Blood‐Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated Cardiomyopathy
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-11-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.121.021101 |
| _version_ | 1797606897813028864 |
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| author | Kento Wada Tomofumi Misaka Tetsuro Yokokawa Yusuke Kimishima Takashi Kaneshiro Masayoshi Oikawa Akiomi Yoshihisa Yasuchika Takeishi |
| author_facet | Kento Wada Tomofumi Misaka Tetsuro Yokokawa Yusuke Kimishima Takashi Kaneshiro Masayoshi Oikawa Akiomi Yoshihisa Yasuchika Takeishi |
| author_sort | Kento Wada |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T05:21:27Z |
| format | Article |
| id | doaj.art-fe8797445ad14ae08b92e81de8004717 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-11T05:21:27Z |
| publishDate | 2021-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-fe8797445ad14ae08b92e81de80047172023-11-17T17:50:23ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802021-11-01102110.1161/JAHA.121.021101Blood‐Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated CardiomyopathyKento Wada0Tomofumi Misaka1Tetsuro Yokokawa2Yusuke Kimishima3Takashi Kaneshiro4Masayoshi Oikawa5Akiomi Yoshihisa6Yasuchika Takeishi7Department of Cardiovascular Medicine Fukushima Medical University Fukushima JapanDepartment of Cardiovascular Medicine Fukushima Medical University Fukushima JapanDepartment of Cardiovascular Medicine Fukushima Medical University Fukushima JapanDepartment of Cardiovascular Medicine Fukushima Medical University Fukushima JapanDepartment of Cardiovascular Medicine Fukushima Medical University Fukushima JapanDepartment of Cardiovascular Medicine Fukushima Medical University Fukushima JapanDepartment of Cardiovascular Medicine Fukushima Medical University Fukushima JapanDepartment of Cardiovascular Medicine Fukushima Medical University Fukushima JapanBackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.121.021101biomarkerdilated cardiomyopathyDNA methylationepigeneticsFKBP5 |
| spellingShingle | Kento Wada Tomofumi Misaka Tetsuro Yokokawa Yusuke Kimishima Takashi Kaneshiro Masayoshi Oikawa Akiomi Yoshihisa Yasuchika Takeishi Blood‐Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated Cardiomyopathy Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease biomarker dilated cardiomyopathy DNA methylation epigenetics FKBP5 |
| title | Blood‐Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated Cardiomyopathy |
| title_full | Blood‐Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated Cardiomyopathy |
| title_fullStr | Blood‐Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated Cardiomyopathy |
| title_full_unstemmed | Blood‐Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated Cardiomyopathy |
| title_short | Blood‐Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated Cardiomyopathy |
| title_sort | blood based epigenetic markers of fkbp5 gene methylation in patients with dilated cardiomyopathy |
| topic | biomarker dilated cardiomyopathy DNA methylation epigenetics FKBP5 |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.121.021101 |
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