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miR-29b-3p protects cardiomyocytes against endotoxin-induced apoptosis and inflammatory response through targeting
Zhigang Li1, Na Yi1, Rou Chen2
1Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Institute of Medical Genetics, Tongji University, Shanghai 200092, China; Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Department of Medical Genetics, Tongji University School of Medicine, Shanghai 200092, China.
Abstract:
Cardiac dysfunction represents a main component of death induced by sepsis in critical care units. And microRNAs (miRNAs) have been reported as important modulators or biomarkers of sepsis. However, the molecular detail of miRNAs involved in septic cardiac dysfunction remains unclear. Here we showed that endotoxin (lipopolysaccharide, LPS) significantly down-regulated expression of miR-29b-3p in heart. Increased expression of miR-29b-3p by lentivirus improved cardiac function and attenuated damage of cardiac induced by LPS in mice. Furthermore, overexpression or knockdown of miR-29b-3p showed its crucial roles on regulation of apoptosis and production of pro-inflammatory cytokines in NRCMs through directly targeting FOXO3A. miR-29b-3p ameliorates inflammatory damage likely via reducing activation of MAPKs and nuclear-translocation of NF-κB to block LPS-activated NF-κB signaling. Notably, miR-29b is also down-regulated in septic patients' plasma compared with normal subjects, indicating a potential clinical relevance of miR-29b. Taken together, our findings demonstrate that upregulation of miR-29b-3p can attenuate myocardial injury induced by sepsis via regulating FOXO3A, which provide a potential therapy target for interference of septic cardiac dysfunction.
Insights
MicroRNA-29b-3p (miR-29b-3p) protects against sepsis-induced heart dysfunction by targeting FOXO3A. Upregulating miR-29b-3p offers a potential therapeutic strategy for sepsis patients.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Immunology
Background:
- Sepsis-induced cardiac dysfunction is a major cause of mortality in critical care.
- MicroRNAs (miRNAs) are implicated in sepsis but their specific roles in cardiac dysfunction are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms of microRNAs in sepsis-induced cardiac dysfunction.
- To investigate the role of miR-29b-3p in myocardial injury during sepsis.
Main Methods:
- Downregulation of miR-29b-3p in mouse hearts by lipopolysaccharide (LPS) administration.
- Lentiviral vectors used to increase miR-29b-3p expression in vivo and in vitro.
- Assessment of cardiac function, apoptosis, and inflammatory cytokine production in cardiomyocytes (NRCMs).
- Target validation of FOXO3A by miR-29b-3p using molecular assays.
- Analysis of MAPK and NF-κB signaling pathways.
Main Results:
- LPS treatment significantly decreased miR-29b-3p expression in the heart.
- Increased miR-29b-3p expression improved cardiac function and reduced LPS-induced cardiac damage in mice.
- miR-29b-3p regulates apoptosis and pro-inflammatory cytokine production in NRCMs by targeting FOXO3A.
- miR-29b-3p ameliorates inflammatory damage by inhibiting LPS-activated NF-κB signaling.
- miR-29b is downregulated in septic patients' plasma.
Conclusions:
- Upregulation of miR-29b-3p attenuates sepsis-induced myocardial injury through FOXO3A regulation.
- miR-29b-3p represents a potential therapeutic target for mitigating septic cardiac dysfunction.
- Downregulation of miR-29b-3p in septic patients suggests clinical relevance.
