title: Hexokinase cellular trafficking in ischemia-reperfusion and ischemic preconditioning is altered in type I diabetic heart.
abstract: Diabetes mellitus (DM) has been reported to alter the cardiac response to ischemia-reperfusion (IR). In addition, cardioprotection induced by ischemic preconditioning (IPC) is often impaired in diabetes. We have previously shown that the subcellular localisation of the glycolytic enzyme hexokinase (HK) is causally related to IR injury and IPC protective potential. Especially the binding of HK to mitochondria and prevention of HK solubilisation (HK detachment from mitochondria) during ischemia confers cardioprotection. It is unknown whether diabetes affects HK localisation during IR and IPC as compared to non-diabetes. In this study we hypothesize that DM alters cellular trafficking of hexokinase in response to IR and IPC, possibly explaining the altered response to IR and IPC in diabetic heart. Control (CON) and type I diabetic (DM) rat hearts (65 mg/kg streptozotocin, 4 weeks) were isolated and perfused in Langendorff-mode and subjected to 35 min I and 30 min R with or without IPC (3 times 5 min I). Cytosolic and mitochondrial fractions were obtained at (1) baseline, i.e. after IPC but before I, (2) 35 min I, (3) 5 min R and (4) 30 min R. DM improved rate-pressure product recovery (RPP; 71 ± 10 % baseline (DM) versus 9 ± 1 % baseline (CON) and decreased contracture (end-diastolic pressure: 24 ± 8 mmHg (DM) vs 77 ± 4 mmHg (CON)) after IR as compared to control, and was associated with prevention of HK solubilisation at 35 min I. IPC improved cardiac function in CON but not in DM hearts. IPC in CON prevented HK solubilisation at 35 min I and at 5 min R, with a trend for increased mitochondrial HK. In contrast, the non-effective IPC in DM was associated with solubilisation of HK and decreased mitochondrial HK at early reperfusion and a reciprocal behaviour at late reperfusion. We conclude that type I DM significantly altered cellular HK translocation patterns in the heart in response to IR and IPC, possibly explaining altered response to IR and IPC in diabetes.
authors: Department of Biology, Faculty of Science, İstanbul University, Istanbul, Turkey.
authors: Ebru
authors: E
authors: Gurel
authors: Savas
authors: S
authors: Ustunova
authors: Aysegul
authors: A
authors: Kapucu
authors: Nadim
authors: N
authors: Yilmazer
authors: Otto
authors: O
authors: Eerbeek
authors: Rianne
authors: R
authors: Nederlof
authors: Markus W
authors: MW
authors: Hollmann
authors: Cihan
authors: C
authors: Demirci-Tansel
authors: Coert J
authors: CJ
authors: Zuurbier
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006593:Hexokinase / Q000378:metabolism*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D051381:Rats; D015427:Reperfusion Injury / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism*; D013997:Time Factors
chemical_list: D006593:Hexokinase
references: Exp Mol Pathol. 2004 Feb;76(1):57-65
references: 14738870
references: Am J Physiol Heart Circ Physiol. 2005 Jul;289(1):H496-9
references: 15764678
references: Lab Anim. 2011 Jul;45(3):160-6
references: 21504994
references: Cell Signal. 2012 Jan;24(1):53-9
references: 21945408
references: J Clin Invest. 1985 Nov;76(5):1713-9
references: 4056048
references: J Appl Physiol (1985). 2012 Aug 15;113(4):608-18
references: 22723631
references: J Mol Cell Cardiol. 2009 Jun;46(6):821-31
references: 19265700
references: Circ Res. 2011 May 13;108(10):1165-9
references: 21527739
references: Basic Res Cardiol. 2011 Jan;106(1):147-62
references: 20981553
references: Cardiovasc Toxicol. 2005;5(3):293-300
references: 16244374
references: J Mol Cell Cardiol. 2007 Feb;42(2):333-42
references: 17188707
references: N Engl J Med. 2007 Sep 13;357(11):1121-35
references: 17855673
references: J Bioenerg Biomembr. 2009 Apr;41(2):181-5
references: 19347573
references: J Biol Chem. 2004 Sep 17;279(38):39846-55
references: 15247300
references: Circulation. 1986 Nov;74(5):1124-36
references: 3769170
references: Anesthesiology. 2011 Jun;114(6):1364-72
references: 21368653
references: Cardiovasc Diabetol. 2012 Jun 13;11:67
references: 22694800
references: IUBMB Life. 2012 Sep;64(9):766-74
references: 22730258
references: Circ Res. 2011 Jan 7;108(1):60-9
references: 21071708
references: Am J Pathol. 2010 Jul;177(1):97-105
references: 20566749
references: Circ Res. 2010 Jan 8;106(1):129-32
references: 19910577
references: Am J Physiol Heart Circ Physiol. 2000 Apr;278(4):H1218-24
references: 10749717
references: Biochem J. 2011 Jun 1;436(2):493-505
references: 21410437
references: J Biol Chem. 1970 Aug 25;245(16):4081-96
references: 4099995
references: Basic Res Cardiol. 2008 May;103(3):274-84
references: 18080084
references: Physiol Rev. 2008 Apr;88(2):581-609
references: 18391174
references: Cancer Res. 2005 Nov 15;65(22):10545-54
references: 16288047
references: Mol Biol Rep. 2011 Oct;38(7):4327-35
references: 21113666
references: Mol Cell Biol. 2004 Jan;24(2):730-40
references: 14701745
references: J Mol Cell Cardiol. 2009 Jul;47(1):32-40
references: 19344728
references: Diabetes. 2009 Dec;58(12):2863-72
references: 19755525
references: J Appl Physiol (1985). 2009 Jun;106(6):1909-16
references: 19228992
references: Cardiovasc Res. 1996 Apr;31(4):526-36
references: 8689644
references: Diabetes. 2008 Mar;57(3):696-705
references: 18083782
references: Cell Death Differ. 2008 Mar;15(3):521-9
references: 18064042
references: Am J Physiol. 1973 Jan;224(1):7-12
references: 4264877
references: J Clin Invest. 2004 Jun;113(11):1535-49
references: 15173880
references: Diabetes. 2007 Jan;56(1):127-36
references: 17192474