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<p>Calcific aortic valve disease (CAVD) is a prevalent valvular disorder that lacks effective pharmacological treatments. Metformin, an oral anti-diabetic drug, has been suggested to protect valvular interstitial cells (VICs) from calcification, but its role in preventing organic phosphate-induced degeneration in VICs and aortic valve (AV) leaflets remains unclear. Using an ex vivo three-dimensional tissue model, we induced degeneration with organic phosphate-rich conditions in ovine VICs and AV leaflets. Metformin treatment reduced calcium deposition, as assessed by alizarin red staining (VICs: <i>p</i> &lt; 0.0001; AV leaflets: <i>p</i> &lt; 0.05), and preserved reduced opacity of AV leaflet (<i>p</i> &lt; 0.01). It inhibited early osteogenic differentiation, evidenced by reduced alkaline phosphatase activity (VICs: <i>p</i> &lt; 0.0001; AV leaflets: <i>p</i> &lt; 0.05), and mitigated gene expression of myofibroblastic markers. Furthermore, metformin improved proliferation (VICs: <i>p</i> &lt; 0.0001; AV leaflets: <i>p</i> &lt; 0.05), lowered lactate dehydrogenase levels (VICs: <i>p</i> &lt; 0.01; AV leaflets: <i>p</i> &lt; 0.001), preserved extracellular matrix architecture, and ameliorated extracellular matrix remodeling at gene expression level. AMPK phosphorylation was increased in both VICs (28%, <i>p</i> &lt; 0.001) and AV leaflets (21%, <i>p</i> &lt; 0.05) under pro-degenerative conditions and metformin treatment. In conclusion, metformin protects against organic phosphate-induced degeneration in both VICs and AV leaflets, highlighting its therapeutic potential in CAVD.</p>

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Metformin mitigates aortic valve degeneration in an ex vivo three-dimensional tissue model

  • 期刊论文

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  • 发表日期：

    2025年12月17日

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  • Friederike Irmgard Schoettler,
  • Andreas Weber,
  • Vera Schmidt,
  • Sebastian Johannes Bauer,
  • Moritz Benjamin Immohr,
  • Artur Lichtenberg,
  • Payam Akhyari,
  • Mareike Barth

摘要

Calcific aortic valve disease (CAVD) is a prevalent valvular disorder that lacks effective pharmacological treatments. Metformin, an oral anti-diabetic drug, has been suggested to protect valvular interstitial cells (VICs) from calcification, but its role in preventing organic phosphate-induced degeneration in VICs and aortic valve (AV) leaflets remains unclear. Using an ex vivo three-dimensional tissue model, we induced degeneration with organic phosphate-rich conditions in ovine VICs and AV leaflets. Metformin treatment reduced calcium deposition, as assessed by alizarin red staining (VICs: p < 0.0001; AV leaflets: p < 0.05), and preserved reduced opacity of AV leaflet (p < 0.01). It inhibited early osteogenic differentiation, evidenced by reduced alkaline phosphatase activity (VICs: p < 0.0001; AV leaflets: p < 0.05), and mitigated gene expression of myofibroblastic markers. Furthermore, metformin improved proliferation (VICs: p < 0.0001; AV leaflets: p < 0.05), lowered lactate dehydrogenase levels (VICs: p < 0.01; AV leaflets: p < 0.001), preserved extracellular matrix architecture, and ameliorated extracellular matrix remodeling at gene expression level. AMPK phosphorylation was increased in both VICs (28%, p < 0.001) and AV leaflets (21%, p < 0.05) under pro-degenerative conditions and metformin treatment. In conclusion, metformin protects against organic phosphate-induced degeneration in both VICs and AV leaflets, highlighting its therapeutic potential in CAVD.