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Published on: January 10, 2025
MiR-501-5p alleviates cardiac dysfunction in septic patients through targeting NR4A3 to prevent its binding with
Lan Gao1, Zhongjie Zhai2, Qindong Shi1
1Department of Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Insights
MicroRNA-501-5p is down-regulated in sepsis-induced heart dysfunction. Restoring miR-501-5p levels protects against cardiomyocyte apoptosis and inflammation by targeting NR4A3, offering a potential therapeutic strategy for sepsis.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Sepsis frequently causes myocardial dysfunction, leading to significant patient mortality.
- Identifying reliable biomarkers for predicting cardiomyocyte apoptosis in sepsis remains a challenge.
Purpose of the Study:
- To investigate the role of microRNA-501-5p (miR-501-5p) in sepsis-induced cardiac dysfunction.
- To explore the therapeutic potential of miR-501-5p in sepsis.
Main Methods:
- Established a cecal ligation and puncture (CLP)-induced septic model in vivo.
- Utilized lipopolysaccharide (LPS) to induce cardiomyocyte apoptosis and inflammation in vitro (HL-1 and HCM cells).
- Assessed cardiac function parameters (LVDP, FS, EF, +dp/dt) and measured myocardial injury indicators. Investigated the interaction between miR-501-5p and nuclear receptor subfamily 4 group A member 3 (NR4A3).
Main Results:
- miR-501-5p expression was significantly downregulated in septic patients with cardiac dysfunction and in septic animal models.
- Overexpression of miR-501-5p improved cardiac function and reduced myocardial injury markers in vivo.
- miR-501-5p reversed LPS-induced apoptosis and inflammation in cardiomyocytes by inhibiting the NR4A3-Bcl-2 interaction.
Conclusions:
- miR-501-5p plays a protective role against sepsis-induced cardiomyocyte apoptosis and inflammation.
- The mechanism involves the NR4A3-dependent regulation of apoptosis and inflammation.
- miR-501-5p represents a promising therapeutic target for sepsis-related cardiac complications.
Abstract:
Sepsis-induced myocardial dysfunction is a common complication in septic patients. To date, a limited number of biomarkers that could predict cardiomyocyte apoptosis have been explored. In this study, we successfully established a cecal ligation and puncture (CLP)-induced septic model, and it was found that miR-501-5p expression was down-regulated in peripheral blood samples of septic patients with cardiac dysfunction, lipopolysaccharide (LPS)-induced cardiomyocytes, and the myocardium and peripheral blood in the septic model. Moreover, it was revealed that miR-501-5p overexpression could increase left ventricular diastolic pressure (LVDP), fractional shortening (FS), ejection fraction (EF), and maximum rate of the rise of left ventricular pressure (+dp/dt) in vivo, while it decreased the levels of myocardial injury-related indicators. In addition, LPS induction accelerated apoptosis and elevated the inflammation in HL-1 and HCM cells, which could be reversed by miR-501-5p overexpression. Mechanistically, we considered nuclear receptor subfamily 4 group A member 3 (NR4A3) as the target of miR-501-5p, and it was found that miR-501-5p prevented the binding between NR4A3 and Bcl-2. It was found that miR-501-5p exerted an inhibitory effect on cardiomyocyte apoptosis and inflammation in a NR4A3-dependent manner. Overall, our results may provide evidence for consideration of miR-501-5p in the therapy of sepsis.
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