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  2. Murine double minute 2-mediated estrogen receptor 1 degradation activates macrophage migration inhibitory factor to promote vascular smooth muscle cell dedifferentiation and oxidative stress during thoracic aortic aneurysm progression

Murine double minute 2-mediated estrogen receptor 1 degradation activates macrophage migration inhibitory factor to promote vascular smooth muscle cell dedifferentiation and oxidative stress during thoracic aortic aneurysm progression

  • Biochim Biophys Acta Mol Cell Res. 2024 Jan 11:119661. doi: 10.1016/j.bbamcr.2024.119661.
Tao Liu 1 Tian Zhang 2 Chenfan Guo 2 Xiangsen Liang 3 Pandeng Wang 4 Baoshi Zheng 5
Affiliations

Affiliations

  • 1 Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China; Department of Cardiovascular Surgery, Guangxi International Zhuang Medicine Hospital, Nanning 530001, Guangxi, PR China.
  • 2 Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China.
  • 3 Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi, PR China.
  • 4 Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China. Electronic address: w18556872136@163.com.
  • 5 Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China. Electronic address: zhengbs25@vip.sina.com.
Abstract

Estrogen Receptor 1 (ESR1) has been recently demonstrated as a potential diagnostic biomarker for thoracic aortic aneurysm (TAA). However, its precise role in the progression of TAA remains unclear. In this study, TAA models were established in ApoE-knockout mice and primary mouse vascular smooth muscle cells (VSMCs) through treatment with angiotensin (Ang) II. Our findings revealed a downregulation of ESR1 in Ang II-induced TAA mice and VSMCs. Upregulation of ESR1 mitigated expansion and cell Apoptosis in the mice aorta, reduced pathogenetic transformation of VSMCs, and reduced inflammatory infiltration and oxidative stress both in vitro and in vivo. Furthermore, we identified macrophage migration inhibitory factor (MIF) as a biological target of ESR1. ESR1 bound to the MIF promoter to suppress its transcription. Artificial MIF restoration negated the mitigating effects of ESR1 on TAA. Additionally, we discovered that murine double minute 2 (MDM2) was highly expressed in TAA models and mediated protein degradation of ESR1 through ubiquitination modification. Silencing of MDM2 reduced VSMC dedifferentiation and suppressed oxidative stress. However, these effects were reversed upon further silencing of ESR1. In conclusion, this study demonstrates that MDM2 activates MIF by mediating ESR degradation, thus promoting VSMC dedifferentiation and oxidative stress during TAA progression.

Keywords

ESR1; MDM2; MIF; Oxidative stress; Thoracic aortic aneurysm; VSMC dedifferentiation.

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