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.

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Published in Blood Advances, v. 2, no. 21, p. 2848-2861.

This research was originally published in Blood Advances. Moua Yang, Andaleb Kholmukhamedov, Marie L. Schulte, Brian C. Cooley, Na’il O. Scoggins, Jeremy P. Wood, Scott J. Cameron, Craig N. Morrell, Shawn M. Jobe and Roy L. Silverstein. Platelet CD36 signaling through ERK5 promotes caspase-dependent procoagulant activity and fibrin deposition in vivo. Blood Adv. 2018;2:2848-2861. © 2018 by The American Society of Hematology.

The copyright holder has granted the permission for posting the article here.

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This work was supported by National Institutes of Health, National Heart, Lung, and Blood Institute grants 5R01HL111614 and 3R01HL111614-S1 (R.L.S.), R01 HL124018 and R01 HL141106-01A1 (C.N.M.), K08HL128856 and HL120200 (S.J.C.), and HL129193 (J.P.W.).

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