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184 toll like receptor 4 and atherosclerosis

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184 toll like receptor 4 and atherosclerosis

  1. 1. Submitted by: Dominique P.V. de Kleijn, PhD Associate Professor Laboratory of Experimental Cardiology, Vascular Biology University Medical Center, Utrecht, The Netherlands Toll-Like Receptor 4 and Atherosclerosis Editorial Slides VP Watch - August 21, 2002 - Volume 2, Issue 33
  2. 2. Toll-like receptor-4 (Tlr-4) Cytokines Chemokines Injury Stress/Necrosis Infection EDA Fibronectin III Hsp 60 Lipopoly- saccharides Tlr-4 NfkB Cell Migration Cell Proliferation + + + + + + + + + + Attraction inflammatory cells Stimulation matrix turn-over Stimulation adhesion molecules
  3. 3. Toll-Like Receptor-4 Polymorhism and Atherogenesis Kiechl et al., N. Eng. J. Med. 2002; 347:185-92 Asp299Gly Tlr-4 polymorphism attenuates receptor signaling Attenuated Tlr-4 receptor signaling is associated with decreased atherosclerosis
  4. 4. What is between Tlr-4 activation and atherosclerosis? Can animal models help us to identify a possible pathway?
  5. 5. Mouse models (I) • Supporting: C3H mouse has a deficient Tlr-4 ApoE KO/C3H mouse gives less atherosclerotic plaque compared to ApoE KO/B6 mouse. (Grimditch et al., 2000) • Not supporting: C57Bl/10ScN has a deletion incl. the Tlr-4 gene ApoE KO/ C57Bl/10ScN and ApoE KO/B6 do not differ in arterial cholesterol levels. Plaque area not measured. (Wright et al., 2000) • Real Tlr-KO mouse models in comparable atherosclerotic backgrounds are necessary to study Tlr-4 function in atherosclerosis
  6. 6. Which cells express Tlr-4? Well known: Bone marrow derived inflammatory cells like: Monocytes/macrophages Lymphocytes
  7. 7. Role of Tlr-4 in bone marrow (BM) derived cells in atherosclerotic mouse models (Shi et al., 2002; Van Eck et al., 2000) Mouse models (I) BM Accep- torBM Donor Tlr-4 deficient C3H Tlr-4 wildtype B6 ApoE KO Tlr4 wt B6 ApoE wt Tlr4 wt B6 Minor Atherosclerosis Minor Atherosclerosis Minor Atherosclerosis Major Atherosclerosis •Pointing to a major role of Tlr-4 in arterial wall cells
  8. 8. Arterial wall cells expressing Tlr-4 Endothelial cells Smooth muscle cells Adventitial fibroblasts Adventitial fibroblasts are relatively unknown
  9. 9. hTLR4 Vimentin Tlr-4 expression in primary human adventitial fibroblasts Vink et al Circulation 2002 in press
  10. 10. Fibroblasts, Tlr-4 activation and plaque/neointima formation • LPS application in adventitia induces plaque formation in hypercholesterolaemic rabbit model (Engelmann et al. 2000 Abstract) • Adventitial fibroblasts play a role in neointima formation (Shi et al., 2000) • LPS application stimulates migration of mouse embryonic fibroblasts in in vitro assay (De Kleijn et al., 2002)
  11. 11. Cuff Femoral artery Mouse Femoral Cuff Model (III) Gelatin ± LPS Right femoral artery
  12. 12. Adventitial LPS Application in Tlr-4 Deficient Balb/C and wt Balb/C Mouse Relative amount of neointima formation with and without LPS application in mouse cuff model Gelatin Gelatin + LPS Balb/C Wildtype Balb/C Tlr-4 deficient 100 % 41 % •Tlr-4 is involved in neointima formation •Atherosclerosis might not be initiated only at the luminal side but also at the advential side. 26 % 14 % Vink et al., Circulation 2002 in press
  13. 13. Cytokines Chemokines Hypothetical adventitial Tlr-4 dependent pathway Injury Stress/Necrosis Infection EDA Fibronectin III Hsp 60 Lipopoly- saccharides Tlr-4 NfkB Adventitial Fibroblast Medial Smooth Muscle Cell Migration Proliferation Neointima Formation Plaque formation Luminal factors e.a. shear stress, lipids + + + + + + + + + + + + + + +?
  14. 14. Neointima formation as the soil for atherosclerosis Adventitial Tlr-4 activation e.a. injury, infection, stress Luminal factors e.a. shear stress, lipids, endothelial dysfunction and activation ? ? Direction of cell migration Most likely: Both luminal and adventitial side are important
  15. 15. Conclusion Preclinical data pointed to a role of Tlr-4 in atherosclerosis Now, also clinical data show that Tlr-4 is associated with atherosclerosis (Kiechl et al., N. Eng. J. Med. 2002; 347:185- 92)
  16. 16. Questions •What is the role of the adventitial endothelial cell? •Does adventitial Tlr-4 activation affects the luminal endothelial cell? •Is plaque matrix turn-over affected by Tlr-4 activation? •Is plaque inflammation affected by Tlr-4 activation? •Are their Tlr-4 antagonists? •Can we use Tlr-4 as a (local) target of intervention? •Should we target the adventitial layer?
  17. 17. References de Kleijn DP, Smeets MB, Kemmeren PP, Lim SK, Van Middelaar BJ, Velema E, Schoneveld A, Pasterkamp G, Borst C. Acute-phase protein haptoglobin is a cell migration factor involved in arterial restructuring.FASEB J. 2002 Jul;16(9):1123-5. Grimsditch DC, Penfold S, Latcham J, Vidgeon-Hart M, Groot PH, Benson GM. C3H apoE(-/-) mice have less atherosclerosis than C57BL apoE(-/-) mice despite having a more atherogenic serum lipid profile. Atherosclerosis. 2000 Aug;151(2):389-97. Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, Willeit J, Schwartz DA. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med. 2002 Jul 18;347(3):185-92. Li G, Chen SJ, Oparil S, et al. Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblasts after balloon injury of rat carotid arteries. Circulation 2000;101:1362-5. Shi W, Wang X, Tangchitpiyanond K, Wong J, Shi Y, Lusis AJ. Atherosclerosis in C3H/HeJ mice reconstituted with apolipoprotein E-null bone marrow. Arterioscler Thromb Vasc Biol. 2002 Apr 1;22(4):650-5. Van Eck M, Herijgers N, Vidgeon-Hart M, Pearce NJ, Hoogerbrugge PM, Groot PH, Van Berkel TJ. Accelerated atherosclerosis in C57Bl/6 mice transplanted with Apo E-deficient bone marrow. Atherosclerosis. 2000 May;150(1):71-80. Vink A., Schoneveld, van der Meer J, Middelaar BJ. , Sluijter JPG, Smeets MB, Quax PHA, Lim SK, Borst C, Pasterkamp G, De Kleijn, DPV. In Vivo Evidence for a Role of Toll-like Receptor 4 in the Development of Intimal Lesions Circulation 2002 in press Wright SD, Burton C, Hernandez M, Hassing H, Montenegro J, Mundt S, Patel S, Card DJ, Hermanowski-Vosatka A, Bergstrom JD, Sparrow CP, Detmers PA, Chao YS. Infectious agents are not necessary for murine atherogenesis. J Exp Med. 2000 Apr 17;191(8):1437-42.

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