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Platelets 2

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  • 1. BISC 675 Cardiovascular Physiology Platelets 2 Ulhas P. Naik, Ph.D Professor and Director Delaware Cardiovascular Research Center
  • 2. Overview
    • Inside-out signaling- agonist-induced integrin activation
    • Outside-in signaling- signaling initiated by binding of fibrinogen to activated integrin
    • Clot retraction- mechano-signal transduction
  • 3. Intracellular Calcium
  • 4. GPVI (Collagen Receptor) Signaling
  • 5. Gq PLC  Ca 2+ G  i  P2Y12 -Adenylyl cyclase cAMP ADP Shape Change PI3K  Akt Rap1b Fibrinogen Receptor Activation, Platelet Aggregation, Secretion and Thromboxane Generation ? ? Indirect role Rho Kinase activation PKC Src tyrosine kinase AR-C69931MX MRS2179 Erk1/2 ? RhoA p160ROCK P2Y1, PAR1/4 TP  TRAP, TXA2 G 12/13 YM254890
  • 6. Thrombin Signaling
  • 7. Platelet Secretion
  • 8. Integrin Inside-out Signaling
  • 9. Integrin Outside-in Signaling
  • 10. Events Leading to Platelet Aggregation
  • 11.  
  • 12. Platelet Aggregate Stabilization
  • 13. Calcium- and Integrin-binding Protein 1
  • 14. CIB1 in Platelet Spreading Discoid Spiky Partially spread Spread
  • 15. CIB1 is Needed for Lamellipodia Formation -DMSO Anti-CIB1 cIgG +DMSO
  • 16. CIB1 Deletion Affects Platelet Spreading on Immobilized Fibrinogen
  • 17. Ablation of CIB1 Results in Delayed Clot Retraction
  • 18. JAM-A and Platelet Activation
    • JAM-A was originally identified as a receptor for a stimulatory monoclonal antibody, mAb F11 (Naik et al., J. Biochem, 1995)
    • JAM-A gene was cloned and shown to localize on chromosome 1 (Naik, et al., J. Cell Sci 2001)
    • JAM-A associates with integrin  v  3 in quiescent endothelial cells (Naik, et al., Blood 2003)
    • Mutation of tyrosine 280 to phenylalanine affects JAM-A function (Naik and Naik, J.Cell Sci. 2006)
  • 19. Ablation of JAM-A Results in Faster Clot Retraction
  • 20. JAM-A movie
  • 21. Platelet Storage
    • They age rapidly outside the body
    • Platelets are easily activated
    • Cold temperature also activate platelets
    • Needs to be stored at 20-24 o C with rocking
    • Platelets should be used for transfusion within 3-4 days of isolation
  • 22. Anti-Platelet Drugs
  • 23. Aspirin Aspirin inhibits both COX-1 and COX-2 Inhibition is 170 fold greater for COX1 Platelet express COX1 more than COX2
  • 24. Anti-ADP Receptors
  • 25.  IIb  3 Antagonists
  • 26. Anti-platelet Therapy
  • 27. Controlling Cardiovascular Disease Through Platelets

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