MiR-302a-3p aggravates myocardial ischemia-reperfusion injury by suppressing mitophagy via targeting FOXO3
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Published on: May 26, 2023
Wei Lv1, Jinping Jiang1, Yan Li2
1Department of Cardiology, Shengjing Hospital of China Medical University, China.
Objective:
This study aimed to investigate whether the protection of miR-302a-3p in myocardial ischemia-reperfusion injury (MIRI) is mediated through the suppression of mitophagy.
Methods:
We constructed a mouse I/R model in vivo by the ligation of left anterior descending coronary artery for 45 min followed by 2 h reperfusion, and an in vitro model by treating mouse cardiomyocytes with hypoxia-reoxygenation (H/R). Knockdown experiments were then performed in vivo and in vitro to determine the effects of miR-302a-3p knockdown on the mitophagy, mitochondrial dysfunction and oxidative stress and apoptosis. The potential targets of miR-302a-3p were further studied by bioinformatics analysis, luciferase assays, quantitative real-time PCR and western blotting.
Results:
MiR-302a-3p expression was significantly upregulated in mice subjected to MIRI and in H/R-treated mouse cardiomyocytes. Functional analyses demonstrated that inhibition of miR-302a-3p protected cardiac tissues against I/R-induced apoptosis and mitophagy, mitochondrial damage and mitochondrial oxidative stress. Furthermore, FOXO3 was identified as the direct target of miR-302a-3p. Mechanistically, knockdown of FOXO3 partially reversed the cardioprotective effects of miR-302a-3p inhibitor.
Conclusion:
Our study suggested that inhibition of miR-302a-3p promoted mitochondrial autophagy and inhibited oxidative stress by targeting FOXO3 to suppress myocardial apoptosis, representing a potential target for MIRI treatment.
Insights
Inhibiting miR-302a-3p protects the heart from ischemia-reperfusion injury by reducing mitophagy and oxidative stress. This occurs through targeting FOXO3, offering a potential therapeutic strategy for myocardial ischemia-reperfusion injury (MIRI).
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cellular Signaling
Background:
- Myocardial ischemia-reperfusion injury (MIRI) is a significant clinical challenge.
- Mitophagy plays a critical role in the pathophysiology of MIRI.
- MicroRNAs (miRNAs) are emerging as key regulators in cardiovascular diseases.
Purpose of the Study:
- To investigate the role of miR-302a-3p in MIRI.
- To determine if miR-302a-3p protection against MIRI is mediated by suppressing mitophagy.
- To identify the molecular targets and mechanisms of miR-302a-3p in MIRI.
Main Methods:
- Established in vivo (mouse ligation model) and in vitro (hypoxia-reoxygenation in cardiomyocytes) MIRI models.
- Performed miR-302a-3p knockdown experiments to assess effects on mitophagy, mitochondrial function, oxidative stress, and apoptosis.
- Utilized bioinformatics, luciferase assays, qPCR, and Western blotting to identify and validate miR-302a-3p targets.
Main Results:
- miR-302a-3p was significantly upregulated in MIRI models.
- Inhibition of miR-302a-3p attenuated MIRI-induced apoptosis, mitophagy, mitochondrial damage, and oxidative stress.
- FOXO3 was identified as a direct target of miR-302a-3p, and its knockdown partially reversed the protective effects of miR-302a-3p inhibition.
Conclusions:
- Inhibition of miR-302a-3p confers cardioprotection in MIRI.
- miR-302a-3p regulates mitophagy and oxidative stress by targeting FOXO3.
- Targeting miR-302a-3p represents a promising therapeutic approach for MIRI.
