Inhibition of miR-155-5p attenuates the valvular damage induced by rheumatic heart disease

Autoimmunity is involved in the valvular damage caused by rheumatic heart disease (RHD). Increased evidence has linked microRNAs (miRNAs/miRs) to autoimmune disease. Signal transducer and activator of transcription 3 (STAT3) and sphingosine-1-phosphate receptor 1 (S1PR1) and suppressor of cytokine signaling 1 (SOCS1) have been widely studied for their roles in autoimmunity and inflammation. Thus, the current study aims to investigate the role played by miR-155-5p in RHD-induced valvular damage via the S1PR1, SOCS1/STAT3 and interleukin (IL)-6/STAT3 signaling pathways. An RHD rat model was induced by inactivated Group A streptococci and complete Freund's adjuvant. A recombinant adeno-associated virus (AAV-miR155-inhibitor) was used to inhibit the expression of miR-155-5p in the heart. Inflammation and fibrosis were assessed by hematoxylin and eosin staining and Sirius red staining. The expression of miR-155-5p in valvular tissues and serum exosomes was detected by reverse transcription-quantitative PCR. S1PR1, SOCS1, STAT3, phosphorylated STAT3, IL-6 and IL-17 protein expression was detected by western blotting and immunohistochemistry. The relationships between miR-155-5p and S1PR1 and SOCS1 were detected by dual luciferase assays. Cytokine concentrations were measured by ELISA. The expression of miR-155-5p in valve tissues and serum exosomes was increased along with decreased S1PR1 and activated SOCS1/STAT3 signaling in the RHD model. The expression of IL-6 and IL-17 was increased in the valves and the serum. Dual luciferase assays showed that miR-155-5p directly targeted S1PR1 and SOCS1. Inhibition of valvular miR-155-5p through AAV pretreatment increased S1PR1 expression and inhibited activation of the SOCS1/STAT3 signal pathway as a result of attenuated valvular inflammation and fibrosis as well as a decrease in IL-6 and IL-17 in the valves and serum. These results suggest that inhibition of miR-155-5p can reduce RHD-induced valvular damage via the S1PR1, SOCS1/STAT3 and IL-6/STAT3 signaling pathways.