Scholarlink

<p>Cardiac fibroblasts (CFs) activation plays a crucial role in cardiac remodeling. However, the molecular mechanisms underlying the fibroblast-to-myofibroblast transition remain largely unknown. Here we found elevated Foxm1 expression in human heart failure (HF) samples as well as in the mouse cardiac remodeling model. CFs were the primary cell type responsible for Foxm1 upregulation. Foxm1 genetic knockout in CFs or myofibroblasts significantly attenuated TAC-induced cardiac remodeling and HF. Conversely, conditional overexpression of Foxm1 in CFs resulted in more severe pathological cardiac remodeling and dysfunction by TAC. Combined RNA-sequencing and MS analysis revealed that Foxm1 promoted p38 mitogen-activated protein kinase (MAPK) signalling pathway. Mechanically, Foxm1 not only upregulates USP10 to reduce the ubiquitination and degradation of p38γ but also directly drives the expression of MKK6 to increase the phosphorylation levels of p38, thereby acting as a dual amplifier for p38 activation. Genetic knockout of p38γ ameliorated the exacerbated TAC-induced cardiac remodeling in mice with Foxm1 overexpression in CFs. Our findings suggest that targeting the Foxm1-USP10/MKK6-p38γ MAPK axis may represent a new potential therapeutic strategy against pathological cardiac remodeling and HF.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Cardiac fibroblast Foxm1 deficiency prevents pressure overload-induced cardiac remodeling via the Usp10/MKK6-p38γ MAPK axis

  • 期刊论文

  • 发表日期：

    2025年11月6日

查看全文
  • Shuai Song,
  • Xiaokai Zhang,
  • Zihang Huang,
  • Linqi Zeng,
  • Fengze Cai,
  • Tongyao Wang,
  • Yining Song,
  • Jiahao Guo,
  • Mohan Li,
  • Chenyan Liu,
  • Xinyu Weng,
  • Shuyang Lu,
  • Li Shen,
  • Xiaochun Zhang,
  • Hao Lu,
  • Ping Zhu,
  • Aijun Sun,
  • Junbo Ge

摘要

Cardiac fibroblasts (CFs) activation plays a crucial role in cardiac remodeling. However, the molecular mechanisms underlying the fibroblast-to-myofibroblast transition remain largely unknown. Here we found elevated Foxm1 expression in human heart failure (HF) samples as well as in the mouse cardiac remodeling model. CFs were the primary cell type responsible for Foxm1 upregulation. Foxm1 genetic knockout in CFs or myofibroblasts significantly attenuated TAC-induced cardiac remodeling and HF. Conversely, conditional overexpression of Foxm1 in CFs resulted in more severe pathological cardiac remodeling and dysfunction by TAC. Combined RNA-sequencing and MS analysis revealed that Foxm1 promoted p38 mitogen-activated protein kinase (MAPK) signalling pathway. Mechanically, Foxm1 not only upregulates USP10 to reduce the ubiquitination and degradation of p38γ but also directly drives the expression of MKK6 to increase the phosphorylation levels of p38, thereby acting as a dual amplifier for p38 activation. Genetic knockout of p38γ ameliorated the exacerbated TAC-induced cardiac remodeling in mice with Foxm1 overexpression in CFs. Our findings suggest that targeting the Foxm1-USP10/MKK6-p38γ MAPK axis may represent a new potential therapeutic strategy against pathological cardiac remodeling and HF.