title: Cardiac-specific hexokinase 2 overexpression attenuates hypertrophy by increasing pentose phosphate pathway flux.
abstract: BACKGROUND
  The enzyme hexokinase-2 (HK2) phosphorylates glucose, which is the initiating step in virtually all glucose utilization pathways. Cardiac hypertrophy is associated with a switch towards increased glucose metabolism and decreased fatty acid metabolism. Recent evidence suggests that the increased glucose utilization is compensatory to the down-regulated fatty acid metabolism during hypertrophy and is, in fact, beneficial. Therefore, we hypothesized that increasing glucose utilization by HK2 overexpression would decrease cardiac hypertrophy.
  
  
  RESULTS
  Mice with cardiac-specific HK2 overexpression displayed decreased hypertrophy in response to isoproterenol. Neonatal rat ventricular myocytes (NRVMs) infected with an HK2 adenovirus similarly displayed decreased hypertrophy in response to phenylephrine. Hypertrophy increased reactive oxygen species (ROS) levels, which were attenuated by HK2 overexpression, thereby decreasing NRVM hypertrophy and death. HK2 appears to modulate ROS via the pentose phosphate pathway, as inhibition of glucose-6-phosphate dehydrogenase with dehydroepiandrosterone decreased the ability of HK2 to diminish ROS and hypertrophy.
  
  
  CONCLUSIONS
  These results suggest that HK2 attenuates cardiac hypertrophy by decreasing ROS accumulation via increased pentose phosphate pathway flux.
authors.affiliation: Department of Biomedical Sciences, University of Missouri, Columbia, MO.
authors.forename: Kyle S
authors.initials: KS
authors.lastname: McCommis
authors.forename: Diana L
authors.initials: DL
authors.lastname: Douglas
authors.forename: Maike
authors.initials: M
authors.lastname: Krenz
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Baines
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D016923:Cell Death; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism*; D007545:Isoproterenol; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D000316:Adrenergic alpha-Agonists; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D010656:Phenylephrine; D003687:Dehydroepiandrosterone; D005954:Glucosephosphate Dehydrogenase; D006593:Hexokinase; D007545:Isoproterenol
keywords: glucose; hexokinase; hypertrophy; oxidative stress