In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study
Abstract Aims Although distinct DNA methylation patterns have been reported, its localization and roles remain to be defined in heart failure. We investigated the cellular and subcellular localization of DNA methylation and its pathophysiological significance in human failing hearts. Methods and res...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-04-01
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| Series: | ESC Heart Failure |
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| Online Access: | https://doi.org/10.1002/ehf2.12593 |
| _version_ | 1818608174857453568 |
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| author | Takatomo Watanabe Hideshi Okada Hiromitsu Kanamori Nagisa Miyazaki Akiko Tsujimoto Chihiro Takada Kodai Suzuki Genki Naruse Akihiro Yoshida Takahide Nawa Toshiki Tanaka Masanori Kawasaki Hiroyasu Ito Shinji Ogura Hiroyuki Okura Takako Fujiwara Hisayoshi Fujiwara Genzou Takemura |
| author_facet | Takatomo Watanabe Hideshi Okada Hiromitsu Kanamori Nagisa Miyazaki Akiko Tsujimoto Chihiro Takada Kodai Suzuki Genki Naruse Akihiro Yoshida Takahide Nawa Toshiki Tanaka Masanori Kawasaki Hiroyasu Ito Shinji Ogura Hiroyuki Okura Takako Fujiwara Hisayoshi Fujiwara Genzou Takemura |
| author_sort | Takatomo Watanabe |
| collection | DOAJ |
| description | Abstract Aims Although distinct DNA methylation patterns have been reported, its localization and roles remain to be defined in heart failure. We investigated the cellular and subcellular localization of DNA methylation and its pathophysiological significance in human failing hearts. Methods and results Using left ventricular (LV) endomyocardial biopsy specimens from 75 patients with dilated cardiomyopathy (DCM; age: 58 ± 14 years old, %female: 32%) and 20 patients without heart failure (controls; age: 56 ± 17 years old, %female: 45%), we performed immunohistochemistry and immunoelectron microscopy for methylated DNA, 5‐methylcytosine (5‐mC). We next investigated possible relations of the incidence of 5‐mC‐positive (%5‐mC+) cardiomyocytes with clinicopathological parameters. Immunopositivity for 5‐mC was detected in the cardiomyocytes and other cell types. The %5‐mC+ cardiomyocytes was significantly greater in DCM hearts than in controls (57 ± 13% in DCM vs. 25 ± 12% in controls, P < 0.0001). The localization of 5‐mC immunopositivity in cardiomyocyte nuclei coincided well with that of heterochromatin, as confirmed by immunoelectron microscopy. Substantial DNA methylation was also observed in interstitial non‐cardiomyocytes, but the incidences did not differ between control and DCM hearts (39 ± 7.9% in DCM vs. 41 ± 10% in controls, P = 0.4099). In DCM patients, the %5‐mC+ cardiomyocytes showed a significant inverse correlation with LV functional parameters such as heart rate (r = 0.2391, P = 0.0388), end‐diastolic pressure (r = 0.2397, P = 0.0397), and ejection fraction (r = −0.2917, P = 0.0111) and a positive correlation with LV dilatation (volume index at diastole; r = 0.2442, P = 0.0347; and volume index at systole; r = 0.3136, P = 0.0062) and LV hypertrophy (mass index; r = 0.2287, P = 0.0484)—that is, LV remodelling parameters. No significant correlations between DNA methylation and the histological parameters of the biopsies, including cardiomyocyte hypertrophy, fibrosis, and inflammatory cell infiltration, were noted. Conclusions The present study revealed increased nuclear DNA methylation in cardiomyocytes, but not other cell types, from DCM hearts, with predominant localization in the heterochromatin. Its significant relations with LV functional and remodelling parameters imply a pathophysiological significance of DNA methylation in heart failure. |
| first_indexed | 2024-12-16T14:38:27Z |
| format | Article |
| id | doaj.art-83259b13074545c28ceca80d29dbff1e |
| institution | Directory Open Access Journal |
| issn | 2055-5822 |
| language | English |
| last_indexed | 2024-12-16T14:38:27Z |
| publishDate | 2020-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | ESC Heart Failure |
| spelling | doaj.art-83259b13074545c28ceca80d29dbff1e2022-12-21T22:28:01ZengWileyESC Heart Failure2055-58222020-04-017249350210.1002/ehf2.12593In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy studyTakatomo Watanabe0Hideshi Okada1Hiromitsu Kanamori2Nagisa Miyazaki3Akiko Tsujimoto4Chihiro Takada5Kodai Suzuki6Genki Naruse7Akihiro Yoshida8Takahide Nawa9Toshiki Tanaka10Masanori Kawasaki11Hiroyasu Ito12Shinji Ogura13Hiroyuki Okura14Takako Fujiwara15Hisayoshi Fujiwara16Genzou Takemura17Department of Cardiology Gifu University Graduate School of Medicine Gifu JapanDepartment of Cardiology Gifu University Graduate School of Medicine Gifu JapanDepartment of Cardiology Gifu University Graduate School of Medicine Gifu JapanDepartment of Internal Medicine Asahi University School of Dentistry 1851 Hozumi Mizuho 501‐0296 JapanDepartment of Cardiology Gifu University Graduate School of Medicine Gifu JapanDepartment of Emergency and Disaster Medicine Gifu University Graduate School of Medicine Gifu JapanDepartment of Emergency and Disaster Medicine Gifu University Graduate School of Medicine Gifu JapanDepartment of Cardiology Gifu University Graduate School of Medicine Gifu JapanDepartment of Cardiology Gifu University Graduate School of Medicine Gifu JapanDepartment of Cardiology Gifu University Graduate School of Medicine Gifu JapanDepartment of Cardiology Gifu University Graduate School of Medicine Gifu JapanDepartment of Cardiology Gifu University Graduate School of Medicine Gifu JapanDepartment of Informative Clinical Medicine Gifu University Graduate School of Medicine Gifu JapanDepartment of Emergency and Disaster Medicine Gifu University Graduate School of Medicine Gifu JapanDepartment of Cardiology Gifu University Graduate School of Medicine Gifu JapanHyogo Prefectural Amagasaki General Medical Center Amagasaki JapanHyogo Prefectural Amagasaki General Medical Center Amagasaki JapanDepartment of Internal Medicine Asahi University School of Dentistry 1851 Hozumi Mizuho 501‐0296 JapanAbstract Aims Although distinct DNA methylation patterns have been reported, its localization and roles remain to be defined in heart failure. We investigated the cellular and subcellular localization of DNA methylation and its pathophysiological significance in human failing hearts. Methods and results Using left ventricular (LV) endomyocardial biopsy specimens from 75 patients with dilated cardiomyopathy (DCM; age: 58 ± 14 years old, %female: 32%) and 20 patients without heart failure (controls; age: 56 ± 17 years old, %female: 45%), we performed immunohistochemistry and immunoelectron microscopy for methylated DNA, 5‐methylcytosine (5‐mC). We next investigated possible relations of the incidence of 5‐mC‐positive (%5‐mC+) cardiomyocytes with clinicopathological parameters. Immunopositivity for 5‐mC was detected in the cardiomyocytes and other cell types. The %5‐mC+ cardiomyocytes was significantly greater in DCM hearts than in controls (57 ± 13% in DCM vs. 25 ± 12% in controls, P < 0.0001). The localization of 5‐mC immunopositivity in cardiomyocyte nuclei coincided well with that of heterochromatin, as confirmed by immunoelectron microscopy. Substantial DNA methylation was also observed in interstitial non‐cardiomyocytes, but the incidences did not differ between control and DCM hearts (39 ± 7.9% in DCM vs. 41 ± 10% in controls, P = 0.4099). In DCM patients, the %5‐mC+ cardiomyocytes showed a significant inverse correlation with LV functional parameters such as heart rate (r = 0.2391, P = 0.0388), end‐diastolic pressure (r = 0.2397, P = 0.0397), and ejection fraction (r = −0.2917, P = 0.0111) and a positive correlation with LV dilatation (volume index at diastole; r = 0.2442, P = 0.0347; and volume index at systole; r = 0.3136, P = 0.0062) and LV hypertrophy (mass index; r = 0.2287, P = 0.0484)—that is, LV remodelling parameters. No significant correlations between DNA methylation and the histological parameters of the biopsies, including cardiomyocyte hypertrophy, fibrosis, and inflammatory cell infiltration, were noted. Conclusions The present study revealed increased nuclear DNA methylation in cardiomyocytes, but not other cell types, from DCM hearts, with predominant localization in the heterochromatin. Its significant relations with LV functional and remodelling parameters imply a pathophysiological significance of DNA methylation in heart failure.https://doi.org/10.1002/ehf2.12593Chromatin remodellingDilated cardiomyopathyDNA methylation, Epigenetics |
| spellingShingle | Takatomo Watanabe Hideshi Okada Hiromitsu Kanamori Nagisa Miyazaki Akiko Tsujimoto Chihiro Takada Kodai Suzuki Genki Naruse Akihiro Yoshida Takahide Nawa Toshiki Tanaka Masanori Kawasaki Hiroyasu Ito Shinji Ogura Hiroyuki Okura Takako Fujiwara Hisayoshi Fujiwara Genzou Takemura In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study ESC Heart Failure Chromatin remodelling Dilated cardiomyopathy DNA methylation, Epigenetics |
| title | In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study |
| title_full | In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study |
| title_fullStr | In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study |
| title_full_unstemmed | In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study |
| title_short | In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study |
| title_sort | in situ nuclear dna methylation in dilated cardiomyopathy an endomyocardial biopsy study |
| topic | Chromatin remodelling Dilated cardiomyopathy DNA methylation, Epigenetics |
| url | https://doi.org/10.1002/ehf2.12593 |
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