A PKM2 signature in the failing heart

Meredith L. Rees, Janani Subramaniam, Yuanteng Li, Dale J. Hamilton, O. Howard Frazier, Heinrich Taegtmeyer

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

A salient feature of the failing heart is metabolic remodeling towards predominant glucose metabolism and activation of the fetal gene program. Sunitinib is a multitargeted receptor tyrosine kinase inhibitor used for the treatment of highly vascularized tumors. In diabetic patients, sunitinib significantly decreases blood glucose. However, a considerable proportion of sunitinib-treated patients develop cardiac dysfunction or failure. We asked whether sunitinib treatment results in shift towards glycolysis in the heart. Glucose uptake by the heart was increased fivefold in mice treated with sunitinib. Transcript analysis by qPCR revealed an induction of genes associated with glycolysis and reactivation of the fetal gene program. Additionally, we observed a shift in the enzyme pyruvate kinase from the adult M1 (PKM1) isoform to the fetal M2 (PKM2) isoform, a hallmark of the Warburg Effect. This novel observation led us to examine whether a similar shift occurs in human heart failure. Examination of tissue from patients with heart failure similarly displayed an induction of PKM2. Moreover, this phenomenon was partially reversed following mechanical unloading. We propose that pyruvate kinase isoform switching represents a novel feature of the fetal gene program in the failing heart.

Original languageEnglish (US)
Pages (from-to)430-436
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume459
Issue number3
DOIs
StatePublished - Apr 10 2015

Keywords

  • Fetal gene program
  • Glycolysis
  • Heart failure
  • Hif1α
  • PKM2
  • Sunitinib

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Rees, M. L., Subramaniam, J., Li, Y., Hamilton, D. J., Frazier, O. H., & Taegtmeyer, H. (2015). A PKM2 signature in the failing heart. Biochemical and Biophysical Research Communications, 459(3), 430-436. https://doi.org/10.1016/j.bbrc.2015.02.122