CVS 16 - Atherosclerosis, role of inflammatory cells Flashcards
How does atherosclerosis begin?
Endothelial Damage (turbulent flow regions)
Endothelial Permeability increases
LDL deposits in the subintimal space and binds to matrix proteoglycans
Trapped LDL to sticky proteoglycans are susceptible to MODIFICATION (oxidation)
LDL is oxidised by free radicals
This is phagocytosed by macrophages which leads to foam cells formation and CHRONIC INFLAMMATION. Smooth muscle cells also develop (stimulated by macrophages)
How does atherosclerosis progress?
Lesion-prone location is subject to morphological changes
Adaptive thickening of smooth muscle
Macrophage foam cells form and extracellular lipids eventually accumulate (macrophages can’t contain it anymore)
Core of extracellular lipids form (necrotic)
Fibrous cap thickening (stimulated by macrophages to strengthen)
Rupture of complicated lesion and thrombus formation
What are the two classes of macrophages and how are their roles different?
Resident - involved in maintaining homeostasis
Inflammatory - kill microorganisms
What is Familial Hyperlipidaemia? State two clinical features.
Massively elevated blood cholesterol level (20 mmol/L)
Autosomal dominant (chr 19)
Xanthoma (accumulations of foam cells in the skin)
Early atherosclerosis
What receptors on macrophages are involved in atherosclerosis?
Scavenger receptors - like LDLR but mops up oxidised LDL
2 types of Scavenger Receptor:
A: CD204, binds to: oxLDL, gram + bacteria; staph and strep, apoptotic cells
B: CD36, binds to: oxLDL, malaria, apoptotic cells
What determines the function of the second LDL receptor?
The level of oxidised LDLs present
At relatively low levels of OxLDLs, the abnormal materials are taken up by macrophages and cleared safely by reverse cholesterol transport.
At high levels of OxLDLs, it triggers an inflammatory reaction
What roles do macrophages within plaques have?
Macrophages:
- Generate free radicals that oxidise LDL (NADPH Oxidase, myeloperoxidase)
- Phagocytose oxLDL and become inflammatory foam cells
Become activated and secrete:
- cytokine mediators (IL-1, MCP1) that recruit monocytes
- Growth factors for VSMC
- Proteinases that degrade the protein cap - dangerous for rupture (metalloproteinases)
- Tissue factor which stimulates coagulation when in contact with blood
- Macrophages die by apoptosis contributing to the lipid rich EC necrotic core
What enzyme do macrophages have that affects oxygen?
NADPH Oxidase - reduces oxygen to make superoxide (O2-)
What does the superoxide end up producing?
Superoxide ends up producing hypochlorous acid (by the action of myeloperoxidase from hydrogen peroxide and chlorine)
What enzyme is involved in the production of HOCl and what other product can it produce?
Myeloperoxidase - also produces a more unstable form called peroxynitrite
What cytokines are released by macrophages?
IL-1 = upregulates VCAM-1 thus increasing leukocyte migration
MCP1
What two growth factors are produced by macrophages and how do they affect smooth muscle cells?
Platelet derived growth factor (PDGF) = stimulates smooth muscle chemotaxis, survival and division
Transforming growth factor - beta = stimulates collagen synthesis
Describe how the normal function of a smooth muscle cell is different to the synthetic smooth muscle cell in atherosclerosis.
Normal - more contractile filaments and less collagen deposition
Synthetic - fewer contractile filaments and more collagen deposition
PDGF and TGF-beta can make the VSMC become the synthetic phenotype
What do the matrix metalloproteinases expressed by macrophages do?
They break down the collagen in the ECM and hence weakens the plaque
What are the characteristics of unstable plaques?
Thin fibrous cap
Reduced VSMC and collagen content
Infiltration of activated macrophages expressing MMPs
Large, soft, eccentric lipid-rich necrotic core
