Differential Expression of miR-145 in Children with Kawasaki Disease

Chisato Shimizu,Christine Trinh,Lucila Ohno-Machado,Clark Chen,Jane C Burns,John T Kanegaye,Jihoon Kim,Johnny C Akers,Hubert D Lau,Adriana Tremoulet,Petra Stepanowsky,Ramiro Garzon

doi:10.1371/journal.pone.0058159

Chisato Shimizu, Christine Trinh + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0058159

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Abstract

BackgroundKawasaki disease is an acute, self-limited vasculitis of childhood that can result in structural damage to the coronary arteries. Previous studies have implicated the TGF-β pathway in disease pathogenesis and generation of myofibroblasts in the arterial wall. microRNAs are small non-coding RNAs that modulate gene expression at the post-transcriptional level and can be transported between cells in extracellular vesicles. To understand the role that microRNAs play in modifying gene expression in Kawasaki disease, we studied microRNAs from whole blood during the acute and convalescent stages of the illness.Methodology/Principal FindingsRNA isolated from the matched whole blood of 12 patients with acute and convalescent Kawasaki disease were analyzed by sequencing of small RNA. This analysis revealed six microRNAs (miRs-143, -199b-5p, -618, -223, -145 and -145* (complementary strand)) whose levels were significantly elevated during the acute phase of Kawasaki disease. The result was validated using targeted qRT-PCR using an independent cohort (n = 16). miR-145, which plays a critical role in the differentiation of neutrophils and vascular smooth muscle cells, was expressed at high levels in blood samples from acute Kawasaki disease but not adenovirus-infected control patients (p = 0.005). miR-145 was also detected in small extracellular vesicles isolated from acute Kawasaki disease plasma samples. Pathway analysis of the predicted targets of the 6 differentially expressed microRNAs identified the TGF-β pathway as the top pathway regulated by microRNAs in Kawasaki disease.ConclusionSequencing of small RNA species allowed discovery of microRNAs that may participate in Kawasaki disease pathogenesis. miR-145 may participate, along with other differentially expressed microRNAs, in regulating expression of genes in the TGF-β pathway during the acute illness. If the predicted target genes are confirmed, our findings suggest a model of Kawasaki disease pathogenesis whereby miR-145 modulates TGF-β signaling in the arterial wall.

Highlights

The self-limited nature of the inflammation in Kawasaki disease (KD) is unique among vasculitis syndromes and argues for effective host mechanisms that successfully down regulate inflammation to terminate the acute, febrile phase of the illness
Sequencing of small RNA species allowed discovery of microRNAs that may participate in Kawasaki disease pathogenesis. miR-145 may participate, along with other differentially expressed microRNAs, in regulating expression of genes in the transforming growth factor (TGF)-b pathway during the acute illness
If the predicted target genes are confirmed, our findings suggest a model of Kawasaki disease pathogenesis whereby miR-145 modulates TGF-b signaling in the arterial wall

Summary

Introduction

The self-limited nature of the inflammation in Kawasaki disease (KD) is unique among vasculitis syndromes and argues for effective host mechanisms that successfully down regulate inflammation to terminate the acute, febrile phase of the illness. Recent studies ofthe histopathology of aneurysmal coronary arteries from KD autopsies suggest that myofibroblasts play an important role in KD pathogenesis by secreting pro-inflammatory cytokines and recruiting inflammatory cells to the arterial wall [8,9]. Immunohistochemical studies implicate signaling through the TGF-b pathway as a possible mechanism of endothelial- or epithelial-to-mesenchymal transformation resulting in myofibroblasts infiltrating the vessel wall [9]. Kawasaki disease is an acute, self-limited vasculitis of childhood that can result in structural damage to the coronary arteries. Previous studies have implicated the TGF-b pathway in disease pathogenesis and generation of myofibroblasts in the arterial wall. To understand the role that microRNAs play in modifying gene expression in Kawasaki disease, we studied microRNAs from whole blood during the acute and convalescent stages of the illness

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