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Atherosclerosis

Atherosclerosis. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis:. Intrinsic Vascular Wall Cells: Endothelium Smooth Muscle Cells Inflammatory Cells: Macrophages T Lymphocytes Mast Cells. Cell Types in the Human Atheroma.

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Atherosclerosis

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  1. Atherosclerosis

  2. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall Cells: • Endothelium • Smooth Muscle Cells Inflammatory Cells: • Macrophages • T Lymphocytes • Mast Cells

  3. Cell Types in the Human Atheroma Monocyte/Macrophage Endothelium Intima TunicaMedia T-lymphocytes Smooth musclecells

  4. Schematic Time Course of Human Atherogenesis Ischemic HeartDisease CerebrovascularDisease Peripheral VascularDisease Lesion initiation No symptoms + Symptoms Symptoms Time (y)

  5. Macrophage Functions in Atherogenesis Attachment

  6. Leukocyte–Endothelial Adhesion Molecules Mono T PMN B

  7. Vascular Cell Adhesion Molecule 1(VCAM-1) • Binds monocytes and lymphocytes- Cells found in atheroma • Expressed by endothelium over nascent fatty streaks • Expressed by microvessels of the mature atheroma

  8. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium Li H et al. Arterioscler Thromb 1993;13:197-204.

  9. VCAM-1 Expression in Rabbit Aorta 3 weeks on atherogenic diet Li H et al. Arterioscler Thromb 1993;13:197-204.

  10. Macrophage Functions in Atherogenesis Penetration

  11. Monocyte Chemoattractant Protein 1(MCP-1) • A potent mononuclear cell chemoattractant • Produced by endothelial and smooth muscle cells • Localizes in human and experimental atheroma

  12. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low-density lipoprotein receptor–deficient mice Gu L et al. Mol Cell 1998;2:275-281.

  13. Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic Mice LDL-R –/–MCP-1 +/+ LDL-R –/–MCP-1 –/– Gu L et al. Mol Cell 1998;2:275-281.

  14. Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic Mice Oil Red Staining % Aortic Surface Stained ** * +/+ -/- +/+ -/- Time on Diet: 12 – 14 weeks 20 – 25 weeks *P = 0.001 compared to +/+**p = 0.005 compared to +/+ Gu L et al. Mol Cell 1998;2:275-281.

  15. Macrophage Functions in Atherogenesis Activation

  16. Macrophage Functions in Atherogenesis Division

  17. Macrophage Colony-Stimulating Factor (M-CSF) • A potent monocyte activator and co-mitogen • Produced by endothelial and smooth muscle cells • Localizes in human and experimental atheroma

  18. Augmented M-CSF gene expression in human and experimental atherogenesis Rosenfeld ME et al. Am J Pathol 1992;140:291-300. Clinton SK et al. Am J Pathol 1992;140:301-316.

  19. M-CSF Expression in Atheroma IntimalM-CSFinAtheroma

  20. M-CSF Promotes Atherogenesis Smith JD et al. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A 1995;92:8264-8268. Qiao JH et al. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol 1997;150:1687-1699. Rajavashisth T et al. Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor–deficient mice. J Clin Invest 1998;101:2702-2710.

  21. M-CSF Deficiency (op mutation) Reduces Atheroma in LDL Receptor–Knockout Mice +/+ op/+ op/op Rajavashisth T et al. J Clin Invest 1998;101:2702-2710.

  22. (12) (10) (4) * * M-CSF Gene Dosage Relates to Atheroma Size in LDLR –/– Mice 107 106 Fatty Lesions in Aortic Root(m2/section) 105 104 103 +/+ op/+ op/op Genotype Rajavashisth T et al. J Clin Invest 1998;101:2702-2710.

  23. Molecular Mediators of Atherogenesis VCAM-1 MCP-1 M-CSF

  24. Anatomy of the Atherosclerotic Plaque Fibrous cap Lumen Shoulder Lipid Core Intima Internal Elastic laminæ Media External

  25. Schematic Time Course of Human Atherogenesis Ischemic HeartDisease CerebrovascularDisease Peripheral VascularDisease Transition from chronic to acute atheroma

  26. Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Syndromes, Results from: • Weakening of the fibrous cap • Thrombogenicity of the lipid core Illustration courtesy of Michael J. Davies, M.D.

  27. Matrix Metabolism and Integrity of the Plaque’s Fibrous Cap Synthesis Breakdown Fibrouscap Collagen-degrading Proteinases IFN- – CD-40L + + IL-1TNF-MCP-1M-CSF + + + + Tissue Factor Procoagulant Lipid core Libby P. Circulation 1995;91:2844-2850.

  28. Increased Expression of Interstitial Collagenase (CL) by Smooth Muscle Cells (SMC) and Macrophages (M) in Human Atheroma Galis ZS et al. J Clin Invest 1994;94:2493-2503.

  29. Plaque Rupture with Thrombosis Fibrous cap Thrombus 1 mm Lipid core Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.

  30. Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Syndromes, Results from: • Weakening of the fibrous cap • Thrombogenicity of the lipid core Illustration courtesy of Michael J. Davies, M.D.

  31. CD40 and Tissue Factor in Atheroma CD40 Tissue Factor Mach F et al. Circulation 1997;96:396-399.

  32. CD40 Ligation Induces Tissue Factor Expression in Human Monocyte-Derived Macrophages 160 120 80 40 0 160 120 80 40 0 T cell/membranes/-CD40L rCD40L/-CD40L T cell/membranes rCD40L Cell Numbers 100 101 102 103 100 101 102 103 Log Fluorescence Mach F et al. Circulation 1997;96:396-399.

  33. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells Henn V et al. Nature 1998;391:591-594.

  34. Fibrin Platelet Platelet Inflammation Can Promote Thrombosis Fibrinogen Via gp llb/llla TissueFactor Platelet-FibrinThrombus CD40L Fibrinopeptides

  35. Inflammation Participates in All Phases of Atherothrombotic Disease • Lesion initiation • Lesion progression • Thrombotic complications

  36. Thanks

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