PMID:22517678

Citation	Wu, R, Wyatt, E, Chawla, K, Tran, M, Ghanefar, M, Laakso, M, Epting, CL and Ardehali, H (2012) Hexokinase II knockdown results in exaggerated cardiac hypertrophy via increased ROS production. EMBO Mol Med 4:633-46
Abstract	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.
Links	PubMed PMC3407950 Online version:10.1002/emmm.201200240
Keywords	Acetylcysteine/pharmacology; Animals; Antioxidants/pharmacology; Cardiomegaly/metabolism; Cardiomegaly/pathology; Cells, Cultured; Fibrosis; Heterozygote; Hexokinase/antagonists & inhibitors; Hexokinase/genetics; Hexokinase/metabolism; Male; Mice; Mitochondria/metabolism; Myocytes, Cardiac/drug effects; Myocytes, Cardiac/metabolism; Oxidative Stress/drug effects; Pressure; Protein Binding; RNA Interference; RNA, Small Interfering/metabolism; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:HXK2		GO:2000378: negative regulation of reactive oxygen species metabolic process	ECO:0000315:		P		Figure 4	complete CACAO 6674
MOUSE:HXK2		GO:0035795: negative regulation of mitochondrial membrane permeability	ECO:0000315:		P		Fig 7	complete CACAO 6675
MOUSE:HXK2	involved_in	GO:2000378: negative regulation of reactive oxygen species metabolic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:HXK2	involved_in	GO:0035795: negative regulation of mitochondrial membrane permeability	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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