T1 L19: Atherogenesis

• What is the mechanism of vasorelaxation by nitric oxide?

  production of NO:

  • generate anti-adhesive environment → inhibits recruitment of monocytes & platelets
  • smooth muscle cell relaxation of tunica media
• What is the role of the endothelium in atherogenesis?

  Early dysfunction/damage of the endothelium is functional rather than structural:

  • Loss of cell-repellent quality
  • Allows inflammatory cells (mainly monocytes) into vascular wall
  • Increased permeability to lipoproteins

  Structural damage is then caused by these processes and observed later
• What is 'endothelial dysfunction'?

  decreased synthesis, release and/or activity of endothelium-derived nitric oxide (NO)
• What are are the properties of normal endothelium?

  anti-coagulant

  anti-adhesive
• What is the progression of atherogenesis?

  normal → fatty streak → fibrous plaque → occlusive atherosclerotic plaque → plaque rupture

  
• Where in the artery do plaques develop and what are they caused by?

  tunica intima of the artery wall

  Caused by migration of cells from the tunica media

  Also caused by recruitment of leucocytes and deposition of lipid from the blood

  
• What are the 3 principle components of Atherogenic plaques?

  1. Cells (smooth muscle cells, macrophages (foam cells), T cells)
  2. Matrix components (collagen, proteoglycans, elastic fibres)
  3. Intracellular and extracellular lipid (cholesterol and cholesterol esters)

  
• What kind of lipoproteins are more atherogenic?

  smaller lipoproteins (remnants of LDL)

  as they enter vascular wall more easily than other particles
• When does entry of lipoproteins into vascular wall occur more easily?

  when lipoproteins present in high concentrations in blood
• What happens to the lipoproteins that got into vascular wall at the intima?

  oxidised

  by oxidases & ROS from macrophages

  ROS from VSMCs (vascular smooth muscle cells)
• How does oxidised LDL direct monocytes to sites of lesions?

  stimulate expression of:

  • VCAM-1 (adhesion molecule in activated endothelium - allows binding of monocytes)
  • MCP-1 (monocyte chemokine - allows chemotaxis to lesion)
• What exact part of LDL gets oxidised in the intima?

  B-100 apoprotein
• How are foam cells generated?

  oxidised B-100 protein on LDL → bind SCAVENGER receptors on macrophages instead of LDL receptors → phagocytosis → no feedback regulation in cholesterol conc. → cells keep phagocytosing → macrophages become full of cholesterol
• What is the role of monocytes in atherogenesis?

  monocytes → attracted to sites of endothelial dysfunction by MCP-1 / CCL2 → cytokines (from endothelium + VSMCs) → transform into macrophages:

  • generate ROS to oxidise LDLs
  • express scavenger receptors (to phagocytose oxidised LDLs)
  • produce pro-inflammatory cytokines
• What are the properties of foam cells?

  • scavenger receptors: to recognise oxidised LDL
  • Receptors controlling cholesterol export downregulated
  • accumulation of lipid as cholesterol esters in cytosol

  
• What is the role of VSMCs on atherogenesis?

  endothelial cells & macrophages → secrete PDGF (platelet derived growth factor) and TGF-beta (transforming growth factor) → activate VSMCs:

  • proliferate → migrate media → intima
  • synthesise extracellular matrix (esp collagen) → deposit in plaque

  → disrupt structure of arterial walls
• What are the two main factors that are involved in atherogenesis?

  monocytes

  VSMCs
• What is Familial hypercholesterolaemia (FH)?

  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

  
• What are the 2 major theories regarding what causes atherogenesis?

  1. Lipid oxidation hypothesis
  2. Response to injury hypothesis
• What is the 'lipid oxidation hypothesis' regarding cause of atherogenesis?

  LDL enters vascular wall + becomes oxidised → Oxidised LDL phagocytosed by macrophages → generation of foam cells → recruitment of macrophages → generation of plaques
• What is the 'response to injury' hypothesis regarding cause of atherogenesis?

  endothelial injury / dysfunction → accumulation of lipoproteins in vessel wall → monocyte adhesion → platelet adhesion → smooth muscle proliferation → lipid accumulation → plaques
• What 3 areas of pathogenesis does atherogenesis involve?

  1. endothelial cell dysfunction
  2. inflammation (mediated by monocytes/macrophages
  3. dysregulation of lipid metabolism
• What are the 2 types of atherosclerotic plaques?

  stable

  unstable
• What are the characteristics of a stable plaque?

  • HIGH VSMC content
  • thick fibrous cap / high collagen content
  • small lipid pool
  • few inflammatory cells

  
• What are the characteristics of an unstable / ruptured plaque?

  • LOW VSMC content
  • thin fibrous cap / low collagen content
  • large lipid pool
  • many inflammatory cells
  • necrotic core and thrombus

  
• What kind of plaque is this image?

  stable plaque

  
• What kind of plaque is this image?

  Ruptured plaque and thrombus

  
• How do we prevent atherogenesis?

  • Protection of artery walls: stop smoking, lower blood pressure
  • Reduce plasma lipid levels
  • Reduce ROS and inflammation
• How do we treat atherogenesis?

  by decreasing plasma lipids:

  • statins
  • Anti-PCSK9 (regulates LDL receptors) antibodies
• How do statins work?

  competitive inhibitors of HMG-CoA reductase

  bulky and literally get “stuck” in the active site

  This prevents the enzyme from binding with its substrate, HMG-CoA

  
• What are the two classes of statins?

  • Natural Statins: Lovastatin (mevacor), Compactin, Pravastatin (pravachol), Simvastatin (Zocor)(Lescol)
  • Synthetic Statins: Atorvastatin (Lipitor), Fluvastatin
• How do statins inhibit cholesterol synthesis?

  SREBP-2 activated in response to low cholesterol

  1. HMG-CoA expression increased, but no activity in presence of statin
  2. Increased LDLR expression – uptake of LDL from plasma increased
  3. Increased PCSK9 expression - degradation of LDLR promoted

  
• What effects does blocking PCSK9 activity have on blood cholesterol?

  • Decreased: Anti-PCSK9 antibodies block binding of PCSK9 to LDLR; reducing LDLR degradation
  • Increased LDLR recycling into membrane & greater uptake of LDL from the plasma