Regulation of Ptbp1-controlled alternative splicing of pyruvate kinase muscle by liver kinase B1 governs vascular smooth muscle cell plasticity in vivo

Aug 27, 2024Cardiovascular research

How a liver enzyme controls gene splicing to regulate blood vessel muscle cell flexibility

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Abstract

Smooth muscle cell-specific deletion of Lkb1 in mice led to progressive aortic dilation and premature death.

  • Lkb1-deficient vascular smooth muscle cells (VSMCs) transformed into fibroblast-like and chondrocyte-like cells, contributing to blood vessel rupture.
  • Decreased Lkb1 expression in human aortic aneurysm tissue was observed compared to control tissue.
  • Lkb1 regulates the expression of a protein that influences the splicing of pyruvate kinase isoforms, affecting metabolism.
  • An increased ratio of one pyruvate kinase isoform was associated with a shift towards aerobic glycolysis in Lkb1-deficient VSMCs.
  • Activation of PKM2 with a specific compound improved VSMC function and reduced aortic dilation in affected mice.

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Key numbers

40 of 42
Aortic Rupture Incidence
Percentage of mice with aortic rupture after Lkb1 deletion.
21.8%
Transformation Rates
Percentage of VSMCs transformed into fibroblast-like cells at 4.5 months post-TAM induction.
18.2%
Transformation Rates
Percentage of VSMCs transformed into chondrocyte-like cells at 4.5 months post-TAM induction.

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