Atherogenesis Flashcards
Atherogenic Plaques
Composed of 3 principle components:
Cells (smooth muscle cells, macrophages (foam cells), T cells)
Matrix components (collaged, proteoglycans, elastic fibres)
Intracellular extracellular lipid (cholesterol and cholesterol esters)
Role of endothelium
Normal endothelium has anti-coagulant and anti-adhesive properties, and production of NO controls vasorelaxation.
Early dysfunction/damage is functional rather than structural - loss or cell repellent quality, allows inflammatory cells into vascular wall, increased permeability to lipoproteins.
Structural damage is caused by processes above and is observed later in atherogenic process
Role of Monocytes
Attracted to developing plaques by MCP-1/CCL2
Transform into macrophages under influence of cytokines (INF-gamma, TNF-alpha, GM-CSF, M-CSF) secreted by endothelium and vascular smooth muscle cells (VSMC)
Generate reactive oxygen species (ROS) which can oxidise DLD in intima
Produce pro-inflammatory cytokines
Express scavenger receptors
Lipid involvement
Smaller lipoproteins (remnants and LDL) enter vascular wall more easily than other articles -> more atherogenic Entry of lipoproteins into the vascular wall occurs more easily when present in higher concentrations in the blood Lipoproteins in the vascular wall can be oxidised in the intima (by oxidases and ROS from macrophages and ROS from VSCMs)
Oxidised LDL
Stimulates expression of VCAM-1 and MCP-1; directs monocytes of lesions
Oxidised B-100 binds to scavenger receptors on macrophages is phagocytosed
No feedback regulation via cholesterol concentration
Generation of foam cells (visible in arterial walls as fatty streaks)
Oxidised LDL not recognised by LDL receptor, but by scavenger receptors
Recpetors controlling cholesterol export are down regulated
Accumulation of lipid in the form of cholesterol esters in cytosol
Migration of VSMC
VSCMs are responsible for structure of the vessel wall
Endothelial cells and macrophages secrete PDGF and TGF-beta –> effect on VSMCs: proliferation and migration into the intima
VSMCs can differentiate into macrophage-like cells and become foam cels
Activated VSCMs also synthesise ECM (collagen in particular) which deposits in the plaque
Stable vs Ruptured Plaque
Stable Plaque: thick fibrous cap/high collagen content, high VSMC content, small lipid pool, few inflammatory cells
Ruptured plaque: thin fibrous cap/low collagen content, low VSMC content, large lipid pool, many inflammatory cells
What causes atherogenesis - 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 causes atherogenesis - Response to injury hypothesis
Endothelial injury/dysfunction Accumulation of lipoprotein in vessel wall Monocyte adhesion Platelet adhesion Smooth muscle proliferation Lipid accumulation - plaques
Atheroma
Endothelial injury due to: raised LDL, toxins, hypertension, haemodynamic stress
Endothelial injury causes: 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
Stimulation VSMC produce matrix material
Foam cells secrete cytokines causing: further VSMC stimulation, recruitment of other inflammatory cells
Treatments to decrease plasma lipids
Statins: competitive inhibitors of HMG-CoA reductase; they are bulky and get stuck in active site; 2 classes - natural (lovastatin, compactin, pravastatin, simvastin) and synthetic (atorvastatin, fluvastatin); inhibit cholesterol synthesis (increased LDLR, HMG-CoA and PCSK9 expression)
Anti-PCSK9 antibodies: block binding of PCSK to LDLR reducing LDLR degradation; increased LDLR recycling in membrane and greater uptake of LDL from plasma
