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Overview of the target cell signaling pathways associated with I/R injury. The RISK pathway is activated by opioid peptides, bradykinins, adenosine, receptor tyrosine kinase G protein-coupled receptors, erythropoietin, cytokines, insulin, or insulin-like growth factor-1. The cGMP/PKG pathway is activated by external stimuli (ANP and BNP) via the activation of natriuretic peptide receptors A and B. The SAFE pathway is activated by IL-6, IL-11, leukemia inhibitory factor (LIF), or TNF-α via the glycoprotein 130 receptor or TNF-α type 2 receptor. Among these pathways, the potential m 6 A methylation targets have been labeled with pink circle.
Source publication
Ischemia–reperfusion (I/R) injury is common during surgery and often results in organ dysfunction. The mechanisms of I/R injury are complex, diverse, and not well understood. RNA methylation is a novel epigenetic modification that is involved in the regulation of various biological processes, such as immunity, response to DNA damage, tumorigenesis,...
Context in source publication
Context 1
... injury salvage kinase (RISK) [62][63][64][65] , survival activating factor enhancement (SAFE) [66][67][68] , and cyclic guanosine monophosphate (cGMP)-protein kinase G (cGMP-dependent kinase) signaling pathways 69,70 are the major pathways involved in the protective effects of various interventions in different organs against I/R injury (Fig. 3). Recently, epigenetic regulation has been suggested to play important roles in I/R ...
Similar publications
Ubiquitylation and deubiquitylation are reversible protein post-translational modification (PTM) processes involving the regulation of protein degradation under physiological conditions. Loss of balance in this regulatory system can lead to a wide range of diseases, such as cancer and inflammation. As the main members of the deubiquitinases (DUBs)...
Citations
... Conversely, the removal of m6A is carried out by demethylases, also termed as "eraser," such as FTO and ALKBH5 [20]. Among them, FTO is an oxygen-dependent enzyme, and its activity has been reported to be severely impaired after ischemia injury in the brain, kidney, liver, heart, and other organs [30][31][32]. Notably, FTO is highly expressed in the brain, especially in neurons, and the deficiency of FTO leads to impaired learning and memory [33]. Recently, Chokkalla et al [26] demonstrated that FTO was neuronal-specific; they found that FTO was mainly expressed in neurons (NeuN+), while absent in astrocytes (GFAP+) and microglia (IBA1+) cells by immunofluorescence staining. ...
Neuronal death following ischemia is the primary cause of death and disability in patients with ischemic stroke. N6-methyladenosine (m6A) modification plays essential role in various physiological and pathological conditions, but its role and mechanism in ischemic neuronal death remain unclear. In the present study, neuronal pyroptosis was an important event in brain injury caused by ischemic stroke, and the upregulation of long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) following cerebral ischemia was a key factor in activating ischemic neuronal pyroptosis via NLRP3/caspase-1/GSDMD signaling. Moreover, we first demonstrated that the demethylase fat mass and obesity-associated protein (FTO), which was decreased following ischemia, regulated MEG3 expression in an m6A-dependent manner by affecting its stability, thereby activating neuronal pyroptosis via NLRP3/caspase-1/GSDMD signaling, and ultimately leading to ischemic brain damage. Therefore, the present study provides new insights for the mechanism of ischemic stroke, and suggests that FTO may be a potential therapeutic target for ischemic stroke.
... Owing to the limitations of current experiments, elucidating the dynamic regulatory mechanisms of individual m 6 A sites and their molecular functions remains challenging [48]. We analysed the sequencing results of primary neurons by bioinformatics methods and showed that four key genes were significantly decreased in the model group but significantly increased in the treatment group. ...
Background
Cerebral ischaemia‒reperfusion (I/R) frequently causes late-onset neuronal damage. Breviscapine promotes autophagy in microvascular endothelial cells in I/R and can inhibit oxidative damage and apoptosis. However, the mediation mechanism of breviscapine on neuronal cell death is unclear.
Methods
First, transcriptome sequencing was performed on three groups of mice: the neuronal normal group (Control group), the oxygen-glucose deprivation/ reoxygenation group (OGD/R group) and the breviscapine administration group (Therapy group). Differentially expressed genes (DEGs) between the OGD/R and control groups and between the Therapy and OGD/R groups were obtained by the limma package. N⁶-methyladenosine (m⁶A) methylation-related DEGs were selected by Pearson correlation analysis. Then, prediction and confirmation of drug targets were performed by Swiss Target Prediction and UniProt Knowledgebase (UniProtKB) database, and key genes were obtained by Pearson correlation analysis between m⁶A-related DEGs and drug target genes. Next, gene set enrichment analysis (GSEA) and Ingenuity pathway analysis (IPA) were used to obtain the pathways of key genes. Finally, a circRNA-miRNA‒mRNA network was constructed based on the mRNAs, circRNAs and miRNAs.
Results
A total of 2250 DEGs between the OGD/R and control groups and 757 DEGs between the Therapy and OGD/R groups were selected by differential analysis. A total of 7 m⁶A-related DEGs, including Arl4d, Gm10653, Gm1113, Kcns3, Olfml2a, Stk26 and Tfcp2l1, were obtained by Pearson correlation analysis. Four key genes (Tfcp2l1, Kcns3, Olfml2a and Arl4d) were acquired, and GSEA showed that these key genes significantly participated in DNA repair, e2f targets and the g2m checkpoint. IPA revealed that Tfcp2l1 played a significant role in human embryonic stem cell pluripotency. The circRNA-miRNA‒mRNA network showed that mmu_circ_0001258 regulated Tfcp2l1 by mmu-miR-301b-3p.
Conclusions
In conclusion, four key genes, Tfcp2l1, Kcns3, Olfml2a and Arl4d, significantly associated with the treatment of OGD/R by breviscapine were identified, which provides a theoretical basis for clinical trials.
... The increased level of IL-6, AST, and ALT in the hepatic IR rat model shows that the results of the present study are in accord with other studies. 25,26 We found that the IPOC procedure was able to reduce the release of AST and ALT enzymes in rats exposed to IR. However, tofacitinib as an inhibitor of JAK-STAT was able to inhibit the improvement of liver function induced by IPOC in the liver exposed to IR. ...
Purpose: Hepatic ischemia post-conditioning (IPOC) is shown to protect the liver from injury induced by ischemia/reperfusion (IR). However, the mechanism underlying this protection has remained elusive. The present study aimed to investigate the role of the interleukin 6-Janus kinase-signal transducers and activators of transcription (IL-6-JAK-STAT) pathway in the protective effect of hepatic IPOC against the IR-induced injury in the liver. Methods: 25 rats were randomly divided into 5 groups of 1) sham-operated, 2) IR, 3) IR+hepatic IPOC, 4) IR+ tofacitinib (TOFA), and 5) IR+TOFA+ hepatic IPOC. The changes induced by IR and the effects of different treatments were assessed by enzyme release, histopathological observations, the serum level of IL-6, and the occurrence of apoptosis detected via the expression of the Bax/Bcl-2 ratio. Results: The hepatic IPOC improved the liver injury induced by IR as shown by histological changes, reduction of IL-6 level, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) compared to the IR group (p<0.001, p<0.05, p<0.05, respectively). There was also downregulation of the Bax/Bcl2 ratio in the rats exposed to IR + hepatic IPOC compared with those in the IR group (p<0.05). However, TOFA, an inhibitor of JAK-STAT activity, inhibited the protective effect of hepatic IPOC. Conclusion: It suggests that the protective effect of hepatic IPOC against IR-induced injury may be mediated by activating the IL-6-JAK-STAT pathway.
... Better and more effective therapeutic targets are urgently needed. Many studies have found that RNA m 6 A methylation is involved in the regulation of IRI in different organs [16][17][18]. However, the specific potential roles of m 6 A-modified transcripts and molecular mechanisms in hepatic IRI remain unclear. ...
... Severe hepatic injury is the outcome of inflammatory processes, liver cell death by apoptosis and oxidative damage through the induction of oxidative stress. RNA m 6 A methylation, the best-characterized internal RNA modification, plays important regulatory roles in the stabilization and translation of mRNA and the occurrence and development of myocardial, brain, and renal ischaemia reperfusion injury [16,24]. The regulatory mechanisms and biological functions of m 6 A methylation are increasingly being understood. ...
N6-Methyladenosine (m⁶A) plays key roles in the regulation of biological functions and cellular mechanisms for ischaemia reperfusion (IR) injury in different organs. However, little is known about the underlying mechanisms of m⁶A-modified mRNAs in hepatic IR injury. In mouse models, liver samples were subjected to methylated RNA immunoprecipitation with high-throughput sequencing (MeRIP-seq) and RNA sequencing (RNA-seq). In total, 16917 m⁶A peaks associated with 4098 genes were detected in the sham group, whereas 21,557 m⁶A peaks associated with 5322 genes were detected in the IR group. There were 909 differentially expressed m⁶A peaks, 863 differentially methylated transcripts and 516 differentially m⁶A modification genes determined in both groups. The distribution of m⁶A peaks was especially enriched in the coding sequence and 3‘UTR. Furthermore, we identified a relationship between differentially m⁶A methylated genes (fold change≥1.5/≤ 0.667, p value≤0.05) and differentially expressed genes (fold change≥1.5 and p value≤0.05) to obtain three overlapping predicted target genes (Fnip2, Phldb2, and Pcf11). Our study revealed a transcriptome-wide map of m⁶A mRNAs in hepatic IR injury and might provide a theoretical basis for future research in terms of molecular mechanisms.
... Considering the complexity, dynamics, and prolongation of inflammation after IS, neuroimmune-targeted therapies have not been clinically applied until recently. A recent study found that modulating post-transcriptional RNA levels using RNA-binding proteins, and epigenetic post-transcriptional modifications may be an effective treatment for post-ischemic pathophysiology (Yao et al., 2020). In light of these observations, abnormal m6A modifications could play a key role in ischemic cascades, in which neurogenesis, glutamate-mediated excitability is involved, and in secondary brain injury after IS (Yao et al., 2020). ...
... A recent study found that modulating post-transcriptional RNA levels using RNA-binding proteins, and epigenetic post-transcriptional modifications may be an effective treatment for post-ischemic pathophysiology (Yao et al., 2020). In light of these observations, abnormal m6A modifications could play a key role in ischemic cascades, in which neurogenesis, glutamate-mediated excitability is involved, and in secondary brain injury after IS (Yao et al., 2020). Therefore, epigenetic regulation in IS has received considerable attention. ...
Background: Ischemic stroke (IS) is a highly heterogeneous disease. Recent studies have shown that epigenetic variables affect the immune response. However, only a few studies have examined the relationship between IS and m6A immunoregulation. Therefore, we aim to explore the methylation of RNA mediated by m6A regulatory factor and the immune microenvironment characteristics of IS.
Methods: Differentially expressed m6A regulators were detected in IS microarray datasets GSE22255 and GSE58294. We used a series of machine learning algorithms to identify key IS-related m6A regulators and validated them on blood samples of IS patients, oxygen-glucose deprivation/reoxygenation (OGD/R) microglia and GSE198710 independent data sets. Different m6A modification modes were determined and the patients were classified. In addition, we systematically associate these modification patterns with the characteristics of immune microenvironment, including infiltrating immune cells, immune function genes and immune response genes. Then we developed a model of m6A score to quantify the m6A modification in IS samples.
Results: Through the analysis of the differences between the control group and IS patients, METTL16, LRPPRC, and RBM15 showed strong diagnostic significance in three independent data sets. In addition, qRT-PCR and Western blotting also confirmed that the expression of METTL16 and LRPPRC was downregulated and the expression of RBM15 was upregulated after ischemia. Two m6A modification modes and two m6A gene modification modes were also identified. m6A gene cluster A (high m6A value group) was positively correlated with acquired immunity, while m6A gene cluster B (low m6A value group) was positively correlated with innate immunity. Similarly, five immune-related hub genes were significantly associated with m6Acore (CD28, IFNG, LTF, LCN2, and MMP9).
Conclusion: The modification of m6A is closely related to the immune microenvironment. The evaluation of individual m6A modification pattern may be helpful for future immunomodulatory therapy of anti-ischemic response.
... N6-methyladenosine (m 6 A) is one of the most prevalent methylation modifications in mRNA that is involved in moderating the RNA structure, function, metabolism, and stability, thereby affecting the expression of many genes. Three types of proteins composed of "writers, " "erasers, " and "readers" are involved in the methylation modification process affecting the m 6 A levels of RNA and associated with various diseases, including cancer, cardiovascular diseases, I/R injury, and diabetes (Oerum et al. 2021;Suo et al. 2022;Chien et al. 2021;Yao et al. 2020;Qin et al. 2022). However, whether the m 6 A modification has beneficial or harmful effects on ER stress-associated diseases remains unclear. ...
Background
With the increasing morbidity and mortality of preeclampsia (PE), it has posed a huge challenge to public health. Previous studies have reported endoplasmic reticulum (ER) stress could contribute to trophoblastic dysfunction which was associated with the N ⁶ -methyladenosine (m ⁶ A) modification by methyltransferase-like 3 (METTL3), resulting in PE. However, little was known about the relationship between METTL3 and ER stress in PE. Thus, in vitro and in vivo studies were performed to clarify the mechanism about how METTL3 affects the trophoblasts under ER stress in PE and to explore a therapeutic approach for PE.
Methods
An ER stress model in HTR-8/SVneo cells and a preeclamptic rat model were used to study the mechanism and explore a therapeutic approach for PE. Western blot, immunohistochemistry, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and methylated RNA immunoprecipitation (MeRIP)-qPCR were performed to detect the protein, RNA, and methylated transmembrane BAX inhibitor motif containing 6 (TMBIM6) expression levels. The m ⁶ A colorimetric and mRNA stability assays were used to measure the m ⁶ A levels and TMBIM6 stability, respectively. Short hairpin RNAs (shRNAs) were used to knockdown METTL3 and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Flow cytometry and Transwell assays were performed to evaluate the apoptosis and invasion abilities of trophoblasts.
Results
Upregulated METTL3 and m ⁶ A levels and downregulated TMBIM6 levels were observed in preeclamptic placentas under ER stress. The ER stress model was successfully constructed, and knockdown of METTL3 had a beneficial effect on HTR-8/SVneo cells under ER stress as it decreased the levels of methylated TMBIM6 mRNA. Moreover, overexpression of TMBIM6 was beneficial to HTR-8/SVneo cells under ER stress as it could neutralize the harmful effects of METTL3 overexpression. Similar to the knockdown of METTL3, downregulation of YTHDF2 expression resulted in the increased expression and mRNA stability of TMBIM6. Finally, improved systemic symptoms as well as protected placentas and fetuses were demonstrated in vivo.
Conclusions
METTL3/YTHDF2/TMBIM6 axis exerts a significant role in trophoblast dysfunction resulting in PE while inhibiting METTL3 may provide a novel therapeutic approach for PE.
... N6-methyladenosine (m6A) modification takes part in RNA processing, stabilization and numerous biological functions (Meyer and Jaffrey 2014;Qin et al. 2020). Suppression of m6A methylation alleviated ischemia-reperfusion damage (Yao et al. 2020;Zhao et al. 2021). M6A dysregulation contributes to neurodegeneration in Alzheimer's disease (Yao et al. 2020;Zhao et al. 2021). ...
... Suppression of m6A methylation alleviated ischemia-reperfusion damage (Yao et al. 2020;Zhao et al. 2021). M6A dysregulation contributes to neurodegeneration in Alzheimer's disease (Yao et al. 2020;Zhao et al. 2021). M6A modification can modulate the stabilization and function of long noncoding RNAs (lncRNAs) via changing the local RNA structure or offering binding sites for m6A reader proteins (Huisman et al. 2017). ...
Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is one of the most common complications following carbon monoxide intoxication. Long noncoding RNAs (lncRNAs) exert critical functions in numerous neurological disorders. We intended to investigate the role of CRNDE in DEACMP. The DEACMP model in rats and the oxygen–glucose deprivation/reoxygenation (OGD/R) model in PC-12 cells were established. Brain and cell injuries were assessed with H&E staining, Nissl staining, TUNEL and CCK8 assays, respectively. Related proteins and RNAs were quantified with western blot and qRT-PCR. The N6-methyladenosine (m6A) level was determined using MeRIP-qPCR and immunofluorescence. Loss and gain function studies were performed to investigate the biological function of CRNDE. The potential mechanisms between each factor were explored using RNA immunoprecipitation, RNA-pull down and co-immunoprecipitation. CRNDE was increased in the hippocampal tissues of DEACMP rats and in OGD/R-treated PC-12 cells, which was positively correlated to m6A modification. Knockdown of CRNDE reduced cell damage and elevated UCHL5 and SMO expressions in OGD/R-treated PC-12 cells. hnRNPA1 was upregulated in DEACMP. In addition, inhibiting hnRNPA1 prevented apoptosis in PC-12 cells subjected to OGD/R. hnRNPA1 bound to CRNDE and remained in the nucleus, which inhibited UCHL5 expression through the formation of CRNDE-hnRNPA1-mRNA complex. UCHL5 could inhibit SMO ubiquitination and suppress PC-12 cell apoptosis during OGD/R. CRNDE silencing blocked brain injury in DEACMP, while knocking down UCHL5 reversed these effects. CRNDE interacted with hnRNPA1 to facilitate DEACMP via inhibition of UCHL5-mediated SMO deubiquitination. CRNDE might be a latent therapeutic target for treating DEACMP.
... Moreover, DNA methylation and microRNA (e.g., miR-9 and miR-144-3p) were recently proposed to be important regulators of TMEM16A expression [30][31][32][33]. Furthermore, epigenetic reprogramming has also been found to regulate various genes during I/R injury [32,34]. For example, miR-9 restrained TMEM16A expression in a canonical manner [31], and upregulation of miR-9 was able to ameliorate hepatic I/R injury [32]. ...
Ischemia/reperfusion (I/R)-induced liver injury with severe cell death is a major complication of liver transplantation. Transmembrane member 16A (TMEM16A), a component of hepatocyte Ca ²⁺ -activated chloride channel, has been implicated in a variety of liver diseases. However, its role in hepatic I/R injury remains unknown. Here, mice with hepatocyte-specific TMEM16A knockout or overexpression were generated to examine the effect of TMEM16A on hepatic I/R injury. TMEM16A expression increased in liver samples from patients and mice with I/R injury, which was correlated with liver damage progression. Hepatocyte-specific TMEM16A knockout alleviated I/R-induced liver damage in mice, ameliorating inflammation and ferroptotic cell death. However, mice with hepatic TMEM16A overexpression showed the opposite phenotype. In addition, TMEM16A ablation decreased inflammatory responses and ferroptosis in hepatocytes upon hypoxia/reoxygenation insult in vitro, whereas TMEM16A overexpression promoted the opposite effects. The ameliorating effects of TMEM16A knockout on hepatocyte inflammation and cell death were abolished by chemically induced ferroptosis, whereas chemical inhibition of ferroptosis reversed the potentiated role of TMEM16A in hepatocyte injury. Mechanistically, TMEM16A interacted with glutathione peroxidase 4 (GPX4) to induce its ubiquitination and degradation, thereby enhancing ferroptosis. Disruption of TMEM16A–GPX4 interaction abrogated the effects of TMEM16A on GPX4 ubiquitination, ferroptosis, and hepatic I/R injury. Our results demonstrate that TMEM16A exacerbates hepatic I/R injury by promoting GPX4-dependent ferroptosis. TMEM16A–GPX4 interaction and GPX4 ubiquitination are therefore indispensable for TMEM16A-regulated hepatic I/R injury, suggesting that blockades of TMEM16A–GPX4 interaction or TMEM16A inhibition in hepatocytes may represent promising therapeutic strategies for acute liver injury.
... Several types of epigenetic regulation, including histone modification (ubiquitination, acetylation, and phosphorylation), chromatin remodeling, DNA and RNA methylation, and the expression and activity of noncoding RNA, are critical hallmarks of CRC progression (11). RNA methylation is an essential biological epigenetic process that has the functional impact on the regulation of transcriptional activation and inactivation (12). To date, more than 100 modifications have been identified for all four ribonucleotides (A, C, G, and U), including N6-methyladenosine (m6A), 5-methylcytosine (m5C), 7-methylguanosine, N1methyladenosine, and 3-methyluracil (13,14). ...
Background
The RNA modification 5-methylcytosine (m5C) is one of the most prevalent post-transcriptional modifications, with increasing evidence demonstrating its extensive involvement in the tumorigenesis and progression of various cancers. Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related deaths worldwide. However, the role of m5C modulators in shaping tumor microenvironment (TME) heterogeneity and regulating immune cell infiltration in CRC requires further clarification.
Results
The transcriptomic sequencing data of 18 m5C regulators and clinical data of patients with CRC were obtained from The Cancer Genome Atlas (TCGA) and systematically evaluated. We found that 16 m5C regulators were differentially expressed between CRC and normal tissues. Unsupervised cluster analysis was then performed and revealed two distinct m5C modification patterns that yielded different clinical prognoses and biological functions in CRC. We demonstrated that the m5C score constructed from eight m5C-related genes showed excellent prognostic performance, with a subsequent independent analysis confirming its predictive ability in the CRC cohort. Then we developed a nomogram containing five clinical risk factors and the m5C risk score and found that the m5C score exhibited high prognostic prediction accuracy and favorable clinical applicability. Moreover, the CRC patients with low m5C score were characterized by “hot” TME exhibiting increased immune cell infiltration and higher immune checkpoint expression. These characteristics were highlighted as potential identifiers of suitable candidates for anticancer immunotherapy. Although the high m5C score represented the non-inflammatory phenotype, the CRC patients in this group exhibited high level of sensitivity to molecular-targeted therapy.
Conclusion
Our comprehensive analysis indicated that the novel m5C clusters and scoring system accurately reflected the distinct prognostic signature, clinicopathological characteristics, immunological phenotypes, and stratifying therapeutic opportunities of CRC. Our findings, therefore, offer valuable insights into factors that may be targeted in the development of precision medicine-based therapeutic strategies for CRC.
... Ischemic heart disease is one of the leading causes of morbidity and mortality and is a severe health issue worldwide [1,2]. Studies have demonstrated that cardiac blood flow restoration can cause ischemia reperfusion (I/R) injury immediately after prolonged ischemia, which further impairs the cardiac functions of the ischemic heart [3][4][5]. Ischemic preconditioning has exhibited protective effects on I/R-induced myocardial infarction and lethal arrhythmia [6]. In addition, ischemic postconditioning (IPost) represents short periods of nonlethal I/R performed at the onset of reperfusion [4,7]. ...
Ischemic postconditioning (IPost) represents short periods of nonlethal ischemia–reperfusion performed at the onset of reperfusion. Studies have shown that IPost involves various biological processes such as cell proliferation, apoptosis, and pyroptosis and can activate complex signaling pathways. CCL12 is a critical mediator in the inflammatory process after tissue injury. In the present study, we examined the potential actions of CCL12-mediated signaling pathways in cardioprotection after IPost using a cardiomyocyte model. By applying the bioinformatics analysis, we found that CCL12 was upregulated in the rat heart tissues after I/R injury, and the expression level of CCL12 was restored in rats with IPost. The in vitro studies showed that CCL12 and CCR2 expression levels were upregulated in the hypoxia/reoxygenation (H/R)-induced H9C2 cells, which was attenuated in the H/R + hypoxia post-conditioning (PostC) group. The functional assays showed that H/R treatment reduced cell viability, increased cell apoptosis, and promoted fibrosis and pyroptosis of H9C2 cells, which was attenuated in the H/R + PostC group. Overexpression of CCL12 impaired the protective action of hypoxia post-conditioning in the H9C2 cells. Further mechanistic studies showed that miR-144-5p could directly target the 3′ untranslated region of CCL12. Overexpression of miR-144-5p markedly repressed the expression levels of CCL12 and CCR2 in H9C2 cells, while miR-144-5p inhibition had the opposite effects. Furthermore, the inhibition of miR-144-5p reduced the cell viability, increased cell apoptosis, and enhanced fibrosis and pyroptosis of H9C2 cells after H/R or H/R + PostC treatment. In conclusion, CCL12 was downregulated in cardiomyocytes following ischemic postconditioning, and CCL12 overexpression impaired the cardioprotective actions of ischemic postconditioning by reducing cell viability, enhancing cell apoptosis, fibrosis, and pyroptosis. Further mechanistic evidence revealed that CCL12 was a direct target of miR-144-5p, and miR-144-5p/CCL12/CCR2 signaling may represent a critical pathway in mediating the cardioprotective effects of ischemic postconditioning.
