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miR-181c-5p Exacerbates Hypoxia/Reoxygenation-Induced Cardiomyocyte Apoptosis via Targeting PTPN4
Liang Ge1, Yin Cai2,3, Fan Ying2,3
1Department of Anesthesiology, The First Hospital, Jilin University, Jilin, China.
Background:
Activation of cell apoptosis is a major form of cell death during myocardial ischemia/reperfusion injury (I/RI). Therefore, examining ways to control cell apoptosis has important clinical significance for improving postischemic recovery. Clinical evidence demonstrated that miR-181c-5p was significantly upregulated in the early phase of myocardial infarction. However, whether or not miR-181c-5p mediates cardiac I/RI through cell apoptosis pathway is unknown. Thus, the present study is aimed at investigating the role and the possible mechanism of miR-181c-5p in apoptosis during I/R injury by using H9C2 cardiomyocytes.
Methods And Results:
The rat origin H9C2 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R, 6 hours hypoxia followed by 6 hours reoxygenation) to induce cell injury. The results showed that H/R significantly increased the expression of miR-181c-5p but not miR-181c-3p in H9C2 cells. In line with this, in an in vivo rat cardiac I/RI model, miR-181c-5p expression was also significantly increased. The overexpression of miR-181c-5p by its agomir transfection significantly aggravated H/R-induced cell injury (increased lactate dehydrogenase level and reduced cell viability) and exacerbated H/R-induced cell apoptosis (greater cleaved caspases 3 expression, Bax/Bcl-2 and more TUNEL-positive cells). In contrast, inhibition of miR-181c-5p in vitro had the opposite effect. By using computational prediction algorithms, protein tyrosine phosphatase nonreceptor type 4 (PTPN4) was predicted as a potential target gene of miR-181c-5p and was verified by the luciferase reporter assay. The overexpression of miR-181c-5p significantly attenuated the mRNA and protein expression of PTPN4 in H9C2 cardiomyocytes. Moreover, knockdown of PTPN4 significantly aggravated H/R-induced enhancement of LDH level, cleaved caspase 3 expression, and apoptotic cell death, which mimicked the proapoptotic effects of miR-181c-5p in H9C2 cardiomyocytes.
Conclusions:
These findings suggested that miR-181c-5p exacerbates H/R-induced cardiomyocyte injury and apoptosis via targeting PTPN4 and that miR-181c-5p/PTPN4 signaling may yield novel strategies to combat myocardial I/R injury.
Insights
MicroRNA-181c-5p aggravates heart injury and apoptosis during ischemia/reperfusion by targeting PTPN4. Inhibiting miR-181c-5p may offer therapeutic strategies for myocardial I/R injury.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Cell Death Mechanisms
Background:
- Myocardial ischemia/reperfusion injury (I/RI) involves significant cell apoptosis.
- miR-181c-5p is upregulated in myocardial infarction, but its role in I/RI is unclear.
- Understanding miR-181c-5p's mechanism in I/RI is clinically significant.
Purpose of the Study:
- To investigate the role of miR-181c-5p in cardiomyocyte apoptosis during I/R injury.
- To elucidate the underlying molecular mechanism of miR-181c-5p in I/R injury.
- To explore potential therapeutic targets for myocardial I/R injury.
Main Methods:
- H9C2 cardiomyocytes and rat cardiac I/RI models were used.
- Hypoxia/reoxygenation (H/R) induced injury and apoptosis.
- miR-181c-5p expression, cell viability, apoptosis markers, and PTPN4 levels were assessed.
- Luciferase reporter assays identified PTPN4 as a target gene.
Main Results:
- H/R increased miR-181c-5p expression in cardiomyocytes and cardiac tissue.
- Overexpression of miR-181c-5p worsened H/R-induced injury and apoptosis.
- Inhibition of miR-181c-5p protected against H/R injury.
- miR-181c-5p directly targets and downregulates PTPN4 expression.
- PTPN4 knockdown mimicked the pro-apoptotic effects of miR-181c-5p.
Conclusions:
- miR-181c-5p exacerbates H/R-induced cardiomyocyte injury and apoptosis by targeting PTPN4.
- The miR-181c-5p/PTPN4 signaling pathway is a potential therapeutic target for myocardial I/R injury.
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