Vitamin D Pathway Activation Reduces Cardiomyocyte DNA Damage and Improves Cardiac Contractility in Preclinical Models
10 affiliations
- 1Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
- 2Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
- 3Center for Epidemiology and Preventive Medicine, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan
- 4Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Setagaya-ku, Tokyo, Japan
- 5Department of Systems Developmental Biology, National Center for Child Health and Development Research Institute, Setagaya-ku, Tokyo, Japan
- 6Department of Biodesign, Division of Biofunctional Restoration Institute of Biomaterials and Bioengineering, Science Tokyo, Chiyoda-ku, Tokyo, Japan
- 7Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan
- 8Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan
- 9Department of Cardiovascular Medicine, Nara Medical University, Kashihara-shi, Nara, Japan
- 10International University of Health and Welfare, Minato-ku, Tokyo, Japan
Abstract
Background: In heart failure (HF), DNA damage caused by various external stressors contributes to cardiac dysfunction through the activation of DNA damage response pathways. To date, no clinical strategies have been established to restore cardiac function by reducing accumulated DNA damage. We previously found that vitamin D improved contractility in lamin A/C (LMNA) p.Q353R–mutant induced pluripotent stem (iPS) cell-derived cardiomyocytes (iPSCMs), but whether this effect extends to other LMNA variants and in vivo models remained uncertain.
Objectives: The objective of the study was to evaluate the association of vitamin D pathway activation with cardiomyocyte phosphorylated histone H2AX (γH2AX) foci and contractile phenotypes in patient-derived iPSCMs and mouse models of HF.
Methods: iPS cell lines were generated from dilated cardiomyopathy patients carrying the LMNA p.R225X mutation, and the effects of vitamin D treatment on γH2AX foci and cardiomyocyte contractility were evaluated. In addition, the effects of the vitamin D analog paricalcitol were evaluated in Lmna p.R225X mice and in a pressure overload mouse model of HF.
Results: Consistent with previous findings, vitamin D treatment reduced γH2AX foci in cardiomyocytes derived from LMNA p.R225X mutant iPS cells through upregulating the expression of DNA repair factors, and improved contractility in these iPSCMs. Furthermore, paricalcitol reduced γH2AX foci and attenuated cardiac dysfunction in both Lmna p.R225X mice and pressure overload HF model mice.
Conclusions: Vitamin D pathway activation improved contractile phenotypes across complementary preclinical models and was accompanied by reduced γH2AX foci or related transcriptional changes. These findings support further mechanistic and preclinical investigation.
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BibTeX
@article{ito2026vitamin,
title = {{Vitamin D Pathway Activation Reduces Cardiomyocyte DNA Damage and Improves Cardiac Contractility in Preclinical Models}},
author = {Masamichi Ito and Manami Katoh and Masayuki Kubota and Masataka Yamasaki and Yanfei Zhang and Jin Komuro and Ayako Tsukihashi and Shintaro Yamada and Toshiyuki Ko and Mikako Katagiri and Ryo Abe and Shunsuke Inoue and Takashi Hiruma and Daigo Nishijo and Zhehao Dai and Hiroyuki Morita and Masashi Toyoda and Shuji Takada and Masashi Ikeuchi and Katsuhisa Matsuura and Akihiro Umezawa and Hiroyuki Aburatani and Kenji Onoue and Seitaro Nomura and Norihiko Takeda and Issei Komuro},
journal = {JACC: Advances},
year = {2026},
month = sep,
doi = {10.1016/j.jacadv.2026.103199},
url = {https://doi.org/10.1016/j.jacadv.2026.103199},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Vitamin D Pathway Activation Reduces Cardiomyocyte DNA Damage and Improves Cardiac Contractility in Preclinical Models
AU - Masamichi Ito
AU - Manami Katoh
AU - Masayuki Kubota
AU - Masataka Yamasaki
AU - Yanfei Zhang
AU - Jin Komuro
AU - Ayako Tsukihashi
AU - Shintaro Yamada
AU - Toshiyuki Ko
AU - Mikako Katagiri
AU - Ryo Abe
AU - Shunsuke Inoue
AU - Takashi Hiruma
AU - Daigo Nishijo
AU - Zhehao Dai
AU - Hiroyuki Morita
AU - Masashi Toyoda
AU - Shuji Takada
AU - Masashi Ikeuchi
AU - Katsuhisa Matsuura
AU - Akihiro Umezawa
AU - Hiroyuki Aburatani
AU - Kenji Onoue
AU - Seitaro Nomura
AU - Norihiko Takeda
AU - Issei Komuro
PY - 2026
DA - 2026/09/09
JO - JACC: Advances
DO - 10.1016/j.jacadv.2026.103199
UR - https://doi.org/10.1016/j.jacadv.2026.103199
AB - Background: In heart failure (HF), DNA damage caused by various external stressors contributes to cardiac dysfunction through the activation of DNA damage response pathways. To date, no clinical strategies have been established to restore cardiac function by reducing accumulated DNA damage. We previously found that vitamin D improved contractility in lamin A/C (LMNA) p.Q353R–mutant induced pluripotent stem (iPS) cell-derived cardiomyocytes (iPSCMs), but whether this effect extends to other LMNA variants and in vivo models remained uncertain. Objectives: The objective of the study was to evaluate the association of vitamin D pathway activation with cardiomyocyte phosphorylated histone H2AX (γH2AX) foci and contractile phenotypes in patient-derived iPSCMs and mouse models of HF. Methods: iPS cell lines were generated from dilated cardiomyopathy patients carrying the LMNA p.R225X mutation, and the effects of vitamin D treatment on γH2AX foci and cardiomyocyte contractility were evaluated. In addition, the effects of the vitamin D analog paricalcitol were evaluated in Lmna p.R225X mice and in a pressure overload mouse model of HF. Results: Consistent with previous findings, vitamin D treatment reduced γH2AX foci in cardiomyocytes derived from LMNA p.R225X mutant iPS cells through upregulating the expression of DNA repair factors, and improved contractility in these iPSCMs. Furthermore, paricalcitol reduced γH2AX foci and attenuated cardiac dysfunction in both Lmna p.R225X mice and pressure overload HF model mice. Conclusions: Vitamin D pathway activation improved contractile phenotypes across complementary preclinical models and was accompanied by reduced γH2AX foci or related transcriptional changes. These findings support further mechanistic and preclinical investigation.
SN - 2772-963X
ER -