PHRD5015 Lecture 13 - Atherosclerosis

  1. pathological process that underlies several important disease states including cerebrovascular disease (stroke) and coronary artery disease (CAD)
  2. involves thickening and hardening of large & medium sized arteries
  3. lesion formed by lipid-rich macrophages lining the walls of the artery
  4. 4 changes lesions undergo
    • 1) endothelial injury
    • 2) fatty streak
    • 3) fibrotic plaque
    • 4) complicated lesion
  5. causes for endothelial injury
    • smoking
    • inactivity
    • obesity
    • hypertension
    • diabetes
    • elevated LDL
    • reduced HDL
  6. what occurs during endothelial injury
    platelets arrive -> monocytes follow -> monocytes differentiate into macrophages
  7. 2 cells involved during endothelial injury
    • platelets
    • macrophages
  8. macrophages that have absorbed oxidized LDL
    foam cells
  9. lesions with foam cells are extremely common - true/false?
  10. composed of lesions containing foam cells producing ROS and continue to promote damage and sustain an inflammatory response with fibroblasts moving inward
    fatty streak
  11. formed when fibroblasts migrate over a fatty streak and combine with collagen produced by proliferating smooth muscle cells
    fibrous plaque
  12. atheroma
    • atherosclerotic lesions 
    • asymmetric thickenings of the intima (innermost layer of the artery)
  13. distinct regions in which atheroma occur
  14. components of an atheroma
    • 1) center core consisting of lipid droplets & foam cells
    • 2) cap of smooth muscle cells
    • 3) ECM enriched in collagen fibers
  15. point of growth in the atheroma where inflammatory & immune cells infiltrate and are most abundant
  16. ruptured plaques
    complicated plaques
  17. formed once a plaque ruptures leading to platelet aggregation and initiation of the clotting cascade
  18. 2 major causes of coronary thrombosis
    • 1) plaque rupture
    • 2) endothelial erosion
  19. condition in which ruptures preferentially occur
    when the cap is thin and partially destroyed
  20. factors secreted by activated inflammatory cells at sites of plaque rupture
    matrix metalloproteinases
  21. break down ECM and weakens plaque cap
    matrix metalloproteinases
  22. 2 causes of endothelial erosion by macrophages
    • 1) induce endothelial cells to undergo apoptosis
    • 2) secrete proteases which cut the endothelial cell free from its basement membrane moorings
  23. protein found on chylomicrons & IDLs, but not LDLs
  24. protein that binds to liver cells and is essential for the uptake and catabolism of fats & cholesterol
  25. phenotype of ApoE-/- mouse
    develops spontaneous atherosclerosis
  26. phenotype of LDLR-/- mouse
    developed hypercholesteremia/massive degree of atherosclerotic plaques when fed high fat diet
  27. endothelial damage is associated with _____.
    oxidized LDL
  28. what LDL is primarily comprised of
  29. where LDL in body comes from
  30. increases both with the eating of high fat meals and with the degree of obesity of the individual
  31. cells that can oxidize lipids while using up anti-oxidant defenses
    activated neutrophils
  32. type of LDL taken up by LDLR
  33. response by VECs to MM-LDL
    secrete MCP-1 to attract monocytes
  34. oxLDL receptor
  35. phenotype of ApoE-/- CD36-/- cross
    do not develop atherosclerosis
  36. components of oxLDL that bind CD36
    • oxPCCD36
    • phosphatidyl choline derivative
  37. first cells to arrive at the site of endothelial activation
  38. important even in disease pathogenesis
    adhesion of platelets
  39. predictor of a future cardiac event in human patients with cardiovascular disease
    platelet reactivity (spontaneous aggregation)
  40. 3 steps platelets undergo during the clotting process
    • 1) adhesion
    • 2) activation
    • 3) aggregation
  41. 3 agonists platelet activation can be mediated by
    • 1) TXA2
    • 2) serotonin
    • 3) ADP
  42. change in platelets when they are activated
    become spiky to create greater surface area to aggregate
  43. how platelets are activated
    activated platelets release agonist mediators
  44. component of serum that promotes platelet activation
    oxPCCD36 of oxLDL
  45. the ability of platelets to aggregate and bind fibrinogen
    platelet activation
  46. factor that can induce platelets to activate
    platelet agonist
  47. CD36-/- people were (more/less) likely to develop atherosclerosis
    • more
    • -> unlike mouse data
  48. M-CSF
    • macrophage colony stimulating factor
    • promotes differentiation of monocytes into macrophages
  49. macrophages upregulate ____
  50. can activate TLR
  51. activated macrophages upregulate this process, resulting in large amounts of LDL entering the cell
  52. receptors (other than CD36) that can take up oxLDL
    scavenger receptors
  53. response by macrophages when large amounts of cholesterol are taken in
    efflux by ABC transporters
  54. MMP
    • matrix metalloproteinases
    • secreted by highly activated macrophage-derived foam cells
  55. source of necrotic core found in atherosclerotic plaques
    foam cells undergoing necrosis
  56. 2 factors leading to propensity to generate oxLDL
    • 1) over-nutrition
    • 2) genetics
Card Set
PHRD5015 Lecture 13 - Atherosclerosis