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. 2017 Jul 28;8(37):60875-60891.
doi: 10.18632/oncotarget.19650. eCollection 2017 Sep 22.

Epigenetic hypomethylation and upregulation of matrix metalloproteinase 9 in Kawasaki disease

Ho-Chang Kuo  1   2 , Sung-Chou Li  3 , Lien-Hung Huang  3 , Ying-Hsien Huang  1   2   4
Affiliations

Epigenetic hypomethylation and upregulation of matrix metalloproteinase 9 in Kawasaki disease

Ho-Chang Kuo et al. Oncotarget. .

Abstract

Background: Kawasaki disease (KD) is a type of febrile coronary vasculitis occurring in children. Some researchers have suggested that changes in genetic signatures, such as matrix metalloproteinases (MMPs), are critical markers for cardiovascular diseases. This study aims to provide a comprehensive survey of global DNA methylation levels and MMP transcripts of KD patients compared to control subjects.

Materials and methods: For chips studies, we recruited a total of 18 KD patients, prior to receiving intravenous immunoglobulin (IVIG) and at least 3 weeks after IVIG treatment, as well as 18 healthy and 18 febrile control subjects. We applied Illumina HumanMethylation450 BeadChip and Affymetrix GeneChip® Human Transcriptome Array 2.0 to evaluate their CpG markers and expression levels, respectively. Then we used a separate cohort to carry out real-time quantitative PCR validations of mRNA levels.

Results: The expressions of mRNA levels of MMP-8, -9, and -25 were significantly upregulated in KD patients compared to the healthy and febrile controls. Once KD patients underwent IVIG treatment, these MMPs considerably decreased. In particular, the methylation status of CpG sites of MMP-9 indicated a significant opposite tendency between both stages of not only the KD samples but also the controls. We also observed the mRNA level of MMP-9 to be higher in KD patients with coronary arterial lesion formation.

Conclusion: This study is the first to report epigenetic hypomethylation, an increased MMP-9 transcript, and the upregulation of MMP-9 in KD patients who had formed coronary arterial lesions.

Keywords: Immune response; Immunity; Immunology and Microbiology Section; Kawasaki disease; genetic methylation; matrix metalloproteinase.

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Conflict of interest statement

CONFLICTS OF INTEREST All of the authors hereby declare that they have no financial interests to disclose with regard to this article.

Figures

Figure 1
Figure 1. Comparison of matrix metalloproteinase (MMP) -8, -9, and -25 mRNA expressions by GeneChip® Human Transcriptome Array 2.0 between acute-stage Kawasaki disease patients and control subjects
* indicates significance (p < 0.05). Data are expressed as mean ± standard error for the three replications.
Figure 2
Figure 2. Integration of CpG marker (cg10505873) methylation pattern and gene expression profile of matrix metalloproteinase (MMP)-9
a. The methylation patterns of the representative CpG marker and gene expression profile of MMP-9 showed negative tendencies and were observed to change in both the healthy and febrile control subjects, as well as KD patients before and after receiving intravenous immunoglobulin treatment. The histogram and curve are presented as mean ± standard error. b. We used scatter plots to demonstrate the correlations between mRNA levels and DNA methylation, which show that mRNA levels were negatively correlated with DNA methylation (Pearson’s correlation coefficient approximately -0.603 and p < 0.001).
Figure 3
Figure 3. Analyses of matrix metalloproteinase (MMP) -8, -9, and -25 mRNA in the peripheral blood mononuclear cells of 31 patients with KD and 46 controls using a real-time quantitative polymerase chain reaction
Data are expressed as mean ±standard error. *indicates a p < 0.05 between the groups.
Figure 4
Figure 4. Comparison of matrix metalloproteinase 9 in patients with KD without (n = 22) and with (n = 9) coronary artery lesion before being treated with intravenous immunoglobulin
Data are presented as mean ±standard error. *indicates a p < 0.05 between the groups.
See this image and copyright information in PMC

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