Table 1.
The lncRNA-miRNA-mRNA axis in myocardial I/R.
| Models | Species | Cell dysfunction | Expression | lncRNA | miRNA | mRNA | Function | Mechanism | Relationship | Prediction tool | Ref |
|---|---|---|---|---|---|---|---|---|---|---|---|
| HL-1 cells and MCM under H/R treatment | Mouse | Autophagy | ↑ | AK088388 | miR-30a | Beclin1/LC3 | Interfering AK088388 can promote the viability of H/R cardiomyocytes, reduce lactate dehydrogenase release, and reduce apoptosis | miR-30a had binding sites on AK088388 | NR | n/a | [75] |
| I/R in rats and newborn rats' primary cardiomyocytes under H/R treatment | Rat | Autophagy; apoptosis | ↑ | AK139128 | miR-499 | FOXO4 | Knockdown of AK139128 impressively alleviates cardiomyocyte autophagy and apoptosis | There are several complementary binding sites within miR-499 and AK139128 | NR | starBase v3.0; TargetScan | [73] |
| IRI in mice and mice primary cardiomyocytes under H/R treatment | Mouse | Autophagy; apoptosis | ↑ | AK139328 | miR-204-3p | CK; CK-MB; LDH | Knockdown of lncRNA AK139328 relieved myocardial I/R injury in DM and inhibited cardiomyocyte autophagy as well as apoptosis of DM | Modulated miR-204-3p directly | NR | n/a | [74] |
| IRI in mice and mice primary cardiomyocytes under A/R | Mouse | Autophagy | ↑ | APF | miR-188-3p | ATG7 | APF conveys the autophagic signal in cardiomyocytes. APF participates in mediating the signal for autophagy and cell death in the heart | Is able to directly bind to miR-188-3p and regulate its activity | NR | n/a | [76] |
| I/R in mice and mice primary cardiomyocytes under anoxia | Mouse | Apoptosis | ↓ | CARL | miR-539 | PHB2 | CARL is able to prevent mitochondrial fission, apoptosis, and myocardial injury in myocardial infarction | Can act as an endogenous miR-539 sponge | NR | n/a | [43] |
| H9C2 cells under H/R treatment | Human; rat | Proliferation; apoptosis | ↓ | FTX | miR-410-3p | Fmr1 | Overexpression of FTX relieved the damage caused by H/R treatment in H9c2 cells | A sponge for miR-410-3p | NR | LncBase predicted v.2 | [41] |
| I/R in mice and mouse primary cardiomyocytes under H2O2 treatment | Mouse | Apoptosis | ↓ | FTX | miR-29b-1-5p | Bcl2l2 | Enhanced expression of FTX inhibits cardiomyocyte apoptosis | Functions as endogenous sponge for miR-29b-1-5p | NR | RNA hybrid | [40] |
| IRI in rats and H9C2 cells under H/R treatment | Rat | Apoptosis | ↑ | GAS5 | miR-532-5p | PI3K/AKT | Silencing of lncRNA GAS5 was able to attenuate myocardial damage, as cell viability increased and the apoptosis rate decreased | Functioned as a molecular sponge of miR-532-5p | NR | RNA hybrid | [44] |
| IRI | n/a | n/a | n/a | GAS5 | miR-137 | Serpina3 | lncRNA GAS5 may exacerbate myocardial I/R injury through regulating serpina3 via targeting miR-137 | Serve as a ceRNA for miR-137 | n/a | n/a | [45] |
| Neonatal rats' primary cardiomyocytes under H/R treatment | Rat | Apoptosis | ↓ | H19 | miR-29b-3p | cIAP1 | H19 mediated the antiapoptotic effect of H/post against H/R-induced injury to aged cardiomyocytes | Participated in the regulation of miR-29b-3p | NR | Bioinformatics analysis | [24] |
| IR | n/a | Apoptosis | n/a | H19 | miR-22-3p | n/a | lncRNA H19/miR-22-3p axis might be a potential regulated signaling pathway of apoptosis in MIRI | Acts as a ceRNA to suppress the activity of miR-22-3p | PR | n/a | [25] |
| I/R in mice and H9C2 cells under H2O2 treatment | Mouse | Necrosis | ↓ | H19 | miR-103/107 | FADD | H19 mediates necrotic cell death in cardiomyocytes | Is able to directly bind to miR-103/107 | NR | n/a | [83] |
| I/R in mice and NMVCs under H2O2 treatment | Mouse | Apoptosis | ↓ | H19 | miR-877-3p | Bcl2 | Overexpression of H19 alleviated myocardial I/RI of mice and cardiomyocyte injury induced by H2O2 | Functions as a miR-877-3p ceRNA | NR | RegRNA2.0；starBase；TargetScan | [26] |
| Mouse primary cardiomyocytes under OGD/R condition | Mouse | Viability; apoptosis; inflammation; oxidative stress | ↑ | H19 | miR-675 | PPARα | Knockdown of H19 significantly reduced infarct size, increased left ventricular systolic pressure, and decreased left ventricular end-diastolic pressure in a mouse model of myocardial I/R | Is a precursor of miR-675 | PR | n/a | [27] |
| I/R in mice | Mouse | Fibrosis; apoptosis | ↑ | HIF1A-AS1 | miR-204 | SOCS2 | Downregulation of HIF1A-AS1 alleviates ventricular remodeling and improve cardiac function in mice after myocardial I/R injury | Adsorbs miR-204 as a ceRNA | NR | RNA22 | [46] |
| IRI in mice and H9C2 cells under H/R treatment | Mouse | Apoptosis | ↑ | HOTAIR | miR-451 | Cab39 | Hotair overexpression prevented I/R-induced oxidative stress, cardiac myocyte apoptosis, and cardiac dysfunction | Contributed to Hotair-mediated miR-451 inhibition | NR | n/a | [38] |
| IR | n/a | n/a | ↓ | HOTAIR | miR-126 | n/a | Circulating HOTAIR/miR-126 axis maybe a potential biomarker and risk factor predictor for MI/R injury | Act as a ceRNA | n/a | n/a | [39] |
| H9C2 cells under H2O2 treatment | Rat | Apoptosis; proliferation | ↓ | HOTAIR | miR-125 | MMP-2 | Repression of HOTAIR accelerates H9c2 cells injury in response to oxidative stress | miR-125 is a target of HOTAIR | NR | Bioinformatic analysis | [37] |
| IRI in rats and H9C2 cells under H/R treatment | Rats | Inflammation; apoptosis | ↓ | HULC | miR-377-5p | NLRP3/Caspase-1/IL-1β | HULC modulated myocardial I/R injury in rat models and cardiomyocyte apoptosis in H/R cell models via targeting miR-377-5p through NLRP3/Caspase-1/IL-1β pathway | Acted as a ceRNA by sponging miR-377-5p | NR | Bioinformatic analysis | [57] |
| IRI in mice and mice primary cardiomyocytes under H/R treatment | Mouse | Apoptosis | ↑ | KCNQ1OT1 | miR-204-5p | LGALS3 | The downregulation of LGALS3 resulted in the alleviation of myocardial IR injury in mouse models | Bind to miR-204-5p | NR | LncBase v.2; miRDB; DIANA TOOLS | [47] |
| AMI in rats and HL-1 cells under H/R treatment | Rat | Apoptosis | n/a | MALAT1 | miR-125b-5p | NLRC5 | Downregulation of MALAT1 attenuated heart damage in an AMI model rat | MALAT1 negatively regulates miR-125b-5p expression | NR | TargetScan | [21] |
| MI in mice and AC16 cells under hypoxia condition | Mouse | Apoptosis; proliferation | ↑ | MALAT1 | miR-200a-3p | PDCD4 | Knockdown of MALAT1 enhanced cell viability, promoted cell cycle progress, and suppressed cell apoptosis | Acted as a ceRNA to sponge miR-200a-3p | NR | starBase v.2.0 | [20] |
| IRI | n/a | Inflammation | ↑ | MALAT1 | miR-26b | PTGS2 | Aggravate inflammation response through regulating PTGS2 by targeting miR-26b in MI/R injury | Can act as ceRNA by binding to consensus MREs of miR-26b | n/a | n/a | [88] |
| IR | n/a | Autophagy | ↑ | MALAT1 | miR-204 | LC3-II | MALAT1/miR-204/LC3-II axis is a potential regulated axis of autophagy in myocardial I/R injury | Can sponge miR-204 | n/a | n/a | [72] |
| IR | n/a | Inflammation | ↑ | MALAT1 | miR-203 | n/a | lncRNA MALAT1 may increase cardiomyocyte inflammation and myocardial injury during I/R | n/a | NR | n/a | [89] |
| IR | n/a | Inflammation | ↑ | MALAT1 | miR-133 | NLRP3 | lncRNA MALAT1 may sponge miR-133 to promote NLRP3 inflammasome expression in ischemia-reperfusion-injured heart | Acted as a ceRNA to inhibit miR-133 action | NR | n/a | [87] |
| I/R in mice and HL-1 under H/R treatment | Mouse | Apoptosis | ↑ | MALAT1 | miR-145 | Bnip3 | MALAT1 overexpression reverses cardioprotective effects of fentanyl as indicated by an increase in LDH release and cell apoptosis | Being regulated by miR-145 of MALAT1 | NR | n/a | [22] |
| H9C2 cells under OGD/R condition | Mouse | Autophagy | ↑ | MALAT1 | miR-20b-5p | Beclin1 | MALAT1 antagonized the inhibitory effects of miR-20b-5p on Beclin1-related cardiomyocyte autophagy in OGD/R injury | Functions as a ceRNA for miR-20b-5p | NR | n/a | [70] |
| IR | n/a | Autophagy | ↑ | MALAT1 | miR-204 | n/a | lncRNA MALAT1 may increase cardiomyocyte autophagy and myocardial injury during I/R by negatively regulating miR-204 expression | Might serve as a sponge to suppress miR-204 action | NR | n/a | [69] |
| I/R in mice and mice primary cardiomyocytes under A/R | Mouse | Apoptosis | ↓ | MDRL | miR-361 | miR-484 | Knockdown of MDRL induced mitochondrial fission and apoptosis | Is a functional sponge for miR-361 | NR | n/a | [42] |
| I/R in rats and H9C2 cells under H/R treatment | Rat | Apoptosis; proliferation | ↑ | MEG3 | miR-7-5p | PARP1; Caspase-3 | Overexpression of MEG3 increased the I/R-induced CK and LDH activities and cell apoptosis and decreased cell proliferation | By directly binding to miR-5-7p | NR | n/a | [48] |
| I/RI | n/a | n/a | ↑ | MEG3 | miR-223 | n/a | Circulating MEG3/miR-223 axis maybe a potential biomarker and risk factor predictor for MI/R injury | Acted as an endogenous sponge for miR-223 | n/a | n/a | [49] |
| MI/R in mice and H9C2 cells under H2O2 treatment | Mouse | Proliferation | ↑ | NEAT1 | miR-495-3p | MAPK6 | Loss of NEAT1 in H9C2 cells could repress the viability and proliferation of cells | Sponges miR-495-3p | NR | n/a | [31] |
| I/R in rats and H9C2 cells under H/R treatment | Rat | Apoptosis | ↑ | NEAT1 | miRNA-520a | n/a | Knockdown of NEAT1 serves a protective role against H/R-induced cardiomyocyte apoptosis | miR-520a was indicated to directly target NEAT1 | NR | Bioinformatics analysis | [32] |
| H9C2 cells under OGD/R condition | Rat | Proliferation; apoptosis | ↑ | NEAT1 | miR-193a | n/a | Downregulation of lnc-NEAT1 promoted cell proliferation and inhibited cell apoptosis | miR-193a was targeted by lnc-NEAT1 in I/R injury H9c2 cells | NR | starBase; miRcode | [33] |
| I/R in mice and rat primary cardiomyocytes under H2O2 treatment | Mouse | Apoptosis | ↓ | NEAT1 | miR-125a-5p | Bcl2l12 | Ectopic overexpression of NEAT1 suppresses cardiomyocyte apoptosis induced by hydrogen peroxide | Functions as miR-125a-5p sponge | NR | starBase v2.0 | [36] |
| IR | n/a | n/a | ↑ | NEAT1 | miR-27b | PINK1 | lncRNA NEAT1 may aggravate diabetic MI/R injury | Can sponge miR-27b | n/a | n/a | [35] |
| IR in mice and newborn rat primary cardiomyocytes under hypoxia condition | Mouse | Proliferation; apoptosis | ↑ | NEAT1 | miR-378a-3p | ATG12 | lncRNA NEAT1 significantly promoted cell proliferation and migration of cardiomyocytes | Was capable of targeting miR-378a-3p | NR | RNA hybrid | [34] |
| I/R in mice and mice primary cardiomyocytes under H2O2 treatment | Mouse | Necrosis | ↑ | NRF | miR-873 | RIPK1/RIPK3 | Knockdown of NRF antagonizes necrosis in cardiomyocytes and reduces necrosis and myocardial infarction upon I/R injury | As an endogenous sponge RNA | NR | n/a | [82] |
| IRI in rats and H9C2 cells under H/R treatment | Rats | Apoptosis | ↓ | Oprm1 | miR-30b-5p | CSE | Overexpression of lncRNA Oprm1 mitigated MIRI and preserved the cardiac function in vivo | Competitively combines with miR-30b-5p | NR | Bioinformatic analysis | [58] |
| IRI in rats and H9C2 cells under OGD/R condition | Rats | Apoptosis | ↓ | OIP5-AS1 | miR-29a | SIRT1/AMPK/PGC1α | OIP5-AS1 overexpression alleviated reactive oxygen species-driven mitochondrial injury and consequently decreased apoptosis in MI/R rats and H9c2 cells exposed to OGD/R | Acted as a ceRNA of miR-29a | NR | DIANA-LncBase; starBase | [59] |
| AMI in rats | Rat | Apoptosis | ↑ | PINT | miR-208a-3p | JUN | Low expression of LINC-PINT could suppress myocardial infarction apoptotic cells | Could sponge miR-208a-3p | NR | n/a | [50] |
| H9C2 cells under hypoxia condition | Rat | Apoptosis | ↑ | RMRP | miR-206 | ATG3 | Upregulation of RMRP may aggravate myocardial I/R injury | Sponging miR-206 | NR | n/a | [51] |
| IRI in rats and HCMs under H/R treatment | Rats | Inflammation; apoptosis | ↑ | ROR | miR-124-3p | TRAF6 | Overexpression of ROR further enhanced the H/R-induced inflammation and cell apoptosis | Sponged and negatively regulated miR-124-3p | NR | Bioinformatics analysis | [56] |
| MI/R in mice and HUVECs under H/R treatment | Human; mouse | Proliferation | ↑ | SNHG1 | miR-140-3p | HIF-1α/VEGF | SNHG1 upregulation under H/R increased HUVEC proliferation, tube formation, and cell migration | Functioned as a ceRNA of miR-140-3p | NR | TargetScan | [55] |
| IR in mice and neonatal mice primary cardiomyocytes under H2O2 treatment | Mouse | Cell viability; apoptosis | ↑ | TUG1 | miR-132-3p | HDAC3 | Knocking down TUG1 significantly improved viability, inhibited apoptosis, and reduced ROS production in H2O2-stressed cardiomyocytes in vitro, and alleviated I/R-induced AMI in vivo | Sponged miR-132-3p | NR | TargetScan | [52] |
| IRI in mice and mice primary cardiomyocytes under H2O2 treatment | Mouse | Autophagy; apoptosis | ↑ | TUG1 | miR-142-3p | HMGB1/Rac1 | Inhibition of TUG1 and overexpression of miR-142-3p inhibited cell apoptosis and autophagy in cardiomyocytes | Sponging miR-142-3p | NR | n/a | [53] |
| IRI in rats and H9C2 cells under H/R treatment | Rat | Autophagy | ↓ | UCA1 | miR-128 | HSP70 | UCA1/miR-128 mediated the mechanism of MPostC on autophagy and myocardial injury | Could bind with miR-128 | NR | n/a | [77] |
| IRI | n/a | Apoptosis | ↓ | UCA1 | miR-143 | n/a | lncRNA UCA1 interferes with miR-143 expression to modulate cardiomyocyte apoptosis in myocardial I/R injury | lncRNA UCA1 directly interactS with miR-143 | NR | n/a | [54] |
↑: the upward arrow indicates increased expression of lncRNAs; ↓: the downward arrow indicates decreased expression of lncRNAs; n/a: not applicable; NR: lncRNAs negatively regulate miRNAs; PR: lncRNAs positively regulate miRNAs; RC: reciprocal correlations between lncRNAs and miRNAs; IRI: ischemia-reperfusion injury; AMI: acute myocardial infarction; H/R: hypoxia-reoxygenation; HCMs: human cardiac myocytes; HUVECs: human umbilical vein endothelial cells; ceRNA: competing endogenous RNA; HIF1A-AS1: hypoxia inducible factor 1α-antisense RNA 1; MALAT1: metastasis-associated lung adenocarcinoma transcript 1; TUG1: taurine-upregulated gene 1; APF: autophagy-promoting factor; GAS5: growth arrest specific 5; MEG3: maternally expressed gene 3; HOTAIR: HOX transcript antisense RNA; HULC: highly upregulated in liver cancer; IL-1β: interleukin-1β; UCA1: urothelial carcinoma-associated 1; NEAT1: nuclear paraspeckle assembly transcript 1; FTX: five prime to Xist; SNHG1: small nucleolar RNA host gene 1; RMRP: mitochondrial RNA-processing endoribonuclease; PINT: p53-induced transcript; NRF: necrosis-related factor; OIP5-AS1: Opa-interacting protein 5-antisense transcript 1; CARL: cardiac apoptosis-related lncRNA; MDRL: mitochondrial dynamic-related lncRNA; KCNQ1OT1: KCNQ1 opposite strand/antisense transcript 1; NLRC5: nucleotide-binding and oligomerization domain-like receptor C5; AKT: protein kinase B; PDCD4: programmed cell death 4; PTGS2: prostaglandin-endoperoxide synthase 2; NLRP3: nod-like receptor protein-3; BNIP3: Bcl2 19 kDa protein-interacting protein 3; SOCS2: suppressor of cytokine signaling 2; HDAC3: histone deacetylase 3; ATG7: autophagy-related gene 7; PI3K: phosphatidylinositol 3 kinase; FADD: Fas-associated protein with death domain; cIAP1: cellular inhibitor of apoptosis protein 1; PARP1: poly(ADP-ribose) polymerase 1; PPARα: peroxisome proliferator-activated receptor α; Cab39: calcium-binding protein 39; MMP-2: matrix metalloproteinase-2; Bcl2: B-cell lymphoma-2; HSP70: heat shock protein 70; MAPK6: mitogen-activated protein kinase 6; ATG3/7/12: autophagy-related gene 3/7/12; Bax: B-cell lymphoma protein 2- (Bcl2-) associated X; PINK1: PTEN-induced putative kinase 1; Bcl2l2/12: B-cell lymphoma-2-like 2/12; HIF-1: hypoxia inducible factor-1; VEGF: vascular endothelial growth factor; Fmr1: fragile X mental retardation 1; FOXO4: forkhead box O4; CK: creatine kinase; CM-MB: creatine kinase MB form; LDH: lactate dehydrogenase; RIPK1/3: receptor-interacting serine/threonine-protein kinase 1/3; CSE: cystathionine-γ-lyase; SIRT1: sirtuin 1; AMPK: adenosine monophosphate-activated protein kinase; PGC1α: peroxisome proliferator-activated receptor-γ coactivator-1α; TRAF6: TNF receptor-associated factor 6; HMGB1: high-mobility group box 1; Rac1: Ras-related C3 botulinum toxin substrate 1; PHB2: prohibitin 2; LGALS3: galectin-3.