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Lumican promotes calcific aortic valve disease through H3 histone lactylation.
Huang, Yuming; Wang, Chunli; Zhou, Tingwen; Xie, Fei; Liu, Zongtao; Xu, Haiying; Liu, Ming; Wang, Shunshun; Li, Lanqing; Chi, Qingjia; Shi, Jiawei; Dong, Nianguo; Xu, Kang.
Afiliação
  • Huang Y; Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • Wang C; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • Zhou T; Hubei Shizhen Laboratory, Wuhan 430065, China.
  • Xie F; School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan 430065, China.
  • Liu Z; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • Xu H; Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • Liu M; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • Wang S; Hubei Provincial Engineering Technology Research Center for Chinese Medicine Processing, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China.
  • Li L; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • Chi Q; Hubei Provincial Engineering Technology Research Center for Chinese Medicine Processing, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China.
  • Shi J; Hubei Provincial Engineering Technology Research Center for Chinese Medicine Processing, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China.
  • Dong N; Department of Engineering Structure and Mechanics, School of Science, Wuhan University of Technology, China.
  • Xu K; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Eur Heart J ; 2024 Jul 08.
Article em En | MEDLINE | ID: mdl-38976370
ABSTRACT
BACKGROUND AND

AIMS:

Valve interstitial cells (VICs) undergo a transition to intermediate state cells before ultimately transforming into the osteogenic cell population, which is a pivotal cellular process in calcific aortic valve disease (CAVD). Herein, this study successfully delineated the stages of VIC osteogenic transformation and elucidated a novel key regulatory role of lumican (LUM) in this process.

METHODS:

Single-cell RNA-sequencing (scRNA-seq) from nine human aortic valves was used to characterize the pathological switch process and identify key regulatory factors. The in vitro, ex vivo, in vivo, and double knockout mice were constructed to further unravel the calcification-promoting effect of LUM. Moreover, the multi-omic approaches were employed to analyse the molecular mechanism of LUM in CAVD.

RESULTS:

ScRNA-seq successfully delineated the process of VIC pathological transformation and highlighted the significance of LUM as a novel molecule in this process. The pro-calcification role of LUM is confirmed on the in vitro, ex vivo, in vivo level, and ApoE-/-//LUM-/- double knockout mice. The LUM induces osteogenesis in VICs via activation of inflammatory pathways and augmentation of cellular glycolysis, resulting in the accumulation of lactate. Subsequent investigation has unveiled a novel LUM driving histone modification, lactylation, which plays a role in facilitating valve calcification. More importantly, this study has identified two specific sites of histone lactylation, namely, H3K14la and H3K9la, which have been found to facilitate the process of calcification. The confirmation of these modification sites' association with the expression of calcific genes Runx2 and BMP2 has been achieved through ChIP-PCR analysis.

CONCLUSIONS:

The study presents novel findings, being the first to establish the involvement of lumican in mediating H3 histone lactylation, thus facilitating the development of aortic valve calcification. Consequently, lumican would be a promising therapeutic target for intervention in the treatment of CAVD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Eur Heart J Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Eur Heart J Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China