Atherosclerosis - Basics and Roles of Inflammatory Cells Flashcards
Describe the difference in the function of macrophages and smooth muscle cells in an atherosclerotic plaque.
Macrophages remove arterial tissue
Smooth muscle cells deposit arterial tissue
Describe the effects of macrophages on smooth muscle cells.
Macrophages stimulate smooth muscle cell proliferation and makes the smooth muscle cells produce more collagen to strengthen the fibrous cap.
What are the two classes of macrophages and how are their roles different?
Resident - involved in maintaining homeostasis
Inflammatory - kill microorganisms
What causes the oxidation of LDLs?
Free radicals
Describe what happens to LDLs after endothelial activation.
Endothelial activation increases the membrane permeability
LDLs enter and are oxidised by free radicals and become stuck in the subendothelial layer
OxLDLs are phagocytosed by macrophages to form foam cells
The foam cells accumulate and cause chronic inflammation
What is Familial Hyperlipidaemia? State two clinical features.
Massively elevated blood cholesterol level (20 mmol/L)
Autosomal recessive
Xanthoma (accumulations of foam cells in the skin)
Early atherosclerosis
What is the LDLR regulated by?
It is negatively regulated by intracellular cholesterol
What is the second LDL receptor?
Scavenger receptor - this is a pathogen receptor that accidentally binds to oxidised LDLs
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 eventually happens to the foam cells?
They eventually become full of fat and die by apoptosis releasing cytotoxic fat and contributing to the lipid 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
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
What is a master transcription factor involved in atherosclerosis and what does it stimulate?
Nuclear Factor Kappa B - stimulates matrix metalloproteinases and stimulates inducible nitric oxide synthase
