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<p>Vascular calcification (VC) is recognized as an independent predictor of cardiovascular events. Although estrogen replacement is a controversial treatment due to its potential carcinogenic effects, it was considered a protective treatment against VC in postmenopausal women. Estrogen receptor α (ERα) co-regulators were considered as potential therapeutic targets for ERα-related cancers. However, ERα activity and the biological function modulation of ERα co-regulators in VC remain elusive. Histone lysine demethylase 4B (KDM4B) was identified to be highly expressed in human and mouse aortic smooth muscle (ASMC) cells treated with β-phosphoglycerol and in mice overloaded with VitD3 during calcification, as evidenced by western blotting and immunofluorescence staining. Co-immunoprecipitation (Co-IP) was performed to show the association between KDM4B and ERα. Our data demonstrated that KDM4B down-regulated ERα-induced transactivation and that KDM4B depletion increased mRNA expression of endogenous ERα target genes. Furthermore, we provided the evidence to show that KDM4B is associated with Polycomb repressive complex 2 (PRC2) and ERα. In addition, KDM4B depletion decreased the recruitment of PRC2 complex to estrogen response element (ERE) regions of ERα target gene, thereby down-regulating the H3K27me3 levels. Finally, KDM4B-mediated enhancement of ASMCs' calcification was partially attenuated by the estrogen treatment. KDM4B inhibits ERα-induced transactivation independent of its Jumanji-C enzyme active region. Taken together, our study suggests that KDM4B acting as ERα co-repressor is involved in the regulation of VC, indicating that KDM4B may be a new potential therapeutic target for VC treatment.</p>

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KDM4B modulates ERα signaling pathway to participate in vascular smooth muscle cell calcification

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月7日

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  • Fei Liu,
  • Yang Lv,
  • Yanxia Lin,
  • Chunyu Wang,
  • Shengli Wang,
  • Kai Zeng,
  • Baosheng Zhou,
  • Lin Lin,
  • Jianwei Feng,
  • Ge Sun,
  • Xiaocen Chang,
  • Mengsu Cao,
  • Hao Li,
  • Xihong Hu,
  • Shigeaki Kato,
  • Yue Zhao,
  • Wen Tian

摘要

Vascular calcification (VC) is recognized as an independent predictor of cardiovascular events. Although estrogen replacement is a controversial treatment due to its potential carcinogenic effects, it was considered a protective treatment against VC in postmenopausal women. Estrogen receptor α (ERα) co-regulators were considered as potential therapeutic targets for ERα-related cancers. However, ERα activity and the biological function modulation of ERα co-regulators in VC remain elusive. Histone lysine demethylase 4B (KDM4B) was identified to be highly expressed in human and mouse aortic smooth muscle (ASMC) cells treated with β-phosphoglycerol and in mice overloaded with VitD3 during calcification, as evidenced by western blotting and immunofluorescence staining. Co-immunoprecipitation (Co-IP) was performed to show the association between KDM4B and ERα. Our data demonstrated that KDM4B down-regulated ERα-induced transactivation and that KDM4B depletion increased mRNA expression of endogenous ERα target genes. Furthermore, we provided the evidence to show that KDM4B is associated with Polycomb repressive complex 2 (PRC2) and ERα. In addition, KDM4B depletion decreased the recruitment of PRC2 complex to estrogen response element (ERE) regions of ERα target gene, thereby down-regulating the H3K27me3 levels. Finally, KDM4B-mediated enhancement of ASMCs' calcification was partially attenuated by the estrogen treatment. KDM4B inhibits ERα-induced transactivation independent of its Jumanji-C enzyme active region. Taken together, our study suggests that KDM4B acting as ERα co-repressor is involved in the regulation of VC, indicating that KDM4B may be a new potential therapeutic target for VC treatment.