title: Improvement of mechanical heart function by trimetazidine in db/db mice.
abstract: OBJECTIVE
  To investigate the influence of trimetazidine, which is known to be an antioxidant and modulator of metabolism, on cardiac function and the development of diabetic cardiomyopathy in db/db mouse.
  
  
  METHODS
  Trimetazidine was administered to db/db mice for eight weeks. Cardiac function was measured by inserting a Millar catheter into the left ventricle, and oxidative stress and AMP-activated protein kinase (AMPK) activity in the myocardium were evaluated.
  
  
  RESULTS
  Untreated db/db mice exhibited a significant decrease in cardiac function compared to normal C57 mice. Oxidative stress and lipid deposition were markedly increased in the myocardium, concomitant with inactivation of AMPK and increased expression of peroxisome proliferator-activated receptor coactivator-1 alpha (PGC-1 alpha). Trimetazidine significantly improved systolic and diastolic function in hearts of db/db mice and led to reduced production of reactive oxygen species and deposition of fatty acid in cardiomyocytes. Trimetazidine also caused AMPK activation and reduced PGC-1 alpha expression in the hearts of db/db mice.
  
  
  CONCLUSIONS
  The data suggest that trimetazidine significantly improves cardiac function in db/db mice by attenuating lipotoxicity and improving the oxidation status of the heart. Activation of AMPK and decreased expression of PGC-1 alpha were involved in this process. Furthermore, our study suggests that trimetazidine suppresses the development of diabetic cardiomyopathy, which warrants further clinical investigation.
authors.affiliation: Department of Internal Medicine and the Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Yuan-jing
authors.initials: YJ
authors.lastname: Li
authors.forename: Pei-hua
authors.initials: PH
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Ming-hui
authors.initials: MH
authors.lastname: Zou
authors.forename: Dao-wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D048909:Diabetes Complications / Q000188:drug therapy*; D003920:Diabetes Mellitus / Q000378:metabolism*; D005223:Fats / Q000032:analysis / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood; D014292:Trimetazidine / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D005223:Fats; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; D055372:AMP-Activated Protein Kinases; D014292:Trimetazidine
references.citation: Am Heart J. 2003 Nov;146(5):E18
references.pmid: 14597947
references.citation: J Clin Invest. 2006 Mar;116(3):615-22
references.pmid: 16511594
references.citation: Heart Fail Rev. 2002 Apr;7(2):115-30
references.pmid: 11988636
references.citation: J Mol Cell Cardiol. 2007 Feb;42(2):333-42
references.pmid: 17188707
references.citation: Diabetes. 1974 Feb;23(2):105-11
references.pmid: 4359625
references.citation: Am J Physiol. 1999 Aug;277(2):E342-51
references.pmid: 10444431
references.citation: Circulation. 2003 Aug 12;108(6):754-9
references.pmid: 12885755
references.citation: J Clin Invest. 2002 Jan;109(1):121-30
references.pmid: 11781357
references.citation: Biochim Biophys Acta. 2005 May 15;1734(2):112-26
references.pmid: 15904868
references.citation: Circulation. 2002 Apr 9;105(14):1727-33
references.pmid: 11940554
references.citation: Circulation. 2007 Feb 20;115(7):909-17
references.pmid: 17261654
references.citation: Heart Vessels. 2009 Jul;24(4):277-82
references.pmid: 19626400
references.citation: Eur J Heart Fail. 2006 Dec;8(8):777-83
references.pmid: 16716661
references.citation: Biochem Biophys Res Commun. 2004 Jun 11;318(4):1066-71
references.pmid: 15147982
references.citation: Ann Intern Med. 2006 Apr 4;144(7):517-24
references.pmid: 16585666
references.citation: Eur J Biochem. 2004 Jun;271(11):2215-24
references.pmid: 15153111
references.citation: Clin Exp Pharmacol Physiol. 2005 Dec;32(12):1061-70
references.pmid: 16445572
references.citation: Cardiovasc Res. 1997 Apr;34(1):25-33
references.pmid: 9217869
references.citation: Circ J. 2006 Sep;70(9):1169-73
references.pmid: 16936431
references.citation: Am J Physiol. 1999 Jul;277(1):E1-10
references.pmid: 10409121
references.citation: Diabetes. 2004 Jun;53(6):1412-7
references.pmid: 15161742
references.citation: J Am Coll Cardiol. 2006 Oct 17;48(8):1688-97
references.pmid: 17045908
references.citation: Diabetes. 2002 Jan;51(1):174-81
references.pmid: 11756338
references.citation: Am J Physiol Endocrinol Metab. 2005 Aug;289(2):E328-36
references.pmid: 15797988
references.citation: J Cardiovasc Pharmacol. 2005 Jul;46(1):89-98
references.pmid: 15965360
references.citation: Circ Res. 2004 Sep 17;95(6):568-78
references.pmid: 15375023
references.citation: Rev Esp Cardiol. 2005 Aug;58(8):895-7
references.pmid: 16053822
references.citation: Cardiovasc Drugs Ther. 1990 Aug;4 Suppl 4:853-9
references.pmid: 2093381
references.citation: Am J Cardiol. 1972 Nov 8;30(6):595-602
references.pmid: 4263660
references.citation: Biochem Biophys Res Commun. 2009 Dec 18;390(3):388-93
references.pmid: 19747896
references.citation: Free Radic Biol Med. 2006 Sep 15;41(6):851-61
references.pmid: 16934665
references.citation: J Cardiovasc Pharmacol. 2004 Jul;44(1):101-8
references.pmid: 15175564
references.citation: Mol Cell Biochem. 2003 Nov;253(1-2):65-70
references.pmid: 14619957
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1784-9
references.pmid: 10677535
references.citation: Diabetes. 2006 Mar;55(3):798-805
references.pmid: 16505246
references.citation: Arch Med Res. 2006 Aug;37(6):700-8
references.pmid: 16824928
references.citation: Br J Clin Pharmacol. 1994 Mar;37(3):279-88
references.pmid: 8198938
references.citation: Diabetes. 2004 May;53(5):1336-43
references.pmid: 15111504
references.citation: FASEB J. 2004 Nov;18(14):1692-700
references.pmid: 15522914
references.citation: Biochem Soc Trans. 2002 Nov;30(Pt 6):1064-70
references.pmid: 12440973
references.citation: Diabetes. 2002 Jun;51(6):1938-48
references.pmid: 12031984
references.citation: Cardiovasc Diabetol. 2003 Nov 28;2:16
references.pmid: 14641923
references.citation: Circ Res. 2000 Mar 17;86(5):580-8
references.pmid: 10720420
references.citation: Mol Cell Biochem. 2006 Feb;283(1-2):147-52
references.pmid: 16444597
references.citation: Heart Fail Rev. 2002 Apr;7(2):149-59
references.pmid: 11988639
references.citation: Magn Reson Med. 2003 Mar;49(3):417-23
references.pmid: 12594743
references.citation: Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2237-45
references.pmid: 16844917
references.citation: J Biol Chem. 2002 Feb 8;277(6):4098-103
references.pmid: 11734553
references.citation: J Mol Cell Cardiol. 2003 Jun;35(6):615-21
references.pmid: 12788379
references.citation: Circ Res. 2007 Apr 27;100(8):1208-17
references.pmid: 17363697
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1226-31
references.pmid: 12552126
references.citation: Diabetes. 2006 Feb;55(2):466-73
references.pmid: 16443782
references.citation: Am J Physiol Endocrinol Metab. 2000 Nov;279(5):E1104-13
references.pmid: 11052966
references.citation: Endocrinology. 2005 Dec;146(12):5341-9
references.pmid: 16141388
references.citation: Am J Physiol Heart Circ Physiol. 2002 Sep;283(3):H976-82
references.pmid: 12181126