Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 5, Issue -, Pages -Publisher
CELL PRESS
DOI: 10.1038/mtna.2016.80
Keywords
apoptosis; cardiac dysfunction; LPS; miR-155; Pea15a; sepsis
Categories
Funding
- National Natural Science Foundation of China [81570362, 81200169, 81400647, 81370362]
- Innovation Program of Shanghai Municipal Education Commission [13YZ014]
- Innovation fund from Shanghai University [sdcx2012038]
- National Basic Research Program of China [2014CB542300]
- National Major Research Plan Training Program [91339108]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant [20152509]
- Program for the integration of production, teaching and research for University Teachers
- Shanghai Municipal Education Commission
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Sepsis-induced myocardial dysfunction represents a major cause of death in intensive care units. Dysregulated microRNAs (miR)-155 has been implicated in multiple cardiovascular diseases and miR-155 can be induced by lipopolysaccharide (LPS). However, the role of miR-155 in LPS-induced cardiac dysfunction is unclear. Septic cardiac dysfunction in mice was induced by intraperitoneal injection of LPS (5 mg/kg) and miR-155 was found to be significantly increased in heart challenged with LPS. Pharmacological inhibition of miR-155 using antagomiR improved cardiac function and suppressed cardiac apoptosis induced by LPS in mice as determined by echocardiography, terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) assay, and Western blot for Bax and Bcl-2, while overexpression of miR-155 using agomiR had inverse effects. Pea15a was identified as a target gene of miR-155, mediating its effects in controlling apoptosis of cardiomyocytes as evidenced by luciferase reporter assays, quantitative real time-polymerase chain reaction, Western blot, and TUNEL staining. Noteworthy, miR-155 was also found to be upregulated in the plasma of patients with septic cardiac dysfunction compared to sepsis patients without cardiac dysfunction, indicating a potential clinical relevance of miR-155. The receiver-operator characteristic curve indicated that plasma miR-155 might be a biomarker for sepsis patients developing cardiac dysfunction. Therefore, inhibition of miR-155 represents a novel therapy for septic myocardial dysfunction.
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