Affiliation:
1. Department of Cardiovascular Medicine Fukushima Medical University Fukushima Japan
2. Department of Arrhythmia and Cardiac Pacing Fukushima Medical University Fukushima Japan
3. Department of Clinical Laboratory Sciences Fukushima Medical University School of Health Science Fukushima Japan
Abstract
Background
Blood‐based DNA methylation patterns are linked to types of diseases. FKBP prolyl isomerase 5 (FKBP5), a protein cochaperone, is known to be associated with the inflammatory response, but the regulatory mechanisms by leukocyte
FKBP5
DNA methylation in patients with dilated cardiomyopathy (DCM) remain unclear.
Methods and Results
The present study enrolled patients with DCM (n=31) and age‐matched and sex‐matched control participants (n=43). We assessed
FKBP5
CpG (cytosine‐phosphate‐guanine) methylation of CpG islands at the 5′ side as well as putative promoter regions by methylation‐specific quantitative polymerase chain reaction using leukocyte DNA isolated from the peripheral blood.
FKBP5
CpG methylation levels at the CpG island of the gene body and the promoter regions were significantly decreased in patients with DCM. Leukocyte
FKBP5
and
IL‐1β
(interleukin 1β) mRNA expression levels were significantly higher in patients with DCM than in controls. The protein expressions of DNMT1 (DNA methyltransferase 1) and DNMT3A (DNA methyltransferase 3A) in leukocytes were significantly reduced in patients with DCM. In vitro methylation assay revealed that
FKBP5
promoter activity was inhibited at the methylated conditions in response to immune stimulation, suggesting that the decreased
FKBP5
CpG methylation was functionally associated with elevation of
FKBP5
mRNA expressions. Histological analysis using a mouse model with pressure overload showed that FKBP5‐expressing cells were substantially infiltrated in the myocardial interstitium in the failing hearts, indicating a possible role of FKBP5 expressions of immune cells in the cardiac remodeling.
Conclusions
Our findings demonstrate a link between specific CpG hypomethylation of leukocyte
FKBP5
and DCM. Blood‐based epigenetic modification in
FKBP5
may be a novel molecular mechanism that contributes to the pathogenesis of DCM.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
7 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献