Pathogenesis of Atherosclerosis - PowerPoint PPT Presentation

pathogenesis of atherosclerosis n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Pathogenesis of Atherosclerosis PowerPoint Presentation
Download Presentation
Pathogenesis of Atherosclerosis

play fullscreen
1 / 63
Pathogenesis of Atherosclerosis
211 Views
Download Presentation
becka
Download Presentation

Pathogenesis of Atherosclerosis

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. Pathogenesis of Atherosclerosis Judith Berliner, Ph.D. Departments of Pathology and Medicine Division of Cardiology David Geffen School of Medicine at UCLA

  2. Fatty Streak

  3. Early Fibrous Plaque

  4. Advanced Plaque

  5. Thrombus

  6. Ages of Progression Fatty Streak – 0-30 Fibrous Plaque – 30-50 Complicated Plaque – 40+ Thrombosis – 50+

  7. Susceptible Sites (SS)

  8. Coronary Distribution of lesions

  9. Lipid Accumulation at Branches

  10. Flow Patterns

  11. Less Susceptible

  12. More Susceptible

  13. Nitric Oxide Function (anti-inflammatory) • Causes smooth muscle cell relaxation (vasodilation) • Suppresses SMC proliferation and matrix synthesis • Reduces the expression of inflammatory genes • Inhibits platelet aggregation

  14. E-NOS Low in More Susceptible Areas

  15. Antioxidant NrF2 is Activated in Non-Susceptible Areas

  16. Inflammatory Molecules are Increased in Susceptible Areas

  17. Early Fatty Streak

  18. Lipids Rapidly Accumulate

  19. Fatty Streak Formation

  20. Fatty Streak • Retention of LDL • Entry of monocytes • Foam cell formation

  21. Fatty Streaks Form in the Fetus of Hypercholesterolemic Mothers

  22. Localization of Macrophages in Fibrous Plaques Human coronary artery lesionImmunoperoxidase with Mab to macrophages (HAM-56)

  23. Endothelial Morphology

  24. Alterations in Endothelial Cells and Monocytes in Fatty Streak Lesions • Endothelial cells display increased adhesion molecules and chemotactic factors. VCAM-1, MCP-1, IL-8. • In fat feeding there is an increase in the number of monocytes in the blood and a change in the ratio of subtypes. • 3. Monocytes become more adhesive for • endothelium.Only specific monocyte subtypes • enter the vessel wall: GR1/ly6C hi

  25. Effects of Leukocyte Trafficking Genes on Atherosclerosis In Knockout Mouse Models Defect Response M-CSF less MCP-1, CCR2 less P, E selectin less VCAM-1 less

  26. Macrophage Foam Cells

  27. Foam Cell Formation Normal LDL does not cause foam cell formation Aggregated LDL-taken up by the LDL receptor Oxidized LDL-taken up by scavenger receptors CD 36, SRA-1, LOX-1 Sphingomyelinase modified LDL-taken up by scavenger receptors Foam cell formation is inhibited by HDL Foam cells accumulate near the EC

  28. Gene CD36 SRA-1 LOX-1 Apo A1 ABC-A1 Effect Less Less Less More More Effect of genes related to foam cell formation on fatty streak formation

  29. Atheroma / Fibrous Plaque

  30. Fibrous Plaque • Cytokines produced by macrophages lead to SMC migration and proliferation • SMC proteases digest elastic lamina to aid migration of SMC into the intima • SMC synthesize collagen and specific proteoglycans • SMC take up lipid forming foam cells • SMC and monocytes die by apoptosis or necrosis liberating cell contents. • Lymphocytes enter the lesion.

  31. Smooth muscle cells migrate into the intima

  32. Effect of genes related to SMC migration, proliferation, matrix synthesis and death of foam cells on plaque formation Gene PDGF IL-1beta FGF Effect on atherogenesis Less Less Less

  33. Formation of the Necrotic Core

  34. Role of Lymphocytes in Atherosclerosis • T cells, mainly of Th-1 subtype,enter the vessel. They produce high levels of gamma interferon.Knockout of gamma in mice decrease atherosclerosis. • 2.B1b cells are increased. B1b are innate • immune cells that make antibodies to oxidized • lipids which also react with bacteria. They may • serve a protective function.

  35. Complex plaque

  36. Characteristics of the complex plaque • Accelerated cell death and growth of necrotic core • Angiogenesis • Formation of small thrombi on lumenal surface • Hemorrhage from newly formed vessels • Incorporation of thrombi and clots into vessel wall

  37. Vasa Vasorum

  38. Angiostatin Decreases Lesions

  39. Small Thrombi

  40. Cell Death in the Intima

  41. Genes associated with formation of the complex plaque • VEGF, angiogenesis • Regulators of thrombosis • Regulators of thrombolysis • Regulators of apoptosis