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Oxidized low-density lipoproteins induce rapid platelet activation and shape change through tyrosine kinase and Rho kinase–signaling pathways

Naseem, Khalid M.; Wraith, Katie S.; Magwenzi, Simbarashe; Aburima, Ahmed; Wen, Yichuan; Leake, David; Naseem, Khalid M.

Authors

Khalid M. Naseem

Katie S. Wraith

Simbarashe Magwenzi

Ahmed Aburima

Yichuan Wen

David Leake

Khalid M. Naseem



Abstract

© 2013 by The American Society of Hematology. Oxidized low-density lipoproteins (oxLDL) generated in the hyperlipidemic state may contribute to unregulated platelet activation during thrombosis. Although the ability of oxLDL to activate platelets is established, the underlying signaling mechanisms remain obscure. We show that oxLDL stimulate platelet activation through phosphorylation of the regulatory light chains of the contractile protein myosin IIa (MLC). oxLDL, but not native LDL, induced shape change, spreading, and phosphorylation of MLC (serine 19) through a pathway that was ablated under conditions that blocked CD36 ligation or inhibited Src kinases, suggesting a tyrosine kinase–dependent mechanism. Consistent with this, oxLDL induced tyrosine phosphorylation of a number of proteins including Syk and phospholipase C γ2. Inhibition of Syk, Ca 2+ mobilization, and MLC kinase (MLCK) only partially inhibited MLC phosphorylation, suggesting the presence of a second pathway. oxLDL activated RhoA and RhoA kinase (ROCK) to induce inhibitory phosphorylation of MLC phosphatase (MLCP). Moreover, inhibition of Src kinases prevented the activation of RhoA and ROCK, indicating that oxLDL regulates contractile signaling through a tyrosine kinase–dependent pathway that induces MLC phosphorylation through the dual activation of MLCK and inhibition of MLCP. These data reveal new signaling events downstream of CD36 that are critical in promoting platelet aggregation by oxLDL.

Citation

Wraith, K. S., Magwenzi, S., Aburima, A., Wen, Y., Leake, D., & Naseem, K. M. (2013). Oxidized low-density lipoproteins induce rapid platelet activation and shape change through tyrosine kinase and Rho kinase–signaling pathways. Blood, 122(4), 580-589. doi:10.1182/blood-2013-04-491688

Journal Article Type Article
Acceptance Date May 14, 2013
Publication Date Jul 25, 2013
Deposit Date Nov 13, 2014
Journal Blood
Print ISSN 0006-4971
Electronic ISSN 1528-0020
Publisher American Society of Hematology
Peer Reviewed Not Peer Reviewed
Volume 122
Issue 4
Pages 580-589
DOI https://doi.org/10.1182/blood-2013-04-491688.
Public URL https://hull-repository.worktribe.com/output/473272
Publisher URL http://www.bloodjournal.org/content/122/4/580