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\begin{document}

\title{Regulatory mechanism of miR-223 on platelet reactivity in ischemic
stroke patients after clopidogrel treatment}



\author[1]{Wenjie Tian}%
\author[1]{Xiaoshuang Xia}%
\author[1]{Yan Sun}%
\author[1]{Xin Li}%
\affil[1]{Tianjin Medical University Second Hospital}%


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  \date{May 25, 2024}


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\begin{abstract}
Background: Recent studies have confirmed that microRNA-223 may
participate in high-on clopidogrel treatment platelet reactivity.
Clopidogrel requires hepatic enzyme metabolic activation to produce its
metabolite with pharmacological activity, as a result, there are few
researches about platelet reactivity. The aim of the current study is to
explore the possible regulatory mechanism between microRNA-223 and
platelet reactivity after clopidogrel treatment. Methods: In this study,
we established an experimental model of MEG-01 cells treated with
clopidogrel and human liver microsomes incubation system, so that the
effects of clopidogrel active metabolites on megakaryocytes and
platelets can be simulated. The relation of microRNA-223, C/EBP \selectlanguage{greek}α \selectlanguage{english}and
P2Y12 was further investigated by both cell experiments and clinical
studies. Results: The ratio of platelet P2Y12 expression before and
after treatment was significantly higher in Low Responders group
(1.14604 vs 0.77097, p=0.031). After treatment at 200 ul/2 ml for 3 and
5 consecutive days, miR-223 expression in MEG-01 cells decreased by
47.3\% and 32\%, respectively (p \textless{} 0.05). P2Y12 mRNA
expression was 193.4\% higher after 3 consecutive days (p \textless{}
0.001), and significantly lower after 5 consecutive days than that in
the negative control group (p \textless{} 0.05). P2Y12 and C/EBP \selectlanguage{greek}α
\selectlanguage{english}protein expression were significantly lower after 5 consecutive days (p
\textless{} 0.01). Conclusions: A negative feedback loop was carried out
by clopidogrel active metabolite to recede its inhibition of P2Y12
signal pathway through P2Y12-PI3K/Akt-C/EBP \selectlanguage{greek}α-\selectlanguage{english}miR-223 pathway, which may
be excessively activated and play a role in the occurrence of high-on
clopidogrel treatment platelet reactivity.%
\end{abstract}%



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