Argonaute2 modulates megakaryocyte development and sex-specific control of platelet protein expression and reactivity.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Argonaute Proteins*/metabolism ; Argonaute Proteins*/genetics ; Megakaryocytes*/metabolism ; Blood Platelets*/metabolism ; Mice, Knockout*; Animals ; Female ; Male ; Mice ; Thrombopoiesis/genetics ; Sex Factors

Platelets are enriched in miRNAs and harbor Ago2 as the principal RNA silencing Argonaute. However, roles in thrombopoiesis and platelet function remain poorly understood. We generated megakaryocyte/platelet-specific Ago2-deleted (Ago2 KO) mice and assessed proteomic and functional effects. We predicted platelet hyperreactivity with Ago2 deletion due to large-scale upregulated protein expression. Platelet counts were normal. Mean volumes were increased, associated with larger, though fewer megakaryocytes. Ago2-deleted platelets from male mice showed hyperreactivity to thromboxane but not to other agonists compared to controls, whereas Ago2-deleted platelets from female mice showed normal reactivity. Ago2 KO mice displayed normal hemostasis and clot dynamics. Proteomes of Ago2-deleted and wild type platelets were mostly similar. However, Ago1 - undetectable in wild type platelets - was upregulated in Ago2-deleted platelets in both males and females, confirmed by immunoblotting. Female Ago2-deleted platelets selectively showed downregulation of a protein cohort established in breast cancer cells to be transcriptionally regulated by estrogen receptor-beta coupled to Ago2, whereas male Ago2-deleted platelets did not. Thus, Ago2 is important for platelet development and function, putatively partially rescued by upregulation of Ago1. Platelet reactivity controlled by Ago2 reflects sex-specific regulation of gene expression potentially at both transcriptional and translational levels in megakaryocytes and platelets.
Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
(© 2025. The Author(s).)

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R01 HL144574 United States HL NHLBI NIH HHS; 20TPA35490278 American Heart Association; R01 HL159006 United States HL NHLBI NIH HHS; R01HL144574 United States NH NIH HHS; R01HL159006 United States NH NIH HHS; 24PRE1195534 American Heart Association; Medical Research Award W. W. Smith Charitable Trust; 24PRE1194157 American Heart Association

Keywords: Ago2; Argonaute; Hemostasis; Megakaryocyte; Proteomics; RISC; miRNA

0 (Argonaute Proteins)
0 (Ago2 protein, mouse)

Date Created: 20250128 Date Completed: 20250128 Latest Revision: 20250131

20250131

PMC11775343

10.1038/s41598-025-88106-0

39875491