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Regulation of Cardiac Fibroblast GLS1 Expression by Scleraxis.

Sikta Chattopadhyaya1,2, Raghu S Nagalingam1,2, D Allison Ledingham1

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Scleraxis regulates glutaminolysis, a key energy pathway in cardiac fibroblast activation. Targeting scleraxis-mediated glutaminase (GLS1) expression may inhibit the energy production required for fibrosis.

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Area of Science:

  • Cardiovascular Biology
  • Cellular Metabolism
  • Molecular Biology

Background:

  • Fibrosis involves energy-intensive fibroblast activation to myofibroblasts, increasing extracellular matrix synthesis.
  • Transcriptional control of energy metabolism in cardiac fibroblast activation is poorly understood, though glutaminolysis is implicated in other fibrotic diseases.
  • Transforming growth factor-beta (TGFβ) and scleraxis drive cardiac fibroblast activation.

Purpose of the Study:

  • To investigate how TGFβ and scleraxis regulate genes involved in glutaminolysis, specifically glutaminase (GLS1), in cardiac fibroblast activation.
  • To determine the role of scleraxis in mediating GLS1 expression and glutaminolysis during cardiac fibroblast activation.
  • To explore the therapeutic potential of targeting scleraxis-mediated GLS1 expression.

Main Methods:

  • Investigated GLS1 gene expression and glutaminolysis in cardiac fibroblasts under TGFβ stimulation and scleraxis manipulation (overexpression, knockout, knockdown).
  • Utilized GLS1 inhibitor CB-839 to assess its effect on TGFβ-induced fibroblast activation.
  • Employed luciferase reporter assays to examine scleraxis transactivation of the GLS1 promoter, focusing on a specific E-box motif.

Main Results:

  • Scleraxis overexpression increased glutaminolysis gene expression, including GLS1, while scleraxis-null fibroblasts showed reduced expression.
  • TGFβ induced GLS1 expression and elevated intracellular glutamine/glutamate levels, indicative of increased glutaminolysis, but these effects were blunted in scleraxis knockout cells.
  • Scleraxis directly transactivated the GLS1 promoter via an E-box motif, and GLS1 knockdown significantly reduced scleraxis-induced fibroblast activation.
  • The GLS1 inhibitor CB-839 attenuated TGFβ-induced fibroblast activation.

Conclusions:

  • Scleraxis is a key regulator of GLS1 expression and glutaminolysis in cardiac fibroblast activation.
  • Targeting scleraxis-mediated GLS1 expression offers a potential strategy to inhibit fibroblast energy metabolism and combat cardiac fibrosis.
  • Blocking scleraxis may starve activated fibroblasts of essential energy, thereby limiting fibrotic processes.