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Module 103: The Heart, Lungs and Blood > Theme 3: Lecture 16 - Atherogenesis > Flashcards

Theme 3: Lecture 16 - Atherogenesis Flashcards

1
Q

Describe the progression of atherogenesis

A
  • Normal vessel to
  • Fatty streak to
  • Fibrous plaque to
  • Occlusive atherosclerotic plaque to
  • Plaque rupture
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2
Q

Where in the artery do plaques develop

A

tunica intima of the artery wall

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3
Q

What is the development of plaques caused by

A
  • Caused by migration of cells from the tunica media

- By recruitment of leucocytes and deposition of lipid from the blood

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4
Q

What are the 3 principle components of atherogenic plaques

A
  • Cells (smooth muscle cells, macrophages (foam cells), T cells)
  • Matrix components (collagen, proteoglycans, elastic fibres)
  • Intracellular and extracellular lipid (cholesterol and cholesterol esters)
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5
Q

What does nitric oxide do in a healthy endothelium

A

controls vasorelaxation, has anti-adhesive and anti-coagulant properties

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6
Q

What does early damage to the endothelium cause

A
  • Loss of cell repellent quality
  • Allows inflammatory cells to enter vascular wall
  • Increased permeability to lipoproteins
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7
Q

Is early endothelial damage structural or functional

A

Functional

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8
Q

When does structural damage to the endothelium occur

A

Later in the atherogenic process

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9
Q

How are monocytes attracted to developing plaques

A

By MCP-1 (monocyte chemoattractant protein 1) AKA CCL2.

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10
Q

How do monocytes transform into macrophages in the tissues

A

Transform into macrophages under influence of cytokines (IFN-γ, TNF-α, GM-CSF, M-CSF) secreted by endothelium and vascular smooth muscle cells (VSMC)

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11
Q

What do the macrophages do

A
  • Generate Reactive Oxygen Species (ROS) which can oxidise LDL in intima
  • Produce pro-inflammatory cytokines
  • Express scavenger receptors (a PRR)
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12
Q

Describe the lipid involvement in atherogenesis

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

How can lipids in the vascular wall be oxidised

A

by oxidases & ROS from macrophages and ROS from VSMCs

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14
Q

Describe how oxidised LDL leads to the generation of fatty streaks in the arterial wall

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 from macrophages that have phagocytosed oxidised LDL (visible in arterial walls as fatty streaks)
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15
Q

Describe how macrophages transform into foam cells

A
  • Oxidised LDL isn’t recognised by the LDL receptor but by scavenger receptors on macrophages
  • They are taken into the macrophages and there’s an accumulation of lipid in the form of cholesterol esters in the macrophage cytosol
  • The receptors controlling cholesterol export are down regulated
  • The macrophage has become a foam cell
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16
Q

Why are foam cells bad in atherogenesis

A

They secrete pro-inflammatory cytokines and ROS, this is the last thing you want as it will further drive the atherogenic process

17
Q

What is responsible for the structure of the vessel wall

A

Vascular smooth muscle cells

18
Q

Describe how VSMCs disrupt the structure of the arterial wall in atherogenesis

A
  • Endothelial cells and macrophages secrete: PDGF and TGF-β
  • This causes VSMCs to proliferate and migrate into the intima
  • VSMCs can differentiate into macrophage-like cells and become foam cells
  • Activated VSMCs also synthesise ECM (collagen in particular) which deposits in the plaque
  • Migrating cells and ECM material all disrupt the structure of the arteriole wall
19
Q

What are the 2 types of atherosclerotic plaque

A

Stable and vulnerable

20
Q

Describe a stable plaque

A
  • Thick fibrous cap/high collagen content
  • High VSMC content
  • Small lipid pool
  • Few inflammatory cells
21
Q

Describe an unstable plaque

A
  • Thin fibrous cap/low collagen content
  • Low VSMC content
  • Large lipid pool
  • Many inflammatory cells
22
Q

What are the 2 major theories for causes of atherogenesis

A
  • Lipid oxidation hypothesis

- Response to injury hypothesis

23
Q

Describe the response to injury hypothesis

A
  • Endothelial injury/dysfunction
  • Accumulation of lipoprotein in vessel wall
  • Monocyte adhesion
  • Platelet adhesion
  • Smooth muscle proliferation
  • Lipid accumulation - Plaques
24
Q

Describe the lipid oxidation hypothesis

A
  • LDL enters vascular wall and becomes oxidised
  • Oxidised LDL phagocytosed by macrophages
  • Generation of foam cells
  • Recruitment of macrophages
  • Generation of plaques
25
Q

What is familial hypercholesterolaemia

A
  • Genetic disorder - autosomal inheritance in genes related to LDL metabolism resulting in lifelong elevation of LDL-C levels
  • If untreated, many patients with FH die of myocardial infarction (MI) or other major CV events in their 20/30s
26
Q

What causes endothelial injury

A
  • raised LDL
  • ‘toxins’ e.g. cigarette smoke
  • hypertension
  • haemodynamic stress
27
Q

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
28
Q

What does foam cells secreting cytokines cause

A
  • further VSMC stimulation

- recruitment of other inflammatory cells

29
Q

How can you prevent atherogenesis

A
  • Protection of artery walls (stop smoking, lower blood pressure)
  • Reduce plasma lipid levels
  • Reduce ROS and inflammation
30
Q

What are the treatments to decrease plasma lipid levels

A
  • Statins

- Anti-PCSK9 antibodies

31
Q

Describe how statins decrease plasma lipid levels

A
  • Statins are competitive inhibitors of HMG-CoA reductase.
  • They are bulky and literally get “stuck” in the active site
  • This prevents the enzyme from binding with its substrate, HMG-CoA
32
Q

What are the 2 classes of statins

A

Natural and synthetic statins

33
Q

Name a statin

A

Simvastatin

34
Q

How do anti-PCSK9 antibodies decrease plasma lipid levels

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
35
Q

What is activated in response to low cholesterol

A

SREBP-2 (intracellular sensor)

36
Q

How do statins lower blood cholesterol level via SREBP-2

A
  • SREBP-2 is activated in response to low cholesterol and
  • Increases HMG-CoA expression but there’s no activity in the presence of statins
  • Increases LDLR expression - uptake of LDL from plasma increased
  • Increases PCSK9 expression -degradation of LDLR promoted, a part of cholesterol homeostasis

Module 103: The Heart, Lungs and Blood (51 decks)

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