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
Macrophages
- remove arterial tissue
VSMC
- make more arterial tissue (angiogenesis)
- Protect plaque integrity by making more tissue to strengthen artery
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.
Smooth muscle cells protect plaque integrity, they make more tissue which strengthens the artery.
What are modifiable and non-modifiable risk factors of atherosclerosis?
Modifiable:
- Smoking
- Fats/lipids
- Blood pressure
- Diabetes
- Obesity
- Lack of exercise
Non-modifiable:
- Age, sex
- Genetic background
Where does atherosclerosis form?
At places of turbulent flow such as bifurcations (branch points).
It forms as the bifurcation of the common carotid artery.
What is the reason for the formation of atherosclerosis at places of turbulent flow?
- Blood flow in arteries is LAMINAR so the blood flows fastest in the middle of the vessel and slower around the outside.
- when the blood goes around a corner too quickly it sets up EDDYs (turbulent flow).
- Therefore atherosclerotic lesions tend to appear on the outside of a bend rather than on the inside.
- Laminar flow maintains the shear stress of a vessel so promotes endothelial cell survival (with secretion of NO etc.)
- In places of turbulent flow, shear stress decreases which is bad (eddy currents can form)
where do LDLs deposit and what does it bind to
-LDLs deposit in the SUBINTIMAL SPACE and binds to matrix proteoglycans
How does atherosclerosis progress?
Low Density Lipoproteins (LDLs) circulate in blood
Carry cholesterol synthesised in liver to body
Phospholipid MONOLAYER
Have APOPROTEINS on their surface
Improve solubility and receptor recognition
LDLs “leak” through endothelium
Mechanism under research
Bind to matrix proteoglycans (carbohydrates in the ECM)
Held in place, so are prone to oxidation
Monocytes circulate in blood Are called MACROPHAGES when in tissue
Normally have receptors to detect pathogenic antigens SCAVENGER RECEPTORS A and B
These “accidently” fit to Oxidised LDL ligands
Macrophages naturally residing in tissue take in oxidised LDL via PHAGOCYTOSIS
Macrophages that have taken up significant LDLs are called FOAM CELLS
Macrophages have enzymes that further oxidise the LDLs
NADPH Oxidase
Myeloperoxide
Internal accumulation of highly oxidised LDLs triggers upregulations of NUCLEAR FACTOR KAPPA B (NFkB)
A transcription factor, called the “master regulator” of INFLAMMATION
NFkB activates genes that code for CYTOKINES and CHEMOKINES
CYTOKINES that activate strengthen endothelium adhesion to monocytes
Interleukin-1 : Upregulates production of VCAM-1
VCAM-1 : Mediates tight monocyte binding
CHEMOKINES that drawn in monocytes via chemotaxis
Monocyte chemotactic protein-1 (MCP-1) : Binds to CCR2 receptors (G-protein) of the monocytes
Monocytes are brought into atheroma and become foam cells
Leads to POSITIVE FEEDBACK LOOP of atheroma proliferation
What are the types of lesions?
Type II lesion
- > Type III (preatheroma)
- > Type IV (atheroma)
- > Type V (fibroatheroma)
- > Type VI (complicated lesion)
Type I: Tunica Media Hypertrophy and Isolated Foam Cells Type II: Foam Cell Layers Type III: Extracellular lipid Type IV: Lipid Core Type V: Fibrosis Type VI: Complications
What are the main cell types and their roles?
- Vascular endothelial cells
- Barrier function e.g. to lipoproteins
- Leukocyte recruitment - Platelets
- Thrombus generation
- Cytokine and growth factor release - Monocyte-macrophages
- Foam cell formation
- Cytokine and growth factor release
- A major source of free radicals
- Metalloproteinases (degrade thickened areas and promote plaque rupture) - VSMCs
- Migration and proliferation
- Collagen synthesis
- Remodeling and fibrous cap formation - T-lymphocytes
- Macrophage activation
what are the 2 systems responsible for homeostasis?
- Clotting cascade
2. Platelet aggregation
What are macrophages derived from?
- In atherosclerosis, the main inflammatory cells are macrophages, which are derived from blood monocytes
what do macrophages produce?
-Macrophages secrete cytokines and growth factors which are a key source of free radicals which the immune system makes as part of the natural immune function to kill microbes.
what happens inside vascular smooth muscle cells in an abnormal artery
In an abnormal artery with an atherosclerotic plaque, can synthesise and secrete collagen which contributes to the stabilisation of the plaque and the fibrous cap.
How are T cells involved in macrophages recruitment
T cells: the feedback of macrophages activated T cell and the activated T cells, in turn, activate macrophages.
what are the main inflammatory cells in atherosclerosis?
Macrophage subtypes are regulated by combinations of transcription factors binding to regulatory sequences on DNA
- Inflammatory: adapted to kill microorganisms
- Resident : normally homeostatic (suppress inflammatory activity)
- e.g alveolar resident macrophages (surfactant lipid homeostasis), osteoclasts (calcium and phosphate homeostasis), spleen (iron homeostasis)
