Atherogenesis Flashcards
Describe the development of atherogenic plaques
- develope in the tunica intima
- caused by migration of cells from the tunica intima
- also caused by recruitment of leukocytes from the blood
- from a fatty streak to a fibrous plaque they remain clinically silent
- occurs in the teenage years
What are the 3 components of atherogenic plaques?
Cells
- smooth muscle cells
- macrophages (foam cells), T cells
Matrix components
- collagen
- proteoglycans: (present especially in connective tissue) versican, biglycan, collagen, hyaluronan
- elastic fibres
Intracellular and extracellular lipid
- cholesterol and cholesterol esters
GTP: guanine triphosphate, cGMP cyclic guanine monophosphate
How does NO function in a healthy endothelium?
- Production of NO control vasorelaxation and as anti-adhesive properties
- prevents the aggregation of neutrophils and platelets, preventing recruitement
- Shear stress and agonists such as acetylcholine, adenosine diphosphate, thrombin, bradykinin and 5-hydroxytryptamine increase intracellular calcium
- this activates NO synthase (eNOS) to form NO from L-arginine
- NO then travells to the smooth muscle where it activates cGMP
- when cGMP is activated by GTP it causes vasorelaxation
What is the role of normal endothelium?
- anti-coagulant and anti-adhesion properties
- early dysfunction/ damge of the endothelium is functional rather than structural
Define and explain Endothelial dysfunction
- the decreased synthesis, release and/or activity of endothelium-derived nitric oxide (NO)
- early dysfunction/damage of the endothelium is functional rather than structural
- loss of cell-repellent quality
- allows inflammatory cells into the vascular wall
- increased permeability to lipoproteins
structural damage is brough on later by the process above
What is the role of monocytes?
- Attracted to developing plaques by MCP-1/CCL2
- Transform into macrophages under the influence of cytokines secreted by endothelium and vascular smooth muscle (VSMC)
- Generate Reactive Oxygen Species (ROS) which oxidise LDL in the intima
- they produce pro-inflammatory cytokines
- express scavenger receptors
What is MCP-1 ?
monocyte chemoattractant protein-1
- a potent mononuclear cell chemoattractant
- produced by endothelial and smooth muscle cells
- localizes in humans and experimental atheroma
What cytokines are secreted by the endothelium?
- IFN-γ: Interferon-gamma
- TNF-α: tumour necrosis factor-alpha
- GM-CSF: Granulocyte-macrophage colony-stimulating factor
- M-CSF: macrophage colony-stimulating factor
Explain the lipid involvement in atherogenesis
- smaller lipoproteins (remnants and LDL) enter the vascular wall more easily: hence more atherogenic
- occurs more easily when there is a high concentration in the blood
- lipoproteins in the vascular wall can be oxidised in the intima by oxidases and ROS (i.e peroxides, hydroxyl radicals) from macrophages and ROS from VSMCs
Describe the result of oxidised LDL
- they stimulate the expression of VCAM-1 and MCP-2: which direct macrophages to the site of the lesion
- Oxidised B-100(the apolipoprotein) then binds to scavenger receptors on the macrophages and is then phagocytosed
- there is no feedback regulation with regards to the cholesterol conc. as scavenger receptors ar not subject to the type of regulation that LDL receptors are
- foam cells are then generated, which are visible in arterial walls as fatty streaks
Describe how macrophages are converted to foam cells
- In normal conditions, cholesterol homeostasis is tightly controlled.
- In atherosclerosis, this control is deregulated.
- increased expression of scavenger receptors, which leads to elevated uptake of oxLDL.
- the expression of cholesterol transporters ABCA1 and ABCG1 is suppressed, which diminishes cholesterol efflux and promotes cholesterol deposition in macrophages
- ACAT1 is upregulated while NCEH is downregulated
- This leads to accumulation of cholesteryl esters (i.e. the storage form of cholesterol) in the cell.
- these mechanisms lead to excessive lipid deposits and transformation of macrophages to foam cells.
Describe the process in this diagram, and name the enzymes and proteins
- SR-A1: scavenger receptor A1
- LOX-1: lectin-like oxidized low-density lipoprotein (LDL) receptor-1
- ACAT1: acyl coenzyme A: cholesterol acyltransferase-1
- NCEH: Neutral cholesteryl ester hydrolase
- ABCA1 & ABCG1: ATP-binding cassette (ABC) transporters
- ApoA1: - Apolipoprotein A-1
- HDL: High density lipoprotein
What are VSMC? And explain their migration into the intima
Vascular Smooth Muscle Cells: responsible for the structure of the cell wall
- PDGF and TGF-ß secreted by endothelial cells and macrophages effect VSMCs
- cause proliferation and migration into the intima
- they also synthesise extracellular matrix (ECM), especially collagen, which deposits in the plaque
- VSMCs are very plastic cells therfore they can can differentiate into macrophage-like cells and become foam cells
Migrating cells and deposits of the EXM material all disrupt the structure of the arterial wall
Use this diagram to give a summary of atherogenesis
- Endothelial dysfunction/injury and/or entry of LDL into intima of artery where is it oxidised by ROS
- Damaged endothelium causes monocytes to adhere and enter the artery wall
- Monocytes differentiate into macrophages and phagocytose oxidised LDL via scavenger receptors to become foam cells
- Foam cells produce a range of inflammatory molecules and growth factors for VSMCs causing them to migrate to the intima of the vessel wall. These inflammatory molecules sustain the inflammatory response and recruit more monocytes and damage the endothelium further.
- Foam cells and VSMCs build up in the intima, producing collagen all of which disrupt the structure of the vessel wall
What is the difference between a stable and a vulnerable plaque?
