INTRODUCTION
Stroke is a major mortality and morbidity cause worldwide
(Ding et al., 2020;
Ma, Jiang, Xu, Liu, & Guo, 2021).
Ischemic stroke, which is caused by thrombosis or embolism in blood
vessels, is the most common stroke
subtype(Mendelson & Prabhakaran, 2021).
Currently, there remains no specific treatment for improving the
prognosis in patients with ischemic stroke given the complex
pathogenesis. A series of post-stroke inflammatory responses are
crucially involved in functional recovery, which compromises the
ischemic stroke prognosis.
Peripheral leukocytes significantly affect the clinical outcome of
stroke and could be a therapeutic target for treating and preventing
ischemic stroke (G. Li, Ma, et al.,
2018). There have been several studies on
non-coding RNA (ncRNA) expression
in peripheral leukocytes in patients with ischemic stroke. ncRNAs in
leukocytes regulate the release of inflammatory factors and promote
inflammatory responses after cerebral ischemic
injury(Liu et al., 2020). ncRNAs can be
classified as short (≤ 200 base pairs) or
long ncRNAs (lncRNAs;
> 200 base pairs) (Palazzo &
Koonin, 2020). MicroRNAs (miRNAs,
miRs) are small ncRNAs with < 22 nucleotides that modulate
protein expression at the posttranscriptional level
(G. Li, Morris-Blanco, et al., 2018).
Mature miRNAs prevent mRNA translation or promote mRNA degradation by
binding to the consensus seed sequences in the 3’
untranslated regions (UTRs) of the
target mRNAs(G. Li, Morris-Blanco, et al.,
2018). Recent studies have demonstrated a mutual regulation between
miRNAs and lncRNAs, including a direct interaction and an indirect role
by binding to target genes in ischemic
stroke(Ghafouri-Fard, Shoorei, & Taheri,
2020).
To identify leukocyte genes related to ischemic stroke, we previously
detected mRNA expression in neutrophils using RNA-seq and compared it
between patients with acute ischemic stroke and healthy controls. We
found altered expression of C1q
and tumour necrosis factor (C1QTNF)6 after ischemic stroke. C1QTNF6 was
originally identified in the heart, brain, and peripheral inflammatory
cells; further, it is involved in diverse processes, including
apoptosis, metabolism, and release of inflammatory
factors(Yan et al., 2021). C1QTNF6 can
directly modulate pro-inflammatory cytokine gene expression in
leukocytes(Lei et al., 2017). Our
preliminary findings demonstrated that C1QTNF6 mRNA can be modulated by
several miRNAs in neutrophils, including miR-29b. miR-29b expression in
leukocytes is significantly decreased after ischemic injury; moreover,
changes in miR-29b are correlated with the prognosis of ischemic
stroke(Y. Wang et al., 2015). miR-29b
overexpression alleviates brain injury and attenuates
blood-brain barrier (BBB) damage
(Y. Wang et al., 2015). Moreover, we
predicted potential targeting lncRNAs related to miR-29b and identified
the binding site of miR-29b in H19 using Starbase
(http://starbase.sysu.edu.cn/index.php). Blood H19 levels are increased
after ischemic stroke in circulating blood, which promotes the release
of inflammatory factors. Therefore, we hypothesised that C1QTNF6 in
leukocytes may be regulated by H19 and miR-29b, which could be involved
in the pathogenesis of ischemic stroke.
This study aimed to elucidate the inflammatory mechanism of lncRNA
H19-mediated regulation of C1QTNF6 by sponging miR-29b in leukocytes
during ischemic stroke.