Theme 3: Lecture 16 - Atherogenesis Flashcards
Describe the progression of atherogenesis
- Normal vessel to
- Fatty streak to
- Fibrous plaque to
- Occlusive atherosclerotic plaque to
- Plaque rupture
Where in the artery do plaques develop
tunica intima of the artery wall
What is the development of plaques caused by
- Caused by migration of cells from the tunica media
- By recruitment of leucocytes and deposition of lipid from the blood
What are the 3 principle components of atherogenic plaques
- Cells (smooth muscle cells, macrophages (foam cells), T cells)
- Matrix components (collagen, proteoglycans, elastic fibres)
- Intracellular and extracellular lipid (cholesterol and cholesterol esters)
What does nitric oxide do in a healthy endothelium
controls vasorelaxation, has anti-adhesive and anti-coagulant properties
What does early damage to the endothelium cause
- Loss of cell repellent quality
- Allows inflammatory cells to enter vascular wall
- Increased permeability to lipoproteins
Is early endothelial damage structural or functional
Functional
When does structural damage to the endothelium occur
Later in the atherogenic process
How are monocytes attracted to developing plaques
By MCP-1 (monocyte chemoattractant protein 1) AKA CCL2.
How do monocytes transform into macrophages in the tissues
Transform into macrophages under influence of cytokines (IFN-γ, TNF-α, GM-CSF, M-CSF) secreted by endothelium and vascular smooth muscle cells (VSMC)
What do the macrophages do
- Generate Reactive Oxygen Species (ROS) which can oxidise LDL in intima
- Produce pro-inflammatory cytokines
- Express scavenger receptors (a PRR)
Describe the lipid involvement in atherogenesis
- 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
How can lipids in the vascular wall be oxidised
by oxidases & ROS from macrophages and ROS from VSMCs
Describe how oxidised LDL leads to the generation of fatty streaks in the arterial wall
- 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)
Describe how macrophages transform into foam cells
- 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
Why are foam cells bad in atherogenesis
They secrete pro-inflammatory cytokines and ROS, this is the last thing you want as it will further drive the atherogenic process
What is responsible for the structure of the vessel wall
Vascular smooth muscle cells
Describe how VSMCs disrupt the structure of the arterial wall in atherogenesis
- 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
What are the 2 types of atherosclerotic plaque
Stable and vulnerable
Describe a stable plaque
- Thick fibrous cap/high collagen content
- High VSMC content
- Small lipid pool
- Few inflammatory cells
Describe an unstable plaque
- Thin fibrous cap/low collagen content
- Low VSMC content
- Large lipid pool
- Many inflammatory cells
What are the 2 major theories for causes of atherogenesis
- Lipid oxidation hypothesis
- Response to injury hypothesis
Describe the response to injury hypothesis
- Endothelial injury/dysfunction
- Accumulation of lipoprotein in vessel wall
- Monocyte adhesion
- Platelet adhesion
- Smooth muscle proliferation
- Lipid accumulation - Plaques
Describe the lipid oxidation hypothesis
- LDL enters vascular wall and becomes oxidised
- Oxidised LDL phagocytosed by macrophages
- Generation of foam cells
- Recruitment of macrophages
- Generation of plaques
What is familial hypercholesterolaemia
- 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
What causes endothelial injury
- raised LDL
- ‘toxins’ e.g. cigarette smoke
- hypertension
- haemodynamic stress
What does endothelial injury cause
- 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
What does foam cells secreting cytokines cause
- further VSMC stimulation
- recruitment of other inflammatory cells
How can you prevent atherogenesis
- Protection of artery walls (stop smoking, lower blood pressure)
- Reduce plasma lipid levels
- Reduce ROS and inflammation
What are the treatments to decrease plasma lipid levels
- Statins
- Anti-PCSK9 antibodies
Describe how statins decrease plasma lipid levels
- 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
What are the 2 classes of statins
Natural and synthetic statins
Name a statin
Simvastatin
How do anti-PCSK9 antibodies decrease plasma lipid levels
- Anti-PCSK9 antibodies block binding of PCSK9 to LDLR reducing LDLR degradation
- Increased LDLR recycling into membrane & greater uptake of LDL from the plasma
What is activated in response to low cholesterol
SREBP-2 (intracellular sensor)
How do statins lower blood cholesterol level via SREBP-2
- 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
