Hexokinase II knockdown results in exaggerated cardiac hypertrophy via increased ROS production

Rongxue Wu, Eugene Wyatt, Kusum Chawla, Minh Tran, Mohsen Ghanefar, Markku Laakso, Conrad L. Epting, Hossein Ardehali*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


Hexokinase-II (HKII) is highly expressed in the heart and can bind to the mitochondrial outer membrane. Since cardiac hypertrophy is associated with a substrate switch from fatty acid to glucose, we hypothesized that a reduction in HKII would decrease cardiac hypertrophy after pressure overload. Contrary to our hypothesis, heterozygous HKII-deficient (HKII +/-) mice displayed increased hypertrophy and fibrosis in response to pressure overload. The mechanism behind this phenomenon involves increased levels of reactive oxygen species (ROS), as HKII knockdown increased ROS accumulation, and treatment with the antioxidant N-acetylcysteine (NAC) abrogated the exaggerated response. HKII mitochondrial binding is also important for the hypertrophic effects, as HKII dissociation from the mitochondria resulted in de novo hypertrophy, which was also attenuated by NAC. Further studies showed that the increase in ROS levels in response to HKII knockdown or mitochondrial dissociation is mediated through increased mitochondrial permeability and not by a significant change in antioxidant defenses. Overall, these data suggest that HKII and its mitochondrial binding negatively regulate cardiac hypertrophy by decreasing ROS production via mitochondrial permeability.

Original languageEnglish (US)
Pages (from-to)633-646
Number of pages14
JournalEMBO Molecular Medicine
Issue number7
StatePublished - Jul 2012


  • Hexokinase
  • Hypertrophy
  • Mitochondria
  • Mitochondrial permeability transition
  • Reactive oxygen species

ASJC Scopus subject areas

  • Molecular Medicine


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