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<p>Ionic signaling in smooth muscle cells (SMCs) is critical for vascular homeostasis. In this study, we untangled the role of the bifunctional TRPM7 channel kinase (chanzyme) in abdominal aortic aneurysm (AAA) pathogenesis. Comparing SMC-specific, macrophage-specific and endothelial cell–specific <i>Trpm7</i> knockout, we revealed that SMC-specific <i>Trpm7</i> deficiency protected mice from AAA in two distinct preclinical models of the disease. We showed that the TRPM7 channel activity increased the Ca<sup>2+</sup> and Zn<sup>2+</sup> influx and the Ca<sup>2+</sup>/calcineurin/CRTC2/CREB-dependent and Zn<sup>2+</sup>/MTF1-dependent <i>Mmp2</i> transcription. Repurposing the clinical drug FTY720 to prevent and treat AAA resulted in improved aortic phenotypes through inhibition of TRPM7 channel activity. This study highlights the ionic mechanisms underlying AAA, identifies TRPM7 as a potential therapeutic target and suggests that blocking TRPM7 channels could be a viable strategy for treating AAA.</p>

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The TRPM7 chanzyme in smooth muscle cells drives abdominal aortic aneurysm in mice

  • 期刊论文

  • 发表日期：

    2025年2月14日

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  • Xuan Wang,
  • Mi Wang,
  • Tian-Tian Zhu,
  • Zi-Jie Zheng,
  • Shuang Li,
  • Zhao-Yi Sui,
  • Xin Guo,
  • Sha Wu,
  • Nai-Ning Zhang,
  • Zhi-Yi Yu,
  • Chang-Ping Hu,
  • Yong-Bo Tang,
  • Qing Wang,
  • Zheng Zhang

摘要

Ionic signaling in smooth muscle cells (SMCs) is critical for vascular homeostasis. In this study, we untangled the role of the bifunctional TRPM7 channel kinase (chanzyme) in abdominal aortic aneurysm (AAA) pathogenesis. Comparing SMC-specific, macrophage-specific and endothelial cell–specific Trpm7 knockout, we revealed that SMC-specific Trpm7 deficiency protected mice from AAA in two distinct preclinical models of the disease. We showed that the TRPM7 channel activity increased the Ca2+ and Zn2+ influx and the Ca2+/calcineurin/CRTC2/CREB-dependent and Zn2+/MTF1-dependent Mmp2 transcription. Repurposing the clinical drug FTY720 to prevent and treat AAA resulted in improved aortic phenotypes through inhibition of TRPM7 channel activity. This study highlights the ionic mechanisms underlying AAA, identifies TRPM7 as a potential therapeutic target and suggests that blocking TRPM7 channels could be a viable strategy for treating AAA.