Reference - Detail
RRC ID | 82152 |
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Author | Tsukiji N, Yokomori R, Takusagawa K, Shirai T, Oishi S, Sasaki T, Takano K, Suzuki-Inoue K. |
Title | C-type lectin-like receptor-2 in platelets mediates ferric chloride-induced platelet activation and attenuates ferroptosis of endothelial cells. |
Journal | J Thromb Haemost |
Abstract |
BACKGROUND:An iron overload status induces ferroptosis, an iron-dependent nonapoptotic cell death, in various pathological conditions. We previously reported that hemin (heme), protoporphyrin-IX with ferric iron, activates platelets via C-type lectin-like receptor-2 (CLEC-2) and glycoprotein VI/FcRγ, but protoporphyrin-IX alone blocks CLEC-2-dependent platelet activation. Therefore, we hypothesized that free iron has the ability to activate platelets. OBJECTIVES:This study aimed to elucidate platelet activation mechanisms of iron (ferric chloride), including the identification of signaling pathways and receptors, and to examine whether platelets regulate ferroptosis. METHODS:Platelet aggregometry, platelet activation marker expression, and protein phosphorylation were examined in ferric chloride-stimulated human and murine platelets. Inhibitors of platelet activation signaling pathways and receptor-deleted platelets were utilized to identify the responsible signaling pathway and receptor. The effect of platelets on ferroptosis of endothelial cells was investigated in vitro. RESULTS:Ferric chloride induced platelet activation dependent on Src family kinase pathways in humans and mice. Ferric chloride-induced platelet aggregation was almost lost in CLEC-2-depleted murine platelets and wild-type platelets preincubated with recombinant CLEC-2 proteins. Furthermore, coculture of wild-type platelets, but not CLEC-2-deficient platelets, attenuated ferroptosis of endothelial cells in vitro. CONCLUSION:Ferric chloride activates platelets via CLEC-2 and Src family kinase pathways, and platelets have a protective role in the ferroptosis of endothelial cells dependent on CLEC-2. |
Volume | 22(6) |
Pages | 1749-1757 |
Published | 2024-6-1 |
DOI | 10.1016/j.jtha.2024.03.003 |
PII | S1538-7836(24)00160-0 |
PMID | 38811291 |
MeSH | Animals Blood Platelets* / drug effects Blood Platelets* / metabolism Chlorides* / metabolism Endothelial Cells / drug effects Endothelial Cells / metabolism Ferric Compounds* / pharmacology Ferroptosis* / drug effects Human Umbilical Vein Endothelial Cells / metabolism Humans Lectins, C-Type* / metabolism Mice Mice, Inbred C57BL* Mice, Knockout Phosphorylation Platelet Activation* / drug effects Platelet Aggregation* / drug effects Signal Transduction* src-Family Kinases / metabolism |
Resource | |
Human and Animal Cells | MAEC(RCB2712) |