrete: PDGF and TGF-β

Effect on VSMCs: proliferation and migration into the intima

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17
Q

What is the role of VSMCs in atherogenesis once they’ve migrated into the intima?

A
  • VSMCs can differentiate into macrophage-like cells and become foam cells
  • Activated VSMCs also synthesise ECM (collagen in particular) which deposits in the plaque
18
Q

What is the result of migration of VSMC?

A

Migrating cells and deposits of ECM material all disrupt the structure of the arterial wall

19
Q

Complete the summary of atherogenesis

A
20
Q

Complete the diagram of atherosclerotic plaque

A
21
Q

What atherosclerotic plaque is this?

A

Stable plaque

22
Q

What atherosclerotic plaque is this?

A

Ruptured plaque and thrombus

23
Q

Complete the diagram

A
24
Q

What are the components of a stable plaque?

A
25
Q

What are the components of a ruptured plaque?

A
26
Q

What are the 2 major theories on the causes of athersclerosis?

A

Lipid oxidation hypothesis

Response to injury hypothesis

27
Q

What is the lipid oxidation hypothesis?

A
  1. LDL enters vascular wall + becomes oxidised
  2. Oxidised LDL phagocytosed by macrophages
  3. Generation of foam cells
  4. Recruitment of macrophages
  5. Generation of plaques
28
Q

What is the response to injury hypothesis?

A
  1. Endothelial injury/dysfunction
  2. Accumulation of lipoproteins in vessel wall
  3. Monocyte adhesion
  4. Platelet adhesion
  5. Smooth muscle proliferation
  6. Lipid accumulation - plaques
29
Q

What is Familial hypercholesterolaemia (FH)?

A

Genetic disorder - autosomal inheritance in genes related to LDL metabolism resulting in lifelong elevation of LDL-C levels

30
Q

What happens if Familial hypercholesterolaemia (FH) is untreated?

A

If untreated, many patients with FH die of myocardial infarction (MI) or other major CV events

31
Q

In the atheroma hypothesis, what is endothelial injury due to?

A
  • raised LDL
  • ‘toxins’ e.g. cigarette smoke
  • hypertension
  • haemodynamic stress
32
Q

In the atheroma hypothesis, what does endothelial injury cause?

A
  • platelet adhesion, PDGF release, migration of monocytes into intima
  • insudation of lipid, LDL oxidation, uptake of lipid by VSMC and macrophages
  • VSMC proliferation and migration
33
Q

In the atheroma hypothesis, what are the last 2 steps?

A

Stimulated VSMC produce matrix material

Foam cells secrete cytokines causing:

  • further VSMC stimulation
  • recruitment of other inflammatory cells
34
Q

What 3 ways are there of preventing atherogenesis?

A

Protection of artery walls (stop smoking, lower blood pressure)

Reduce plasma lipid levels

Reduce ROS and inflammation

35
Q

What 2 treatments decrease plasma lipid levels?

A
  • Statins
  • Anti-PCSK9 antibodies
36
Q

What are statins?

A

Statins are competitive inhibitors of HMG-CoA reductase.

37
Q

What are the 2 classes of statins and name some examples

A

Natural Statins: Lovastatin (mevacor), Compactin, Pravastatin (pravachol), Simvastatin (Zocor).

Synthetic Statins: Atorvastatin (Lipitor), Fluvastatin (Lescol)

38
Q

How do statins work?

A
39
Q

How do statins lower cholesterol synthesis?

A

SREBP-2 activated in response to low cholesterol

  1. HMG-CoA expression increased, but no activity in presence of statin
  2. Increased LDLR expression – uptake of LDL from plasma increased
  3. Increased PCSK9 expression – degradation of LDLR promoted
40
Q

How does blocking PCSK9 lower blood cholesterol?

A

Anti-PCSK9 antibodies block binding of PCSK9 to LDLR reducing LDLR degradation

Increased LDLR recycling into membrane & greater uptake of LDL from the plasma

103 Theme 3 - Cardiovascular System (19 decks)

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