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<p>Abdominal aortic aneurysms (AAAs) occur in 1–2% of the elderly. The rupture of an AAA usually causes uncontrollable lethal hemorrhage, and its risk increases with AAA size. However, there is no effective pharmacological therapy for hindering AAA growth. Here we show that global or vascular smooth muscle cell (VSMC)-specific transient receptor potential melastatin 7 (TRPM7) knockout in mice prevented AAA formation, as indicated by inhibited VSMC reprogramming, reduced inflammatory infiltration and suppressed matrix degradation. Mechanistically, we showed that TRPM7-mediated Ca<sup>2+</sup> signaling promotes Kruppel-like factor 4 (KLF4) activation, driving VSMC reprogramming and accelerating AAA growth. By generating channel-dead and using kinase-inactive knockin mice, we found that it is the channel function, rather than kinase activity, that is required for TRPM7-mediated AAA pathogenesis. Importantly, TRPM7 inhibitor NS8593 suppressed VSMC reprogramming and protected mice against AAA formation. Our data suggest that TRPM7 is a promising therapeutic target for developing effective prophylactic medications to limit AAA progression. In addition, the channel-dead TRPM7 knockin mice will serve as a valuable tool for elucidating the roles of TRPM7 in other pathophysiological conditions.</p>

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TRPM7 channel activity promotes the pathogenesis of abdominal aortic aneurysms

  • 期刊论文

  • 发表日期：

    2025年2月14日

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  • Pengyu Zong,
  • Cindy X. Li,
  • Jianlin Feng,
  • Zhichao Yue,
  • Thushara Nethramangalath,
  • Yangzhouyun Xie,
  • Xin Qin,
  • Mara Cicchetti,
  • Yujun Cai,
  • Evan Jellison,
  • Masayuki Matsushita,
  • Loren W. Runnels,
  • Lixia Yue

摘要

Abdominal aortic aneurysms (AAAs) occur in 1–2% of the elderly. The rupture of an AAA usually causes uncontrollable lethal hemorrhage, and its risk increases with AAA size. However, there is no effective pharmacological therapy for hindering AAA growth. Here we show that global or vascular smooth muscle cell (VSMC)-specific transient receptor potential melastatin 7 (TRPM7) knockout in mice prevented AAA formation, as indicated by inhibited VSMC reprogramming, reduced inflammatory infiltration and suppressed matrix degradation. Mechanistically, we showed that TRPM7-mediated Ca2+ signaling promotes Kruppel-like factor 4 (KLF4) activation, driving VSMC reprogramming and accelerating AAA growth. By generating channel-dead and using kinase-inactive knockin mice, we found that it is the channel function, rather than kinase activity, that is required for TRPM7-mediated AAA pathogenesis. Importantly, TRPM7 inhibitor NS8593 suppressed VSMC reprogramming and protected mice against AAA formation. Our data suggest that TRPM7 is a promising therapeutic target for developing effective prophylactic medications to limit AAA progression. In addition, the channel-dead TRPM7 knockin mice will serve as a valuable tool for elucidating the roles of TRPM7 in other pathophysiological conditions.