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BISC 675 Cardiovascular Physiology Platelets 2 Ulhas P. Naik, Ph.D Professor and Director Delaware Cardiovascular Research...
Overview <ul><li>Inside-out signaling- agonist-induced integrin activation </li></ul><ul><li>Outside-in signaling- signali...
Intracellular Calcium
GPVI (Collagen Receptor) Signaling
Gq PLC   Ca   2+ G  i  P2Y12 -Adenylyl  cyclase cAMP ADP Shape  Change PI3K   Akt Rap1b Fibrinogen Receptor Activ...
Thrombin Signaling
Platelet Secretion
Integrin Inside-out Signaling
Integrin Outside-in Signaling
Events Leading to Platelet Aggregation
 
Platelet Aggregate Stabilization
Calcium- and Integrin-binding Protein 1
CIB1 in Platelet Spreading Discoid Spiky Partially spread Spread
CIB1 is Needed for Lamellipodia Formation -DMSO Anti-CIB1 cIgG +DMSO
CIB1 Deletion Affects Platelet Spreading  on Immobilized Fibrinogen
Ablation of CIB1 Results in Delayed Clot Retraction
JAM-A and Platelet Activation <ul><li>JAM-A was originally identified as a receptor for a stimulatory monoclonal antibody,...
Ablation of JAM-A Results in Faster Clot Retraction
JAM-A movie
Platelet Storage <ul><li>They age rapidly outside the body </li></ul><ul><li>Platelets are easily activated </li></ul><ul>...
Anti-Platelet Drugs
Aspirin Aspirin inhibits both COX-1 and COX-2 Inhibition is 170 fold greater for COX1 Platelet express COX1  more than COX2
Anti-ADP Receptors
 IIb  3 Antagonists
Anti-platelet Therapy
Controlling Cardiovascular Disease Through Platelets
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Platelets 2

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Platelets 2

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

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