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Nuclear Tkt promotes ischemic heart failure via the cleaved Parp1/Aif axis

Zhiyan Wang1,2, Zeping Qiu1,2, Sha Hua3

  • 1Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200023, People's Republic of China.

Basic Research in Cardiology
|April 5, 2022
PubMed

Insights

Transketolase (Tkt) elevation worsens heart attack outcomes by promoting heart cell death. Inhibiting Tkt in heart cells protects against cardiac dysfunction following ischemic injury.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Enzymology

Background:

  • Transketolase (Tkt) is known to affect cancer cell survival and genome stability.
  • Its role in cardiac ischemic injury, such as myocardial infarction (MI), is not well understood.

Purpose of the Study:

  • To investigate the function of Transketolase (Tkt) in the context of myocardial ischemic injury.
  • To elucidate the molecular mechanisms by which Tkt influences cardiomyocyte apoptosis and cardiac function.

Main Methods:

  • Label-free proteomics to identify protein changes in murine hearts post-MI.
  • Lentivirus-mediated Tkt knockdown and overexpression in cardiomyocytes.
  • Generation of inducible conditional cardiomyocyte Tkt-knockout mice.
  • Luciferase assay and chromatin immunoprecipitation to determine Tkt's transcriptional regulation.
  • Analysis of Tkt's interaction with Poly(ADP-ribose) polymerase 1 (Parp1) and Apoptosis Inducible Factor (Aif).

Main Results:

  • Proteomics revealed significantly elevated Tkt levels in hearts after MI.
  • Tkt knockdown improved cardiac function and reduced cardiomyocyte apoptosis post-MI, while overexpression worsened outcomes.
  • Cardiomyocyte-specific Tkt knockout mice exhibited reduced heart failure.
  • Tkt was identified as a direct target of Krüppel-like factor 5 (Klf5).
  • Nuclear Tkt directly binds to Parp1, facilitates its cleavage, and activates Aif, promoting apoptosis.

Conclusions:

  • Elevated Transketolase (Tkt) plays a detrimental, non-metabolic role in ischemic heart failure.
  • Nuclear Tkt promotes cardiomyocyte apoptosis through the Parp1/Aif pathway, contributing to cardiac dysfunction.
  • Targeting Tkt may offer a therapeutic strategy for myocardial ischemic injury.
Keywords:
ApoptosisIschemic heart failurePoly(ADP-ribose) polymerase 1Transketolase

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