miR-222-3p reduces myocardial injury in sepsis by regulating NFATc3

To investigate the function and basic molecular pathways of miR-222-3p in sepsis-induced myocardial injury (SIMI), focusing on its post-transcriptional regulation of the NFATc3 signalling network, and to explore its use as a therapeutic target for SIMI.

Septicemia was induced in rodents by cecal ligation and puncture (CLP). The animals were divided into the following seven groups: Sham, Sepsis, Sepsis + miR-222-3p, Sepsis + anti-222-3p, Sepsis + ad-GFP, Sepsis + miR-222-3p + NFAT inhibitor, and Sepsis + anti-222-3p + NFAT inhibitor. A NFAT inhibitor (100 µg/d) was administered intraperitoneally for three days before CLP surgery, and 24 hours prior to CLP, miR-222-3p, anti-222-3p, or ad-GFP (100 μL each) were infused intravenously through the tail vein. The levels of miR-222-3p in myocardial tissue were determined by qRT-PCR, and NFATc3 protein level 24 hours after surgery was determined by western blot. H&E staining of the myocardial cells and TUNEL assays were used to detect apoptosis in myocytes. Echocardiogram was performed to assess the heart, and the plasma levels of CK-MB, cTnI, IL-6, IL-10 and TNF-α were measured by ELISA.

Myocardial miR-222-3p expression was significantly upregulated in septic mice compared to sham-operated controls. NFATc3 levels decreased in the miR-222-3p injection group and increased in the anti-miR-222-3p group. miR-222-3p reduced myocardial cell apoptosis, improved left ventricular ejection fraction, lowered plasma concentrations of CK-MB, cTnI, IL-6 and TNF-α, and promoted IL-10. Suppressing miR-222-3p produced the inverse outcome. The activity of NFAT was also reduced somewhat.

MiR-222-3p inhibits NFATc3 to reduce myocardial damage in septic mice, suggesting that miR-222-3p may represent a therapeutic target for sepsis-induced heart failure.