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Exosomal miR-17-3p Alleviates Programmed Necrosis in Cardiac Ischemia/Reperfusion Injury by Regulating TIMP3
Zhuyuan Liu1, Didi Zhu1, Fuchao Yu1
1Department of Cardiology, Zhongda Hospital, Southeast University, Hunan Road, Nanjing, 210009 Jiangsu, China.
Objective:
Myocardial ischemia/reperfusion (I/R) injury can aggravate myocardial injury. Programmed necrosis plays a crucial role in this injury. However, the role of exosomal miRNAs in myocardial I/R injury remains unclear. Therefore, this study is aimed at exploring the function and mechanism of exosomal miR-17-3p in myocardial I/R injury.
Methods:
The myocardial I/R injury animal model was established in C57BL/6 mice. Exosomes were identified using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. Programmed necrosis was detected by PI staining. Heart function and myocardial infarct size were evaluated using echocardiography and triphenyl tetrazolium chloride (TTC) staining, respectively. Histopathological changes were visualized by hematoxylin and eosin (H&E) and Masson staining. The regulation of TIMP3 expression by miR-17-3p was verified using a dual-luciferase reporter assay. Lactate dehydrogenase (LDH) and tumor necrosis factor-α (TNF-α) levels were measured by enzyme-linked immunosorbent assays (ELISA). TIMP3 expression was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting.
Results:
We demonstrated that miR-17-3p was significantly downregulated in peripheral blood exosomes after cardiac I/R injury. Further analysis indicated that exosomal miR-17-3p attenuated H2O2-induced programmed necrosis in cardiomyocytes in vitro. Moreover, TIMP3 was a target for miR-17-3p. TIMP3 affected H2O2-induced programmed necrosis in cardiomyocytes. This effect was modulated by miR-17-3p in vitro. Furthermore, exosomal miR-17-3p greatly alleviated cardiac I/R injury in vivo.
Conclusions:
The present study demonstrated that exosomal miR-17-3p alleviated the programmed necrosis associated with cardiac I/R injury by regulating TIMP3 expression. These findings could represent a potential treatment for I/R injury.
Insights
Exosomal miR-17-3p alleviates myocardial ischemia/reperfusion (I/R) injury by reducing programmed necrosis. This microRNA targets TIMP3, offering a potential therapeutic strategy for I/R injury.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Exosome Biology
Background:
- Myocardial ischemia/reperfusion (I/R) injury exacerbates heart damage, with programmed necrosis playing a key role.
- The involvement of exosomal microRNAs (miRNAs) in myocardial I/R injury is not well understood.
Purpose of the Study:
- To investigate the function and mechanism of exosomal miR-17-3p in myocardial I/R injury.
- To explore the potential of exosomal miR-17-3p as a therapeutic agent for I/R injury.
Main Methods:
- Established a mouse model of myocardial I/R injury.
- Utilized transmission electron microscopy, nanoparticle tracking analysis, and Western blotting to characterize exosomes.
- Assessed programmed necrosis, cardiac function, infarct size, and histopathological changes.
- Verified the interaction between miR-17-3p and TIMP3 using a dual-luciferase reporter assay.
- Measured relevant molecular markers via ELISA and qRT-PCR.
Main Results:
- Exosomal miR-17-3p was significantly downregulated in peripheral blood following cardiac I/R injury.
- Exosomal miR-17-3p attenuated hydrogen peroxide-induced programmed necrosis in cardiomyocytes.
- TIMP3 was identified as a direct target of miR-17-3p, and its expression modulated programmed necrosis.
- Administration of exosomal miR-17-3p ameliorated cardiac I/R injury in vivo.
Conclusions:
- Exosomal miR-17-3p mitigates programmed necrosis in cardiac I/R injury by regulating TIMP3 expression.
- These findings suggest exosomal miR-17-3p as a promising therapeutic candidate for treating I/R injury.
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