%0 Journal Article
%T Intraplatelet miRNA-126 regulates thrombosis and its reduction contributes to platelet inhibition.
%A Zhang LJ
%A Hu YX
%A Huang RZ
%A Xu YY
%A Dong SH
%A Guo FH
%A Guo JJ
%A Qiu JJ
%A Cao ZY
%A Wei LJ
%A Mao JH
%A Lyu A
%A Liu JL
%A Zhao XX
%A Guo ZF
%A Jing Q
%J Cardiovasc Res
%V 0
%N 0
%D 2024 Jun 20
%M 38900927
%F 13.081
%R 10.1093/cvr/cvae138
%X <B>OBJECTIVE: </B>MicroRNA-126 (miR-126), one of the most abundant microRNAs in platelets, is involved in the regulation of platelet activity and the circulating miR-126 is reduced during antiplatelet therapy. However, whether intraplatelet miR-126 plays a role in thrombosis and platelet inhibition remains unclear.<BR><B>RESULTS: </B>Here, using tissue-specific knockout mice, we reported that the deficiency of miR-126 in platelets and vascular endothelial cells significantly prevented thrombosis and prolonged bleeding time. Using chimeric mice, we identified that the lack of intraplatelet miR-126 significantly prevented thrombosis. Ex vivo experiments further demonstrated that miR-126-deficient platelets displayed impaired platelet aggregation, spreading and secretory functions. Next, miR-126 was confirmed to target phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) in platelet, which encodes a negative regulator of the PI3 K/AKT pathway, enhancing platelet activation through activating the integrin αIIbβ3-mediated outside-in signaling. After undergoing myocardial infarction (MI), chimeric mice lacking intraplatelet miR-126 displayed reduced microvascular obstruction and prevented MI expansion in vivo. In contrast, overexpression of miR-126 by the administration of miR-126 agonist (agomiR-126) in wild-type mice aggravated microvascular obstruction and promoted MI expansion, which can be almost abolished by aspirin administration. In patients with cardiovascular diseases, antiplatelet therapies, either aspirin alone or combined with clopidogrel, decreased the level of intraplatelet miR-126. The reduction of intraplatelet miR-126 level was associated with the decrease of platelet activity.<BR><B>CONCLUSIONS: </B>Our murine and human data reveal that (i) intraplatelet miR-126 contributes to platelet activity and promotes thrombus formation, and (ii) the reduction of intraplatelet miR-126 contributes to platelet inhibition during antiplatelet therapy.