Reduction in hexokinase II levels results in decreased cardiac function and altered remodeling after ischemia/reperfusion injury

Rongxue Wu, Kirsten M. Smeele, Eugene Wyatt, Yoshihiko Ichikawa, Otto Eerbeek, Lin Sun, Kusum Chawla, Markus W. Hollmann, Varun Nagpal, Sami Heikkinen, Markku Laakso, Kentaro Jujo, J. Andrew Wasserstrom, Coert J. Zuurbier, Hossein Ardehali*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Rationale: Cardiomyocytes switch substrate utilization from fatty acid to glucose under ischemic conditions; however, it is unknown how perturbations in glycolytic enzymes affect cardiac response to ischemia/reperfusion (I/R). Hexokinase (HK)II is a HK isoform that is expressed in the heart and can bind to the mitochondrial outer membrane. Objective: We sought to define how HKII and its binding to mitochondria play a role in cardiac response and remodeling after I/R. Methods and Results: We first showed that HKII levels and its binding to mitochondria are reduced 2 days after I/R. We then subjected the hearts of wild-type and heterozygote HKII knockout (HKII+/-) mice to I/R by coronary ligation. At baseline, HKII+/- mice have normal cardiac function; however, they displaylower systolic function after I/R compared to wild-type animals. The mechanism appears to be through an increase in cardiomyocyte death and fibrosis and a reduction in angiogenesis; the latter is through a decrease in hypoxia-inducible factor- dependent pathway signaling in cardiomyocytes. HKII mitochondrial binding is also critical for cardiomyocyte survival, because its displacement in tissue culture with a synthetic peptide increases cell death. Our results also suggest that HKII may be important for the remodeling of the viable cardiac tissue because its modulation in vitro alters cellular energy levels, O2 consumption, and contractility. Conclusions: These results suggest that reduction in HKII levels causes altered remodeling of the heart in I/R by increasing cell death and fibrosis and reducing angiogenesis and that mitochondrial binding is needed for protection of cardiomyocytes.

Original languageEnglish (US)
Pages (from-to)60-69
Number of pages10
JournalCirculation research
Volume108
Issue number1
DOIs
StatePublished - Jan 7 2011

Keywords

  • Apoptosis
  • Hexokinase
  • Ischemia/reperfusion
  • Mitochondria
  • Vascular endothelial growth factor (VEGF)

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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