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AMPK-Dependent YAP Inhibition Mediates the Protective Effect of Metformin against Obesity-Associated Endothelial

Lijing Kang1,2,3, Juanjuan Yi4, Chi-Wai Lau2

  • 1Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China.

Antioxidants (Basel, Switzerland)
|September 28, 2023
PubMed

Insights

Metformin protects against high glucose-induced vascular dysfunction by inhibiting Yes-associated protein 1 (YAP) activation. This study reveals a new therapeutic target, the AMPK-YAP-JNK axis, for diabetic cardiovascular complications.

Area of Science:

  • Cardiovascular Biology
  • Metabolic Diseases
  • Molecular Cell Biology

Background:

  • Hyperglycemia and chronic inflammation are key risk factors for cardiovascular diseases, particularly in obesity.
  • Yes-associated protein 1 (YAP) signaling is implicated in cellular dysfunction under high glucose conditions.
  • The role of YAP in metformin's vasoprotective effects in diabetic endothelial dysfunction remains unclear.

Purpose of the Study:

  • To investigate YAP activation in obesity-associated endothelial dysfunction and inflammation.
  • To determine if metformin's vasoprotective effects are mediated by YAP inhibition.
  • To explore the AMPK-YAP-JNK signaling axis in diabetic vascular complications.

Main Methods:

  • Reanalysis of clinical sequencing data from diabetic patients.
  • Assessment of endothelium-dependent relaxations (EDRs) in mouse aortas.
  • In vitro studies using human umbilical vein endothelial cells (HUVECs) under high glucose conditions.
  • Investigation of signaling pathways including AMPK, YAP, and JNK.

Main Results:

  • YAP signaling and its target genes (CTGF, CYR61) were upregulated in diabetic vascular tissues.
  • YAP overexpression impaired EDRs and increased inflammation and reactive oxygen species in endothelial cells.
  • High glucose activated YAP via AMPK inhibition, leading to increased JNK activity.
  • Metformin activated AMPK, promoted YAP phosphorylation, improved EDRs, and suppressed JNK activity.

Conclusions:

  • YAP activation contributes to high glucose-induced endothelial dysfunction and inflammation.
  • Metformin exerts vasoprotective effects by inhibiting the AMPK-YAP-JNK axis.
  • Targeting the AMPK-YAP-JNK pathway offers a potential therapeutic strategy for diabetic vascular complications.
Keywords:
AMPKJNKYAPendothelial dysfunctionhigh glucosemetforminobesity

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