Downregulation of miR-34c-5p alleviates chronic intermittent hypoxia-induced myocardial damage by targeting sirtuin 1
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Jun Zhang1, Bo Xie1, Yanrong Tang1
1Department of Cardiology, Chengdu First People's Hospital, Chengdu, Sichuan, China.
Abstract:
Numerous microRNAs (miRs) are abnormally expressed in response to hypoxia-induced myocardial damage. Herein, miR-34c-5p as a potential pharmaco-target was investigated in a mouse model of chronic intermittent hypoxia (CIH)-induced myocardial damage. A mouse model of myocardial damage was established using CIH with 7% or 21% O2 alternating 60 s for 12 h/day, 21% O2 for 12 h/day. AntagomiR-34c-5p (20 nM/0.1 ml; once a week for 12 weeks) was used as a miR-34c-5p inhibitor in a mouse model with tail-vein injection. In another experiment, mice were administrated with Sirt1 activator SRT1720 (50 mg/kg/day) by intraperitoneal injection. Gene Expression Omnibus database showed a significant upregulation of miR-34c-5p expression in the ischemic myocardium of male mice. In CIH-stimulated mice, miR-34c-5p expression was also significantly increased compared with normal mice. Treatment of antagomiR-34c-5p significantly restrained CIH-triggered myocardial apoptosis. After administration of antagomiR-34c-5p or Sirt1 activator SRT1720, cardiac hypertrophy and oxidative stress were attenuated in CIH-stimulated mice. We also found sirtuin 1 (Sirt1) as a direct target of miR-34c-5p, which was able to mediate Sirt1 protein expression in cardiomyocytes. AntagomiR-34c-5p injection markedly elevated Sirt1 protein expression in CIH-stimulated mice. AntagomiR-34c-5p or Sirt1 activator SRT1720 administration exhibited the antioxidative activity and cardioprotective roles in CIH-stimulated mice.
Insights
MicroRNA-34c-5p inhibition protects against chronic intermittent hypoxia (CIH)-induced heart damage by increasing Sirt1 expression. This finding suggests miR-34c-5p as a therapeutic target for heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- MicroRNA Therapeutics
Background:
- Hypoxia-induced myocardial damage is linked to abnormal microRNA expression.
- MicroRNAs (miRs) play critical roles in regulating cellular responses to stress.
- Identifying specific miRs involved in cardiac injury is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of miR-34c-5p in chronic intermittent hypoxia (CIH)-induced myocardial damage.
- To evaluate miR-34c-5p as a potential therapeutic target for CIH-induced cardiac injury.
- To explore the relationship between miR-34c-5p and sirtuin 1 (Sirt1) in the context of cardiac protection.
Main Methods:
- A mouse model of myocardial damage was established using chronic intermittent hypoxia (CIH).
- miR-34c-5p inhibition was achieved using antagomiR-34c-5p via tail-vein injection.
- Sirt1 activation was induced using the activator SRT1720 administered via intraperitoneal injection.
- Gene Expression Omnibus (GEO) database analysis and cardiomyocyte experiments were performed.
Main Results:
- miR-34c-5p expression was significantly upregulated in ischemic myocardium and in CIH-stimulated mice.
- AntagomiR-34c-5p treatment significantly reduced CIH-induced myocardial apoptosis, cardiac hypertrophy, and oxidative stress.
- Sirt1 was identified as a direct target of miR-34c-5p, and its protein expression was increased by antagomiR-34c-5p.
- Both antagomiR-34c-5p and Sirt1 activator SRT1720 demonstrated cardioprotective and antioxidative effects in CIH-stimulated mice.
Conclusions:
- miR-34c-5p is upregulated in response to CIH and contributes to myocardial damage.
- Inhibition of miR-34c-5p confers cardioprotection against CIH by upregulating Sirt1.
- miR-34c-5p and its target Sirt1 represent a promising therapeutic axis for managing hypoxia-related heart conditions.
