Platelet CD36 signaling through ERK5 promotes caspase-dependent procoagulant activity and fibrin deposition in vivo. Blood Adv 2018 Nov 13;2(21):2848-2861
Date
11/02/2018Pubmed ID
30381401Pubmed Central ID
PMC6234364DOI
10.1182/bloodadvances.2018025411Scopus ID
2-s2.0-85062651330 (requires institutional sign-in at Scopus site) 55 CitationsAbstract
Dyslipidemia is a risk factor for clinically significant thrombotic events. In this condition, scavenger receptor CD36 potentiates platelet reactivity through recognition of circulating oxidized lipids. CD36 promotes thrombosis by activating redox-sensitive signaling molecules, such as the MAPK extracellular signal-regulated kinase 5 (ERK5). However, the events downstream of platelet ERK5 are not clear. In this study, we report that oxidized low-density lipoprotein (oxLDL) promotes exposure of procoagulant phosphatidylserine (PSer) on platelet surfaces. Studies using pharmacologic inhibitors indicate that oxLDL-CD36 interaction-induced PSer exposure requires apoptotic caspases in addition to the downstream CD36-signaling molecules Src kinases, hydrogen peroxide, and ERK5. Caspases promote PSer exposure and, subsequently, recruitment of the prothrombinase complex, resulting in the generation of fibrin from the activation of thrombin. Caspase activity was observed when platelets were stimulated with oxLDL. This was prevented by inhibiting CD36 and ERK5. Furthermore, oxLDL potentiates convulxin/glycoprotein VI-mediated fibrin formation by platelets, which was prevented when CD36, ERK5, and caspases were inhibited. Using 2 in vivo arterial thrombosis models in apoE-null hyperlipidemic mice demonstrated enhanced arterial fibrin accumulation upon vessel injury. Importantly, absence of ERK5 in platelets or mice lacking CD36 displayed decreased fibrin accumulation in high-fat diet-fed conditions comparable to that seen in chow diet-fed animals. These findings suggest that platelet signaling through CD36 and ERK5 induces a procoagulant phenotype in the hyperlipidemic environment by enhancing caspase-mediated PSer exposure.
Author List
Yang M, Kholmukhamedov A, Schulte ML, Cooley BC, Scoggins NO, Wood JP, Cameron SJ, Morrell CN, Jobe SM, Silverstein RLAuthor
Roy L. Silverstein MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBlood Platelets
CD36 Antigens
Caspases
Crotalid Venoms
Diet, High-Fat
Disease Models, Animal
Egtazic Acid
Fibrin
Humans
Hyperlipidemias
Lectins, C-Type
Lipoproteins, LDL
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase 7
Phosphatidylserines
Platelet Activation
Signal Transduction
Thrombosis
src-Family Kinases
