title: Hexokinase II knockdown results in exaggerated cardiac hypertrophy via increased ROS production.
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.
authors.affiliation: Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, IL, USA.
authors.forename: Rongxue
authors.initials: R
authors.lastname: Wu
authors.forename: Eugene
authors.initials: E
authors.lastname: Wyatt
authors.forename: Kusum
authors.initials: K
authors.lastname: Chawla
authors.forename: Minh
authors.initials: M
authors.lastname: Tran
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ghanefar
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Conrad L
authors.initials: CL
authors.lastname: Epting
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardehali
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D005355:Fibrosis; D006579:Heterozygote; D006593:Hexokinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011312:Pressure; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D006593:Hexokinase; D000111:Acetylcysteine