Role of miRNA-1 and miRNA-21 in Acute Myocardial Ischemia-Reperfusion Injury and Their Potential as Therapeutic Strategy
<p>HMDD pipeline to filter for miRs dysregulated in myocardial IR injury and other cardiac diseases. miR-1 and miR-21 are dysregulated in myocardial IR injury, CAD, and MI. The findings from the HMDD analysis for miR-1 have been modified with a literature search to include CAD and myocardial IR injury. IR: ischemia-reperfusion injury; MI: myocardial infarct. Created with BioRender.com.</p> "> Figure 2
<p>Overview of Action of miR-1 and miR-21 on Cardiomyocytes, Fibroblasts, and Immune Cells in Hearts Subjected to I/R Injury. In cardiomyocytes, inhibition of miR-1 prevents apoptosis via Bcl-2 and PKC, whereas miR-21 inhibits apoptosis via PDCD4. In cardiac fibroblasts, inhibition of miR-21 prevents TGF-β signaling and ECM synthesis via SMAD7, TGFβIII, or SPRY1. In immune cells, miR-21 regulates multiple aspects of macrophage function, including inhibition of cytokine production and activation of macrophage polarization through P38, NF-kB. Created with BioRender.com.</p> ">
Abstract
:1. Introduction
2. miRNAs: A Link between IR Injury and Other Cardiac Diseases in Humans
2.1. Role of Cardiac miR-1 in IR Injury
2.2. Role of Cardiac miR-21 in IR Injury
miR | Findings | Function | Therapeutic Potential | Reference |
---|---|---|---|---|
miR-1 | ↓ miR-1 in rodent hearts in response to IR injury. | ↑ Bcl-2 after IR (HR) injury | miR-1 inhibition ↑ Bcl-2 and ↓ IA/AAR and cell apoptosis after IR(HR) injury | [31] |
↑ miR-1 in rodent hearts in response to IR injury | ↓ Bcl-2 and Cnx43 after IR (HR) injury | miR-1 mimic ↓ Bcl-2 and Cnx43 in H9C2 cells subjected to HR injury; Telmisartan ↑ Bcl-2 and Cnx43 and ↓ miR-1 after IR (HR) injury | [32] | |
↑ miR-1 in rodent hearts in response to IR injury or MI | ↓ KCNJ2/Kir2.1 and GJA1/Cx43 in ischemic myocardium | miR-1 overexpression ↓ KCNJ2/Kir2.1 and GJA1/Cx43 after MI; sEHIs reversed the effects | [33] | |
↓ miR-1 in infarcted human hearts in response to MI | N/A | N/A | [41,42] | |
↓ miR-1 in H9c2 cells in response to HR | ↑ Bcl-2 after IR (HR) injury | miR-1 inhibition ↑ Bcl-2 and ↓ IA/AAR and cell apoptosis after IR(HR) injury | [31] | |
↑ miR-1 in neonatal cardiac myocytes in response to HR | ↑ apoptosis and ↓ Bcl-2 after HR injury | miR-1 mimic ↑ apoptosis and ↓ Bcl-2 in neonatal rat cardiomyocytes subjected to HR injury; H2S reverses the effects | [34] | |
↑ miR-1 in remote myocardium compared to infarcted zone or healthy hearts in infarcted human hearts | N/A | N/A | [43] | |
↑levels of serum miR-1 after acute MI in pigs and humans | N/A | N/A | [44] | |
miR-1 overexpression worsened cardiac I/R injury in transgenic mice | ↑ LDH, CK levels, caspase-3 expression, apoptosis and cardiac infarct area after IR (HR) injury | miR-1 overexpression exacerbate IR (HR) injury by ↑ LDH, CK levels, caspase-3 expression, apoptosis and cardiac infarct area | [35] | |
miR-1 inhibition protects against IR (HR) injury in rodents and cardiomyocytes | ↑ LDH, CK levels, caspase-3 expression, apoptosis and cardiac infarct area after IR (HR) injury | LNA-antimiR-1 attenuated IR (HR) by ↑ PKCε and HSP60 | [35] | |
miR-1 inhibition protects against IR (HR) injury in rodents and H9c2 cells | ↑ Bcl-2 after IR (HR) injury | miR-1 inhibition ↑ Bcl-2 and ↓ IA/AAR and cell apoptosis after IR(HR) injury | [31] | |
miR-21 | ↓ miR-21 in infarct areas of mouse IR model | ↑ apoptosis and PDCD4, Bax/Bcl-2 and cleaved caspase-3/caspase-3 ratio after IR injury | miR-21 mimics ↓ apoptosis by inhibiting PDCD4 in cardiomyocytes subjected to OGD/R | [70] |
diverse time-dependent changes in circulating miR-21 in post-MI patients | N/A | N/A | [13] | |
miR-21 protected cultured cardiac myocytes against HR-induced apoptosis via its target PDCD4 | ↑ apoptosis and PDCD4, Bax/Bcl-2 and cleaved caspase-3/caspase-3 ratio after IR injury | miR-21 mimics ↓ apoptosis by inhibiting PDCD4 in cardiomyocytes subjected to OGD/R | [70] | |
miR-21 protected cultured cardiac myocytes against HR-induced apoptosis via its target PDCD4 | ↑ apoptosis in cardiomyocytes treated with H2O2 | pre-miR-21 ↓ H2O2-induced apoptosis of cardiomyocytes; overexpression of PDCD4 inhibited pre-miR-21 mediated protective effect | [71] |
3. Role of miR-1 and miR-21 in Different Cell Types of IR Injured Hearts
3.1. Single-Cell Sequencing Data on IR Injury
3.2. Role of miR-1 and miR-21 in Cardiac Cell Types Post-MI
3.2.1. Cardiomyocytes
3.2.2. Fibroblasts
3.2.3. Immune Cells
3.3. Studies Integrating mRNA Expression Data from Single-Cell with miRNAs Evident in IR Injury
4. Therapeutic Potential of miRNAs in IR Injury
4.1. Modes of miRNA Therapy Delivery
4.2. Potential Benefits of Delivering miRNA Therapies Post-MI
5. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
MI | myocardial infarction |
PCI | percutaneous coronary intervention |
IR | ischemia-reperfusion |
miRNAs | microRNAs |
miR-1 | miRNA-1 |
miR-21 | miRNA-21 |
CVD | cardiovascular disease |
Cx43 | connexin 43 |
Irx5 | iroquois homeobox domain 5 |
KCND2 | potassium voltage-gated channel subfamily D member 2 |
EPCs | endothelial progenitor cells |
ROS | reactive oxygen species |
PDCD4 | programmed cell death 4 |
scRNAseq | single-cell RNA sequencing |
M1 | pro-inflammatory macrophage |
M2 | anti-inflammatory macrophage |
PKCε | protein kinase C epsilon |
TGF-β | transforming growth factor-β |
SMADs | decapentaplegic homologs |
TGFβIII | TGF-β receptor III |
DAMP | damage-associated molecular patterns |
LNA | locked nucleic acids |
OME | 2′-O-methyl group |
AAV | adeno-associated viruses |
MSC-EV | mesenchymal stem cell-derived extracellular vesicles |
miR-133 | miRNA-133 |
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Jayawardena, E.; Medzikovic, L.; Ruffenach, G.; Eghbali, M. Role of miRNA-1 and miRNA-21 in Acute Myocardial Ischemia-Reperfusion Injury and Their Potential as Therapeutic Strategy. Int. J. Mol. Sci. 2022, 23, 1512. https://doi.org/10.3390/ijms23031512
Jayawardena E, Medzikovic L, Ruffenach G, Eghbali M. Role of miRNA-1 and miRNA-21 in Acute Myocardial Ischemia-Reperfusion Injury and Their Potential as Therapeutic Strategy. International Journal of Molecular Sciences. 2022; 23(3):1512. https://doi.org/10.3390/ijms23031512
Chicago/Turabian StyleJayawardena, Eranthi, Lejla Medzikovic, Gregoire Ruffenach, and Mansoureh Eghbali. 2022. "Role of miRNA-1 and miRNA-21 in Acute Myocardial Ischemia-Reperfusion Injury and Their Potential as Therapeutic Strategy" International Journal of Molecular Sciences 23, no. 3: 1512. https://doi.org/10.3390/ijms23031512