Comprehensive microRNA profiling reveals potential augmentation of the IL1 pathway in rheumatic heart valve disease

Qiyu Lu,Yi Sun,Bin Li,Songhua Yu,Guimin Zhang,Jianming Xia,Yuyin Duan

doi:10.1186/s12872-018-0788-2

Abstract

BackgroundValvular heart disease is a leading cause of cardiovascular mortality, especially in China. More than a half of valvular heart diseases are caused by acute rheumatic fever. microRNA is involved in many physiological and pathological processes. However, the miRNA profile of the rheumatic valvular heart disease is unknown. This research is to discuss microRNAs and their target gene pathways involved in rheumatic heart valve disease.MethodsSerum miRNA from one healthy individual and four rheumatic heart disease patients were sequenced. Specific differentially expressed miRNAs were quantified by Q-PCR in 40 patients, with 20 low-to-moderate rheumatic mitral valve stenosis patients and 20 severe mitral valve stenosis patients. The target relationship between certain miRNA and predicted target genes were analysis by Luciferase reporter assay. The IL-1β and IL1R1 expression levels were analyzed by immunohistochemistry and western blot in the mitral valve from surgery of mitral valve replacement.ResultsThe results showed that 13 and 91 miRNAs were commonly upregulated or downregulated in all four patients. Nine miRNAs, 1 upregulated and 8 downregulated, that had a similar fold change in all 4 patients were selected for quantitative PCR verification. The results showed similar results from miRNA sequencing. Within these 9 tested miRNAs, hsa-miR-205-3p and hsa-miR-3909 showed a low degree of dispersion between the members of each group. Hsa miR-205-3p and hsa-miR-3909 were predicted to target the 3’UTR of IL-1β and IL1R1 respectively. This was verified by luciferase reporter assays. Immunohistochemistry and Western blot results showed that the mitral valve from rheumatic valve heart disease showed higher levels of IL- 1β and IL1R1 expression compared with congenital heart valve disease. This suggested a difference between rheumatic heart valve disease and other types of heart valve diseases, with more inflammatory responses in the former.ConclusionIn the present study, by next generation sequencing of miRNAs, it was revealed that interleukin 1β and interleukin 1 receptor 1 was involved in rheumatic heart diseases. And this is useful for diagnosis and understanding of mechanism of rheumatic heart disease.

Highlights

Valvular heart disease is a leading cause of cardiovascular mortality, especially in China
We point out two miRNAs, hsa-miR205-3p and hsa-miR-3909 and their target genes interleukin 1β (IL-1β) and interleukin 1 receptor 1 (IL1R1) are involved in the progression of rheumatic heart disease (RHD), and suggested a potential augmentation of the IL1 pathway in rheumatic heart valve disease
Different miRNAs expression in mild-tomoderate mitral stenosis patient LM1 and their expression fold of change compare to NC healthy control individual. (XLSX 46 kb)

Summary

Introduction

Valvular heart disease is a leading cause of cardiovascular mortality, especially in China. MicroRNA is involved in many physiological and pathological processes. The miRNA profile of the rheumatic valvular heart disease is unknown. This research is to discuss microRNAs and their target gene pathways involved in rheumatic heart valve disease. Valvular heart disease (VHD) is a major leading cause of cardiovascular mortality. MicroRNAs are the best characterized non-coding RNA family. They have a fundamental importance in normal development, differentiation and growth control. Though the roles of miRNAs in many physiological and pathological processes have been widely and deeply investigated, the roles of miRNAs in valvular heart disease have just begun to be studied [1]. MiRNAs are potentially involved in the regulation of key VHD-related pathways, such as cell cycle control, inflammation and fibrosis. Due to their role in VHD, miRNA molecules could become diagnostic and prognostic biomarkers for patient stratification and therapeutic targets and agents [4]

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Conclusion