title: Oxidized low-density lipoproteins induce rapid platelet activation and shape change through tyrosine kinase and Rho kinase-signaling pathways.
abstract: 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.
authors.affiliation: Centre for Cardiovascular and Metabolic Research, Hull York Medical School, Thrombosis Research Laboratory, University of Hull, Hull, United Kingdom.
authors.forename: Katie S
authors.initials: KS
authors.lastname: Wraith
authors.forename: Simbarashe
authors.initials: S
authors.lastname: Magwenzi
authors.forename: Ahmed
authors.initials: A
authors.lastname: Aburima
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Wen
authors.forename: David
authors.initials: D
authors.lastname: Leake
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Naseem
mesh_terms: D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D018955:CD36 Antigens / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D048430:Cell Shape / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D020742:rhoA GTP-Binding Protein / Q000378:metabolism / Q000502:physiology*
chemical_list: D018955:CD36 Antigens; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D011505:Protein-Tyrosine Kinases; D009219:Myosin-Light-Chain Kinase; D024507:Nonmuscle Myosin Type IIA; D020742:rhoA GTP-Binding Protein