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BRS YEAR 2 > Atherosclerosis > Flashcards

Atherosclerosis Flashcards

1
Q

risk factors for coronary heart disease modifiable vs non

A
  • Smoking
  • Lipids intake
  • Blood Pressure
  • Diabetes
  • Obesity
  • Sedentary Lifestyle
    non modifaible
  • Age
  • Sex
  • Genetic background (e.g. ethnicity)
    smoking high cholesterol and hypertension increase risk by 16X
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2
Q

plaques

A

occur exactly at locations of vortex in blood flow
change in flow activates endothelial cells

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3
Q

where do plaques commonly form

A

Bifurcation of carotid artery

Bifurcation of abdominal aorta into iliac arteries

Origins of the subclavians and the carotids

Renal arteries

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4
Q

main cell types invollved

A
  • Vascular endothelial cells
    Functions:
  • Barrier function (e.g. to lipoproteins)
  • Leukocyte recruitment
  • Platelets
    Functions:
  • Thrombus generation
  • Cytokine and growth factor release
  • Monocyte-macrophages
    Functions:
  • Foam cell formation
  • Cytokine and growth factor release
  • Major source of free radicals
  • Metalloproteinases
  • Vascular smooth muscle cells
  • Migration and proliferation
  • Collagen synthesis
  • Remodeling and fibrous cap formation
  • T lymphocytes
  • Macrophage activation - CD4 Th1
  • Macrophage deactivation - CD4 Treg
  • VSMC death - CD8 CTL
  • B cell / Antibody help - CD4 Th2
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5
Q

CANTOS trial

A

showed that atherosclerosis has an inflammatory basis
Patients at high risk of atherosclerosis complications were injected with antibodies to IL-1 (Canakinumab)

This resulted in fewer major adverse cardiovascular events (MACE)

Cholesterol crystal formation connecting lipids drives IL-1 secretion leading to inflammation implicated in atherosclerosis

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6
Q

macrophages

A

main inflammatory cell in atherosclerosis
derived from blood monocytes
can injure host tissue if excessively activated
subtypes regulated by combinations of transcription factors binding to regulatory sequences on dna

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7
Q

2 main types and functions of macrophages

A
  1. Inflammatory Macrophages
    - Adapted to kill microorganisms
  2. Non-inflammatory and Resident Macrophages
    - Normal homeostatic function - may be parenchymal
    - Alveolar resident macrophages have a function in surfactant lipid homeostasis
    - Macrophages in spleen have a role in iron homeostasis
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8
Q

LDL

A

made in liver
carries cholesterol from liver to the rest of the body including arteries
J curve-no ldl worse risk for cardiovascular accidents than small amount of LDL
bad cholesterol

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9
Q

HDL

A

carries cholesterol from peripheral tissue including arteries back to liver
reverses cholsterol transport

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10
Q

oxidised/modifier ldl

A

Chemical and physical modification of LDL by: free radicals, enzymes, aggregation
- Families of highly inflammatory and toxic forms of LDL found in vessel walls

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11
Q

LDL structure

A

lipid monolayer
docking molecule addresses for fat delivery and may interact with clotting or clot lysis
cargo fat for fuel

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12
Q

modificationn of subendothelial trapped LDL

A
  • LDLs leak through endothelial barrier, likely due to endothelial activation in areas of vortex
  • LDL is bound to sticky matrix carbohydrates (proteoglycans) in the sub-endothelial layer and becomes susceptible to modification
  • Best studied modification is oxidation ⇒ due to free radical attack from activated macrophages
  • Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation
  • Macrophages which have phagocytosed macrophages are known as “foam cells”
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13
Q

familial hyperlipidaemia

A

Autosomal Genetic Disease

Caused massively elevated cholesterol (20mmol/L, as opposed to the normal range of ~1-5mmol/L)

Result of failure to clear LDL from blood

Causes xanthomas and early atherosclerosis, if untreated causes fatal MI before age 20

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14
Q

what is cholesterol synthesis negatively regulated by

A

cellular cholesterol which led to discovery of HMG-COA reductase (statins) to lower plasma cholesterol

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15
Q

what accumulaes cholesterol in LDL-R negative patients

A

macrophages

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16
Q

what hoovers up chemically modified LDL

A

scavenger receptors
are pathogen receptors which accidentally bind to OxLDL

17
Q

PCSK9

A

Decrease activity of LDL-R whilst statins inhibit cholesterol synthesis
This is because PCSK9 degrades the LDLR, which removes cholesterol from the blood and into the hepatocytes. Conversely , patients with a PCSK9 deficiency are protected from cardiovascular disease as more LDLR receptors are present
PCSK9 inhibitors are useful for severe or statin-resistant hyperlipidaemia
found as antibodies,srna,antisense

18
Q

what do ABCA1 and ABCG1 pumps do

A

ABCA1 and ABCG1 pumps add cholesterol to HDL, and take fat from the arteries to the liver
These pumps may be found on macrophages, and help remove the oxidised LDL of foam cells
selective to apolipoprotein as an interactor

19
Q

macrophage scavenger receptor A

A

A = CD204
This binds to oxidised LDL, gram positive bacteria (e.g. staphylococci and streptococci), & dead cells

20
Q

macrophage receptor b

A

B = CD36
This binds to oxidised LDL, malaria parasites, and dead cells

21
Q

modification of native LDL with oxidative enzymes

A
  • NADPH oxidase generates superoxide O2
  • Myeloperoxidase, such as HOCl (hypochlorous acid) from ROS + Cl-, HONOO (peroxynitrite)
  • Generation of H2O2
22
Q

phagocytosis of lipoproteins

A
  • Macrophages become larger, with fats in vacuole
  • This results in foam cells
23
Q

excretion of cytokines and chemokines

A

Cytokines:
- IL-1 triggered by intracellular cholesterol crystals and NFkB. This helps coordinate processes such as cell death and proliferation.
Chemokines
- Monocyte Chemotactic Protein 1 (MCP-1) which binds to monocyte G-protein coupled receptor CCR2 they attract monocytes
Therefore immunosuppression is a big side effect
Side note: mice without IL-1, MCP-1 or CCR2 show reduced atherosclerosis, as do humans with anti IL-1 antibodies
As these inflammatory factors result in monocyte recruitment, this causes a positive feedback loop

24
Q

expression of chemo attractants and growth factors

A
  • Macrophages release growth factors which recruit VSMC and stimulate migration, survival, proliferation and deposition of extracellular matrix
  • Platelet derived growth factor, which has roles in vascular smooth muscle cell chemotaxis, survival and mitosis
  • Transforming growth factor beta, which increased collagen synthesis and matrix deposition
  • Presence of these factors upregulates matrix deposition genes and decreases contractile fibres in VSMCs
25
Q

expression of proteinases that degrade tissue

A
  • Metalloproteinases, a family of 28 enzymes which activate each other by proteolysis
  • These degrade collagen
  • Catalytic mechanisms is based on Zinc
  • This can lead to plaque rupture, which causes blood coagulation and may lead to an occlusive thrombus and cessation of blood flow
26
Q

macrophage apoptosis

A
  • OxLDL derived metabolites are toxic, such as 7-keto-cholesterol
  • Macrophage foam cells have protective systems that maintain survial in the face of toxic lipid loading
  • Once they are overwhelmed, macrophages die via apoptosis
  • They release macrophage tissue factors and toxic lipids into the “central death zone” known as the lipid necrotic core
  • Thrombogenic and toxic material accumulates, until the plaque ruptures which then introduces the material to blood
27
Q

symptoms of atherosclerosis

A
  • Death of downstream tissues, such as heart and brain
  • Loss of function of one side of the body as a result of major ischaemic stroke
  • Severe central crushing chest pain with fear, dizziness and nausea (MI)
  • Angina
  • Thrombogenic and toxic material accumulates until plaques rupture
28
Q

characteristics of a vulnerable and stable plaque

A

large soft eccentric lipid rich necrotic core
increased VSMC apoptosis
reduced vsmc and collagen content
thin fibrous cap
infiltrate of activated macrophages expressing MMPs

29
Q

nuclear factor kappa b

A

Transcription factor known as “Master Regulator” of inflammation
- Predominant non-redundant highly connected network hub

Activated by numerous inflammatory stimuli, including:

  • Scavenger receptors
  • Toll-like receptors
  • Cytokine receptor such as IL-1

Switches on numerous inflammatory genes

  • Matrix metalloproteinases
  • Inducible NO synthase
  • Interleukin-1

BRS YEAR 2 (39 decks)

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