Introduction: High platelet reactivity (HPR) caused by clopidogrel tolerance is an adverse reaction of acute coronary syndrome (ACS) patients who receive clopidogrel antiplatelet therapy after percutaneous coronary intervention (PCI) surgery. Platelet microRNA (miRNA) is related to platelet reactivity. This study explored the mechanism of platelet miRNA in regulating platelet reactivity. Methods: We recruited 50 ACS/PCI patients and divided them into the HPR group (P2Y12 reaction units [PRU] ≥300) and the LPR group (PRU < 170) according to the PRU through the VerifyNow P2Y12 assay. P2Y12-related miRNAs were screened by TargetScan, miRWalk, and Gene Expression Omnibus. The expressions of P2Y12 and miRNAs in the HPR group and the LPR group were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Pearson correlation analysis was used to determine the correlation between P2Y12 and miRNAs. The interactions between P2Y12 and miR-107 were predicted by TargetScan and verified by dual-luciferase reporter assay. The regulation of miR-107 mimic or inhibitor on P2Y12 expression was detected by qRT-PCR and Western blot. Results: There were 22 patients in the LPR group and 28 patients in the HPR group. PY212 was highly expressed in the HPR group compared with the LPR group. We screened the P2Y12-related miRNAs (miR-145-5p, miR-4701-3p, miR-107, and miR-15b-5p), but only miR-107 and miR-15b-5p expressions were downregulated in the HPR group and were negatively correlated with PY212 expression. P2Y12 was the target gene of miR-107. PY212 expression was inhibited by miR-107 overexpression but suppressed by miR-107 silencing. Conclusion: Platelet miR-107 participated in clopidogrel resistance in ACS/PCI patients by regulating P2Y12 expression.

1.
Timmis
A
.
Acute coronary syndromes
.
BMJ
.
2015 Oct 20
;
351
:
h5153
. .
2.
Bhatt
DL
.
Percutaneous coronary intervention in 2018
.
JAMA
.
2018 May 22
;
319
(
20
):
2127
8
. .
3.
Giannini
F
,
Candilio
L
,
Mitomo
S
,
Ruparelia
N
,
Chieffo
A
,
Baldetti
L
,
A practical approach to the management of complications during percutaneous coronary intervention
.
JACC Cardiovasc Interv
.
2018 Sep 24
;
11
(
18
):
1797
810
. .
4.
Levine
GN
,
Bates
ER
,
Blankenship
JC
,
Bailey
SR
,
Bittl
JA
,
Cercek
B
,
2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients With ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction
.
J Am Coll Cardiol
.
2016 Mar 15
;
67
(
10
):
1235
50
. .
5.
Grifoni
E
,
Gori
AM
,
Giusti
B
,
Valenti
R
,
Migliorini
A
,
Basili
S
,
On-treatment platelet reactivity is a predictor of adverse events in peripheral artery disease patients undergoing percutaneous angioplasty
.
Eur J Vasc Endovasc Surg
.
2018 Oct
;
56
(
4
):
545
52
. .
6.
Pereira
NL
,
Rihal
CS
,
So
DYF
,
Rosenberg
Y
,
Lennon
RJ
,
Mathew
V
,
Clopidogrel pharmacogenetics
.
Circ Cardiovasc Interv
.
2019 Apr
;
12
(
4
):
e007811
. .
7.
Lewis
JP
,
Shuldiner
AR
.
Clopidogrel pharmacogenetics: beyond candidate genes and genome-wide association studies
.
Clin Pharmacol Ther
.
2017 Mar
;
101
(
3
):
323
5
. .
8.
Cui
G
,
Zhang
S
,
Zou
J
,
Chen
Y
,
Chen
H
.
P2Y12 receptor gene polymorphism and the risk of resistance to clopidogrel: a meta-analysis and review of the literature
.
Adv Clin Exp Med
.
2017 MarApr
;
26
(
2
):
343
9
. .
9.
Jäger
B
,
Stojkovic
S
,
Haller
PM
,
Piackova
E
,
Kahl
BS
,
Andric
T
,
Course of platelet miRNAs after cessation of P2Y12 antagonists
.
Eur J Clin Invest
.
2019 Aug
;
49
(
8
):
e13149
. .
10.
Lu
TX
,
Rothenberg
ME
.
MicroRNA
.
J Allergy Clin Immunol
.
2018 Apr
;
141
(
4
):
1202
7
. .
11.
Edelstein
LC
,
Bray
PF
.
MicroRNAs in platelet production and activation
.
Blood
.
2011 May 19
;
117
(
20
):
5289
96
. .
12.
Hussein
K
,
Theophile
K
,
Dralle
W
,
Wiese
B
,
Kreipe
H
,
Bock
O
.
MicroRNA expression profiling of megakaryocytes in primary myelofibrosis and essential thrombocythemia
.
Platelets
.
2009 Sep
;
20
(
6
):
391
400
. .
13.
Denis
MM
,
Tolley
ND
,
Bunting
M
,
Schwertz
H
,
Jiang
H
,
Lindemann
S
,
Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets
.
Cell
.
2005 Aug 12
;
122
(
3
):
379
91
. .
14.
Nagalla
S
,
Shaw
C
,
Kong
X
,
Kondkar
AA
,
Edelstein
LC
,
Ma
L
,
Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity
.
Blood
.
2011 May 12
;
117
(
19
):
5189
97
. .
15.
Gatsiou
A
,
Boeckel
JN
,
Randriamboavonjy
V
,
Stellos
K
.
MicroRNAs in platelet biogenesis and function: implications in vascular homeostasis and inflammation
.
Curr Vasc Pharmacol
.
2012 Sep
;
10
(
5
):
524
31
. .
16.
Chen
S
,
Qi
X
,
Chen
H
,
Li
M
,
Gu
J
,
Liu
C
,
Expression of miRNA-26a in platelets is associated with clopidogrel resistance following coronary stenting
.
Exp Ther Med
.
2016 Jul
;
12
(
1
):
518
24
. .
17.
Wang
J
,
Yao
Y
,
Zhang
J
,
Tang
X
,
Meng
X
,
Wang
M
,
Platelet microRNA-15b protects against high platelet reactivity in patients undergoing percutaneous coronary intervention through Bcl-2-mediated platelet apoptosis
.
Ann Transl Med
.
2020 Mar
;
8
(
6
):
364
. .
18.
Livak
KJ
,
Schmittgen
TD
.
Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method
.
Methods
.
2001 Dec
;
25
(
4
):
402
8
. .
19.
Alegria-Schaffer
A
,
Lodge
A
,
Vattem
K
.
Chapter 33 performing and optimizing western blots with an emphasis on chemiluminescent detection
.
Guide to protein purification. Methods in enzymology
. 2nd ed.;
2009
. p.
573
99
. .
20.
Ault
KA
,
Cannon
CP
,
Mitchell
J
,
McCahan
J
,
Tracy
RP
,
Novotny
WF
,
Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial. Thrombolysis in myocardial infarction
.
J Am Coll Cardiol
.
1999 Mar
;
33
(
3
):
634
9
. .
21.
Tousoulis
D
,
Paroutoglou
IP
,
Papageorgiou
N
,
Charakida
M
,
Stefanadis
C
.
Recent therapeutic approaches to platelet activation in coronary artery disease
.
Pharmacol Ther
.
2010 Aug
;
127
(
2
):
108
20
. .
22.
Motovska
Z
.
Stent thrombosis after ACS-PCI: does adherence to antiplatelet therapy involve more than its intensity?
Rev Esp Cardiol
.
2019 Apr
;
72
(
4
):
282
4
. .
23.
Mahdieh
N
,
Rabbani
A
,
Firouzi
A
,
Zahedmehr
A
,
Hoseinimoghaddam
M
,
Saedi
S
,
Clopidogrel pharmacogenetics in iranian patients undergoing percutaneous coronary intervention
.
Cardiovasc Toxicol
.
2018 Oct
;
18
(
5
):
482
91
. .
24.
Chen
YC
,
Lin
FY
,
Lin
YW
,
Cheng
SM
,
Chang
CC
,
Lin
RH
,
Platelet MicroRNA 365-3p expression correlates with high on-treatment platelet reactivity in coronary artery disease patients. Cardiovascular drugs and therapy
.
2019 Apr
;
33
(
2
):
129
37
.
25.
von Kügelgen
I
.
Structure, pharmacology and poles in physiology of the P2Y(12) receptor
.
Adv Exp Med Biol
.
2017
;
1051
:
123
38
.
26.
von Kügelgen
I
,
Hoffmann
K
.
Pharmacology and structure of P2Y receptors
.
Neuropharmacology
.
2016 May
;
104
:
50
61
. .
27.
Daimiel-Ruiz
L
,
Klett-Mingo
M
,
Konstantinidou
V
,
Micó
V
,
Aranda
JF
,
García
B
,
Dietary lipids modulate the expression of miR-107, a miRNA that regulates the circadian system
.
Mol Nutr Food Res
.
2015 Sep
;
59
(
9
):
1865
78
. .
28.
Ohkura
N
,
Oishi
K
,
Sudo
T
,
Hayashi
H
,
Shikata
K
,
Ishida
N
,
CLOCK regulates circadian platelet activity
.
Thromb Res
.
2009
;
123
(
3
):
523
7
. .
29.
Wang
X
,
Sundquist
K
,
Svensson
PJ
,
Rastkhani
H
,
Palmér
K
,
Memon
AA
,
Association of recurrent venous thromboembolism and circulating microRNAs
.
Clin Epigenetics
.
2019 Feb 13
;
11
(
1
):
28
. .
30.
Becker
KC
,
Kwee
LC
,
Neely
ML
,
Grass
E
,
Jakubowski
JA
,
Fox
KAA
,
Circulating MicroRNA profiling in Non-ST elevated coronary artery syndrome highlights genomic associations with serial platelet reactivity measurements
.
Sci Rep
.
2020 Apr 10
;
10
(
1
):
6169
. .
31.
Cheng
BJ
,
Nie
XM
,
Zeng
XL
,
Yuan
H
,
Ma
X
,
Zhao
YX
,
Expression of platelet miR-223 in coronary artery disease patients and its clinical significance
.
Zhonghua Yi Xue Za Zhi
.
2018 Jun 12
;
98
(
22
):
1766
70
. .
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