Atheroscelerosis and Peripheral Vascular disease Tutorial 2 Flashcards
What do activated macrophages within plaques do?
- Generate free radicals that further oxidise lipoproteins
2. Phagocytose modified lipoproteins and become foam cells
What type of enzymes do macrophages have?
oxidative enzymes that can modify native LDL
What are two examples of these enzymes?
- NADPH Oxidase, for examples superoxide O2-
2. Myeloperoxidase, for example HOCl hypochlorus acid (bleach) from ROS + Cl-, HONOO peroxynitrite
What do macrophages accumulate?
modified lipoproteins and become foam cells
What do activated macrophages within plaques express?
3a. Express cytokine mediators that recruit monocytes
3b. Express chemo-attractants and growth factors for VSMC
3c. Express proteinases that degrade tissue
What do plaque macrophages express?
inflammatory factors that are involved in monocyte recruitment
What are cytokines?
protein immune hormones that activate endothelial cell adhesion molecules
What are chemokines?
small proteins chemoattractant to monocytes
What doe IL-1 do? (cytokine)
upregulates vascular cell adhesion molecule 1 VCAM-1
What does VCAM-1 do? (cytokine)
mediates tight monocyte binding
What does MCP-1 do? (chemokine)
Monocyte chemotactic protein-1 binds to a monocyte G-protein coupled receptor CCR2
When is there reduced atherosclerosis?
- reduced in mice without IL-1 or VCAM-1
- reduced in MCP-1 or CCR2 deficient mice
What type of loop is expressed cytokine mediators that recruit monocytes?
- positive feedback loop / vicious cycle leading to self-perpetuating inflammation
- Macrophages make these and activated by LDL and then recruit more macrophages
What is the would healing role of macrophage in atherosclerosis?
- Macrophages release complementary protein growth factors that recruit VSMC and stimulate them to proliferate and deposit extracellular matrix
- Platelet derived growth factor and transforming growth factor beta
What is platelet derived growth factor for vascular smooth muscle?
- Vascular smooth muscle cell chemotaxis
- Vascular smooth muscle cell survival
- Vascular smooth muscle cell division (mitosis)
What is transforming growth factor beta for vascular smooth muscle?
- Increased collagen synthesis
2. Matrix deposition
What happens in normal medial?
- Increased contractile filaments
- Decreased matrix deposition genes
- Contractile
What happens when contractile has PDGF + TGF-b?
- Atherosclerotic
1. Decreased contractile filaments
2. Increased matrix deposition genes - Synthetic
What are metalloproteinases (MMPS) secreted by macrophages?
- Family of around 28 homologous enzymes
- Activate each other by proteolysis
- Degrade collagen
- Catalytic mechanism based on Zn
What is the effect of plaque erosion/rupture?
Blood coagulation at the site of rupture may lead to an occlusive thrombus and cessation of blood flow.
What are the characteristics of vulnerable and stable plaques?
- Large soft eccentric lipid-rich necrotic core
- Increased VSMC apoptosis
- Reduced VSMC and collagen content
- Thin fibrous cap
- Infiltrate of activated macrophages expressing MMPs
What are OxLDL derived metabolites in macrophage apoptosis?
toxic eg 7-keto-cholesterol
What do macrophage foam cells have to protect in macrophage apoptosis?
protective systems that maintain survival in face of toxic lipid loading
When does macrophage apoptosis happen?
Once overwhelmed, macrophages die via apoptosis
What happens in the lipid necrotic core?
Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core
What happens to the thromobgenic and toxic material?
accumulates, walled off, until plaque rupture causes it to meet blood
What is Nuclear Factor kappa B (NFkB)?
transcription factor
What does NFkB do?
master regulator of inflammation
How is NFkB activated?
-by numerous inflammatory stimuli
•Scavenger receptors
•Toll-like receptors
•Cytokine receptors e.g. IL-1
What inflammatory genes does NFkB turn on?
- Matrix metalloproteinases
- Inducible nitric oxide synthase
- Interleukin-1
What does NFkB direct?
multiple genes in concert
- Multiple different inflammatory stimuli including IL-1 and cholesterol crystals
- Correlation of multiple different inflammatory genes (also include IL-1)
What is macrophage activation regulated by?
NFkB
What does plaque rupture cause?
myocardial infarction and stroke and is closely related to damage from activated macrophages, particularly activation of collagen degradation
What is a summary of macrophages in atheroscelrosis?
- Lumen with risk factors
- These activate endothelial cells
- These endothelial cells contract which allow LDL in
- Once in artery wall LDL binds to matrix and oxidises to form OxLDL
- The endothelial cells become sticky and express VCAM-1
- This attaches monocytes which then immigrate into the vessel wall
- The monocytes express scavenger receptors which meets OxLDL and this causes monocytes to take up fat and to differentiate into macrophages
- Continuing to take up more and more fat buy scavenger receptors which activate NFkB which then secrete reactive oxygen specific (ROS) and this causes a positive feedback loop as it oxidises LDL to OxLDL
- Macrophage also secretes cytokines which further activates endothelial cells (second vicious scale)
- Trigger macrophages to secrete chemokine which attracts more monocytes (third vicious cycle)
- Also causes macrophages to secrete MMPS which degrades collagen and this generates weakening of the plaque and eventual degradation of artery wall causing thrombosis
- But in good way (green arrow) macrophage will also secrete growth factors which will trigger smooth muscle sells to divide to make more collagen and monocytes can directly send cholesterol straight out HDL for reverse cholesterol transport
- Eventually macrophage die and release and accumulate tissue factor and toxic oxidised lipids into lipid necrotic core
