Thrombospondin-1 induces platelet activation through CD36-dependent inhibition of the cAMP/protein kinase A signaling cascade

Aburima, A.; Naseem, Khalid M.; Roberts, Wayne; Magwenzi, Simbarashe; Aburima, Ahmed; Naseem, Khalid

Abstract

Cyclic adenosine monophosphate (cAMP)-dependent signaling modulates platelet function at sites of vascular injury. Here we show that thrombospondin-1 (TSP-1) prevents cAMP/protein kinase A (PKA) signaling through a CD36-dependent mechanism. Prostaglandin E 1 (PGE 1 ) induced a robust inhibition of both platelet aggregation and platelet arrest under physiologic conditions of flow. Exogenous TSP-1 reduced significantly PGE 1 -mediated inhibition of both platelet aggregation and platelet arrest. TSP-1 prevented PGE 1 -stimulated cAMP accrual and phosphorylation of PKA substrates, through a mechanism requiring phosphodiesterase3A. TSP-1 also inhibited VASP phosphorylation stimulated by the nonhydrolyzable cAMP analog, 8-bromocAMP, indicating that it may regulate cAMPmediated activation of PKA. The inhibitory effect of TSP-1 on cAMP signaling could be reproduced with a peptide possessing a CD36 binding sequence of TSP-1, while the effects of TSP-1 were prevented by a CD36 blocking antibody. TSP-1 and the CD36 binding peptide induced phosphorylation of Src kinases, p38 and JNK. More-over, inhibition of Src kinases blocked TSP-1-mediated regulation of cAMP concentrations and the phosphorylation of VASP, indicating that TSP-1 modulated the cAMP/PKA signaling events through a tyrosine kinase-dependent pathway downstream of CD36. These data reveal a new role for TSP-1 in promoting platelet aggregation through modulation of the cAMP-PKA signaling pathway. © 2010 by The American Society of Hematology.

Citation

Roberts, W., Magwenzi, S., Aburima, A., & Naseem, K. (2010). Thrombospondin-1 induces platelet activation through CD36-dependent inhibition of the cAMP/protein kinase A signaling cascade. Blood, 116(20), 4297-4306. https://doi.org/10.1182/blood-2010-01-265561

• Journal Article Type: Article
• Online Publication Date: Jul 27, 2010
• Publication Date: Nov 18, 2010
• Deposit Date: Nov 13, 2014
• Journal: Blood
• Print ISSN: 0006-4971
• Publisher: American Society of Hematology
• Peer Reviewed: Peer Reviewed
• Volume: 116
• Issue: 20
• Pages: 4297-4306
• DOI: https://doi.org/10.1182/blood-2010-01-265561
• Keywords: Immunology; Cell Biology; Biochemistry; Hematology
• Public URL: https://hull-repository.worktribe.com/output/462695
• Contract Date: Nov 13, 2014