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Published on: May 19, 2020
Inhibition of miR‑155‑5p attenuates the valvular damage induced by rheumatic heart disease
Ang Chen1, Jianlin Wen1, Chuanghong Lu1
1Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
Abstract:
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.
Insights
Inhibiting microRNA-155-5p (miR-155-5p) reduces valvular damage in rheumatic heart disease (RHD) by targeting sphingosine-1-phosphate receptor 1 (S1PR1) and SOCS1/STAT3 pathways. This approach alleviates inflammation and fibrosis, offering a potential therapeutic strategy for RHD.
Area of Science:
- Immunology and Cardiovascular Research
- Molecular Biology and Genetics
- Biomedical Sciences
Background:
- Rheumatic heart disease (RHD) involves autoimmune-mediated valvular damage.
- MicroRNAs (miRNAs) are increasingly implicated in autoimmune diseases.
- Key signaling molecules like STAT3, S1PR1, and SOCS1 play roles in autoimmunity and inflammation.
Purpose of the Study:
- To investigate the role of miR-155-5p in RHD-induced valvular damage.
- To elucidate the involvement of S1PR1, SOCS1/STAT3, and IL-6/STAT3 signaling pathways.
- To evaluate the therapeutic potential of inhibiting miR-155-5p in RHD.
Main Methods:
- Established an RHD rat model using inactivated Group A streptococci and complete Freund's adjuvant.
- Utilized recombinant adeno-associated virus (AAV-miR155-inhibitor) to inhibit miR-155-5p expression.
- Assessed inflammation and fibrosis via histological staining; quantified molecular targets (miRNAs, proteins, cytokines) using RT-qPCR, Western blotting, immunohistochemistry, dual luciferase assays, and ELISA.
Main Results:
- RHD model exhibited increased miR-155-5p in valve tissues and serum exosomes, decreased S1PR1, and activated SOCS1/STAT3 signaling.
- Elevated levels of interleukin (IL)-6 and IL-17 were observed in valves and serum.
- Dual luciferase assays confirmed direct targeting of S1PR1 and SOCS1 by miR-155-5p; inhibition of miR-155-5p attenuated RHD pathology and inflammatory markers.
Conclusions:
- miR-155-5p promotes RHD-induced valvular damage by modulating S1PR1, SOCS1/STAT3, and IL-6/STAT3 pathways.
- Inhibition of miR-155-5p demonstrates a therapeutic effect, reducing valvular inflammation and fibrosis in RHD.
- Targeting miR-155-5p represents a promising strategy for managing RHD.
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