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Dapagliflozin protects heart function against type-4 cardiorenal syndrome through activation of

Yang Shen1, Xiaojie Peng2, Haizhe Ji3

  • 1Department of Cardiology, School of Medicine, South China University of Technology, Guangzhou, 510006; Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, China.

International Journal of Biological Macromolecules
|August 4, 2023
PubMed

Insights

Dapagliflozin protects against heart and kidney disease. It may alleviate cardiorenal syndrome type 4 cardiomyopathy by activating the PKM2/PP1/FUNDC1-mitophagy pathway, preserving heart function.

Area of Science:

  • Cardiology
  • Nephrology
  • Molecular Biology

Background:

  • Dapagliflozin (DAPA) shows cardioprotective and nephroprotective effects.
  • The impact of DAPA on cardiorenal syndrome type 4 (CRS-4)-related cardiomyopathy is not well understood.

Purpose of the Study:

  • To investigate if DAPA mitigates CRS-4-induced myocardial damage.
  • To explore the role of pyruvate kinase isozyme M2 (PKM2) and FUNDC1-dependent mitophagy in DAPA's protective mechanism.

Main Methods:

  • Established a CRS-4 mouse model using subtotal nephrectomy.
  • Utilized cardiomyocyte-specific PKM2 and FUNDC1 knockout mice.
  • Assessed myocardial function, mitochondrial activity, and mitophagy markers.
  • Performed co-immunoprecipitation and molecular docking to identify protein interactions.

Main Results:

  • DAPA treatment improved myocardial function and structure in CRS-4 mice, an effect dependent on PKM2.
  • DAPA enhanced mitochondrial function and reduced apoptosis in cardiomyocytes.
  • DAPA restored FUNDC1-dependent mitophagy via PKM2 and protein phosphatase 1 (PP1)-mediated dephosphorylation of FUNDC1.
  • PKM2 directly interacts with PP1 and FUNDC1.

Conclusions:

  • Dapagliflozin attenuates CRS-4-related cardiomyopathy.
  • The protective mechanism involves the activation of the PKM2/PP1/FUNDC1-mitophagy pathway.
  • This pathway is crucial for preserving cardiac and mitochondrial integrity under CRS-4 conditions.

Keywords:
CRS-4DapagliflozinFUNDC1MitochondriaPKM2PP1

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