title: Protection of the heart by treatment with a divalent-copper-selective chelator reveals a novel mechanism underlying cardiomyopathy in diabetic rats.
abstract: BACKGROUND
  Intracellular calcium (Ca²⁺) coordinates the cardiac contraction cycle and is dysregulated in diabetic cardiomyopathy. Treatment with triethylenetetramine (TETA), a divalent-copper-selective chelator, improves cardiac structure and function in patients and rats with diabetic cardiomyopathy, but the molecular basis of this action is uncertain. Here, we used TETA to probe potential linkages between left-ventricular (LV) copper and Ca²⁺ homeostasis, and cardiac function and structure in diabetic cardiomyopathy.
  
  
  METHODS
  We treated streptozotocin-diabetic rats with a TETA-dosage known to ameliorate LV hypertrophy in patients with diabetic cardiomyopathy. Drug treatment was begun either one (preventative protocol) or eight (restorative protocol) weeks after diabetes induction and continued thereafter for seven or eight weeks, respectively. Total copper content of the LV wall was determined, and simultaneous measurements of intracellular calcium concentrations and isometric contraction were made in LV trabeculae isolated from control, diabetic and TETA-treated diabetic rats.
  
  
  RESULTS
  Total myocardial copper levels became deficient in untreated diabetes but were normalized by TETA-treatment. Cardiac contractility was markedly depressed by diabetes but TETA prevented this effect. Neither diabetes nor TETA exerted significant effects on peak or resting [Ca²⁺](i). However, diabetic rats showed extensive cardiac remodelling and decreased myofibrillar calcium sensitivity, consistent with observed increases in phosphorylation of troponin I, whereas these changes were all prevented by TETA.
  
  
  CONCLUSIONS
  Diabetes causes cardiomyopathy through a copper-mediated mechanism that incorporates myocardial copper deficiency, whereas TETA treatment prevents this response and maintains the integrity of cardiac structure and myofibrillar calcium sensitivity. Altered calcium homeostasis may not be the primary defect in diabetic cardiomyopathy. Rather, a newly-described copper-mediated mechanism may cause this disease.
authors: School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. g.cooper@auckland.ac.nz.
authors: Lin
authors: L
authors: Zhang
authors: Marie-Louise
authors: ML
authors: Ward
authors: Anthony R J
authors: AR
authors: Phillips
authors: Shaoping
authors: S
authors: Zhang
authors: John
authors: J
authors: Kennedy
authors: Bernard
authors: B
authors: Barry
authors: Mark B
authors: MB
authors: Cannell
authors: Garth J S
authors: GJ
authors: Cooper
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002614:Chelating Agents / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006339:Heart Rate / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014266:Trientine / Q000494:pharmacology*; D019210:Troponin I / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D002614:Chelating Agents; D019210:Troponin I; D003300:Copper; D014266:Trientine; D002118:Calcium
references: Am J Clin Nutr. 1998 May;67(5 Suppl):1069S-1073S
references: 9587154
references: Diabetes. 2008 Aug;57(8):2158-66
references: 18492789
references: Circulation. 2007 Jun 26;115(25):3213-23
references: 17592090
references: PLoS Biol. 2010 Jun 29;8(6):e1000412
references: 20613859
references: J Physiol. 1990 Apr;423:221-40
references: 1696985
references: J Exp Med. 2007 Mar 19;204(3):657-66
references: 17339407
references: Diabetes Res Clin Pract. 2010 Jan;87(1):4-14
references: 19896746
references: Nature. 2002 Jan 10;415(6868):198-205
references: 11805843
references: J Physiol. 1992 Feb;447:83-102
references: 1593465
references: J Nutr. 2005 Sep;135(9):2130-6
references: 16140888
references: Hypertension. 2001 Apr;37(4):1053-9
references: 11304502
references: Anesthesiology. 2006 May;104(5):978-87
references: 16645450
references: J Endocrinol Invest. 2004 Feb;27(2):175-81
references: 15129815
references: Diabetologia. 2009 Apr;52(4):715-22
references: 19172243
references: Diabetes. 2005 Nov;54(11):3082-8
references: 16249429
references: Diabetologia. 2008 Sep;51(9):1741-51
references: 18636238
references: Diabetes. 2003 Jul;52(7):1825-36
references: 12829653
references: QJM. 1995 Sep;88(9):609-16
references: 7583074
references: Am J Clin Nutr. 1998 May;67(5 Suppl):1091S-1097S
references: 9587158
references: Mol Cell Biochem. 2004 Jun;261(1-2):227-33
references: 15362508
references: Diabetologia. 2010 Jun;53(6):1217-26
references: 20221822
references: Cardiovasc Diabetol. 2012 Oct 15;11:129
references: 23066908
references: J Nutr Biochem. 2004 Jun;15(6):316-22
references: 15157936
references: Kidney Int. 1992 Mar;41(3):557-9
references: 1573828
references: Am J Physiol. 1987 Sep;253(3 Pt 1):C364-8
references: 2443015
references: Circ Res. 1997 Dec;81(6):1027-33
references: 9400384
references: Cardiovasc Diabetol. 2013 Jan 31;12:28
references: 23368770
references: Cardiovasc Diabetol. 2012 Jun 19;11:73
references: 22713251
references: Am J Cardiol. 1972 Nov 8;30(6):595-602
references: 4263660
references: Curr Med Chem. 2012;19(17):2828-60
references: 22455587
references: Lancet. 2002 Apr 20;359(9315):1430-2
references: 11978359
references: Diabetes. 2005 May;54(5):1468-76
references: 15855335
references: Basic Res Cardiol. 1989 Nov-Dec;84(6):591-6
references: 2619697
references: J Nutr. 1981 Nov;111(11):1900-9
references: 7028924
references: J Toxicol Environ Health. 1981 Jan;7(1):139-47
references: 6455537
references: Exp Biol Med (Maywood). 2003 Jul;228(7):811-7
references: 12876300
references: J Biol Chem. 1996 Sep 20;271(38):23277-83
references: 8798526
references: Physiol Genomics. 2007 Feb 12;28(3):284-93
references: 17062650
references: Am J Physiol Heart Circ Physiol. 2002 Oct;283(4):H1398-408
references: 12234790
references: Cardiovasc Diabetol. 2003 Jan 08;2:1
references: 12556246
references: Biochem J. 1984 Apr 1;219(1):1-14
references: 6326753
references: Cell Metab. 2010 May 5;11(5):353-63
references: 20444417
references: Am J Physiol. 1996 May;270(5 Pt 2):H1529-37
references: 8928857
references: Pflugers Arch. 2002 Jun;444(3):446-51
references: 12111255
references: Circulation. 2000 Apr 11;101(14):1679-85
references: 10758050
references: Am J Physiol Endocrinol Metab. 2002 Oct;283(4):E658-66
references: 12217882
references: Physiol Rev. 2007 Jul;87(3):1011-46
references: 17615395
references: J Clin Pharmacol. 2009 Aug;49(8):916-28
references: 19602718
references: Prog Biophys Mol Biol. 2010 Sep;103(1):28-34
references: 20553743
references: J Physiol. 2003 Jan 15;546(Pt 2):537-50
references: 12527740
references: Acta Neurol Scand. 1991 Jun;83(6):364-6
references: 1887758
references: Basic Res Cardiol. 1990 Jul-Aug;85(4):358-66
references: 2146947
references: Toxicol Appl Pharmacol. 1981 Apr;58(2):211-20
references: 7245197
references: Diabetes. 2004 Sep;53(9):2501-8
references: 15331567
references: Arch Biochem Biophys. 2005 Mar 1;435(1):166-74
references: 15680918
references: Peptides. 2005 Apr;26(4):691-700
references: 15752585
references: Dalton Trans. 2013 May 7;42(17):6161-70
references: 23202417
references: Proteomics Clin Appl. 2007 Jun;1(6):565-76
references: 21136708
references: Mol Cell Biochem. 1995 Oct 18;151(2):165-72
references: 8569762
references: Drugs. 2011 Jul 9;71(10):1281-320
references: 21770477
references: Ann N Y Acad Sci. 2006 Nov;1084:178-90
references: 17151301
references: J Nutr Biochem. 2005 May;16(5):312-20
references: 15866232
references: J Nutr. 1982 Nov;112(11):2142-50
references: 6215471
references: Mol Pharmacol. 2006 Dec;70(6):2045-51
references: 16973718
references: Cardiovasc Res. 1997 Apr;34(1):41-7
references: 9217871
references: Mol Cell Biochem. 2006 Sep;289(1-2):21-9
references: 16583133
references: Biochim Biophys Acta. 1996 Jun 7;1316(2):78-84
references: 8672554
references: Cardiovasc Res. 2000 Jun;46(3):450-62
references: 10912456
references: J Nutr. 2004 Apr;134(4):855-60
references: 15051837
references: Cardiovasc Diabetol. 2012 Nov 02;11:135
references: 23116444
references: J Hypertens. 1998 Dec;16(12 Pt 2):1921-9
references: 9886878
references: Circ Res. 1994 Mar;74(3):408-15
references: 8118949
references: J Physiol. 1985 Mar;360:1-12
references: 3921690
references: Biol Trace Elem Res. 1996 Oct-Nov;55(1-2):55-70
references: 8971354
references: Circ Res. 1995 Apr;76(4):600-6
references: 7534660
references: Am J Physiol. 1983 Nov;245(5 Pt 1):H855-66
references: 6638205
references: Cardiovasc Res. 1997 Apr;34(1):91-8
references: 9217877
references: Free Radic Biol Med. 1991;10(5):339-52
references: 1855674
references: Jpn Circ J. 1993 May;57(5):449-57
references: 8510315