title: Abnormal mitochondrial L-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury.
abstract: BACKGROUND
  Impaired mitochondrial function is fundamental feature of heart failure (HF) and myocardial ischemia. In addition to the effects of heightened oxidative stress, altered nitric oxide (NO) metabolism, generated by a mitochondrial NO synthase, has also been proposed to impact upon mitochondrial function. However, the mechanism responsible for arginine transport into mitochondria and the effect of HF on such a process is unknown. We therefore aimed to characterize mitochondrial L-arginine transport and to investigate the hypothesis that impaired mitochondrial L-arginine transport plays a key role in the pathogenesis of heart failure and myocardial injury.
  
  
  RESULTS
  In mitochondria isolated from failing hearts (sheep rapid pacing model and mouse Mst1 transgenic model) we demonstrated a marked reduction in L-arginine uptake (p<0.05 and p<0.01 respectively) and expression of the principal L-arginine transporter, CAT-1 (p<0.001, p<0.01) compared to controls. This was accompanied by significantly lower NO production and higher 3-nitrotyrosine levels (both p<0.05). The role of mitochondrial L-arginine transport in modulating cardiac stress responses was examined in cardiomyocytes with mitochondrial specific overexpression of CAT-1 (mtCAT1) exposed to hypoxia-reoxygenation stress. mtCAT1 cardiomyocytes had significantly improved mitochondrial membrane potential, respiration and ATP turnover together with significantly decreased reactive oxygen species production and cell death following mitochondrial stress.
  
  
  CONCLUSIONS
  These data provide new insights into the role of L-arginine transport in mitochondrial biology and cardiovascular disease. Augmentation of mitochondrial L-arginine availability may be a novel therapeutic strategy for myocardial disorders involving mitochondrial stress such as heart failure and reperfusion injury.
authors.affiliation: Heart Failure Research Group, Baker IDI Heart & Diabetes Institute, Melbourne, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.affiliation: Heart Failure Research Group, Baker IDI Heart & Diabetes Institute, Melbourne, Australia; Department of Medicine, Monash University, Melbourne, Australia.
authors.forename: Kylie M
authors.initials: KM
authors.lastname: Venardos
authors.affiliation: Heart Failure Research Group, Baker IDI Heart & Diabetes Institute, Melbourne, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Byrne
authors.affiliation: Heart Failure Research Group, Baker IDI Heart & Diabetes Institute, Melbourne, Australia.
authors.forename: Mandar
authors.initials: M
authors.lastname: Joshi
authors.affiliation: Heart Failure Research Group, Baker IDI Heart & Diabetes Institute, Melbourne, Australia.
authors.forename: Duncan
authors.initials: D
authors.lastname: Horlock
authors.affiliation: Heart Failure Research Group, Baker IDI Heart & Diabetes Institute, Melbourne, Australia.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Lam
authors.affiliation: Muscle Research & Therapeutics Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.affiliation: Metabolic Research Unit, Deakin University, Geelong, Australia.
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
authors.affiliation: Heart Failure Research Group, Baker IDI Heart & Diabetes Institute, Melbourne, Australia; Department of Medicine, Monash University, Melbourne, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001692:Biological Transport; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D006335:Heart Injuries / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D012756:Sheep; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D050916:TRPV Cation Channels; C120776:TRPV6 channel; D009569:Nitric Oxide; D001120:Arginine; D010100:Oxygen
references.citation: J Clin Invest. 2003 May;111(10):1463-74
references.pmid: 12750396
references.citation: J Hypertens. 2004 Oct;22(10):1917-25
references.pmid: 15361763
references.citation: J Clin Invest. 2005 Mar;115(3):547-55
references.pmid: 15765136
references.citation: Am J Physiol Heart Circ Physiol. 2012 Dec 1;303(11):H1283-93
references.pmid: 23023869
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):14126-31
references.pmid: 11717466
references.citation: Nat Protoc. 2007;2(2):287-95
references.pmid: 17406588
references.citation: Basic Res Cardiol. 2004 May;99(3):159-64
references.pmid: 15088100
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 Jun;284(6):L1037-44
references.pmid: 12562561
references.citation: Science. 2005 Oct 14;310(5746):314-7
references.pmid: 16224023
references.citation: Curr Med Chem. 2007;14(14):1539-49
references.pmid: 17584062
references.citation: J Nutr. 2004 Oct;134(10 Suppl):2752S-2759S; discussion 2765S-2767S
references.pmid: 15465780
references.citation: Neurosci Lett. 2005 Aug 26;384(3):254-9
references.pmid: 15923083
references.citation: Aging (Albany NY). 2011 May;3(5):464-78
references.pmid: 21566257
references.citation: J Clin Invest. 2005 May;115(5):1232-40
references.pmid: 15841216
references.citation: Circulation. 2004 Dec 14;110(24):3680-6
references.pmid: 15569830
references.citation: Free Radic Biol Med. 2001 Dec 15;31(12):1609-15
references.pmid: 11744335
references.citation: Circulation. 2007 Mar 13;115(10):1269-74
references.pmid: 17325243
references.citation: Biochim Biophys Acta. 2006 May-Jun;1757(5-6):562-6
references.pmid: 16584707
references.citation: Cardiovasc Res. 2006 Jul 1;71(1):10-21
references.pmid: 16515774
references.citation: Circ Res. 2000 Feb 4;86(2):119-20
references.pmid: 10666404
references.citation: Anesth Analg. 2008 Apr;106(4):1049-55, table of contents
references.pmid: 18349172
references.citation: Circ Res. 2002 Dec 13;91(12):1198-203
references.pmid: 12480822
references.citation: Am J Physiol Cell Physiol. 2005 Oct;289(4):C836-45
references.pmid: 15901603
references.citation: Nat Med. 2013 Jun;19(6):753-9
references.pmid: 23708290
references.citation: Eur J Biochem. 1998 Dec 1;258(2):702-9
references.pmid: 9874237
references.citation: Am J Physiol. 1997 Feb;272(2 Pt 2):H769-75
references.pmid: 9124437
references.citation: J Cell Biochem. 2009 Sep 1;108(1):156-68
references.pmid: 19544385
references.citation: Circulation. 2000 Nov 28;102(22):2707-12
references.pmid: 11094036
references.citation: Biochemistry. 1991 May 7;30(18):4480-6
references.pmid: 2021638
references.citation: Free Radic Biol Med. 2013 Jan;54:105-12
references.pmid: 22989471
references.citation: Pharmacol Ther. 2005 May;106(2):147-62
references.pmid: 15866317
references.citation: Circ Res. 1999 Aug 20;85(4):357-63
references.pmid: 10455064
references.citation: Biochemistry. 2005 Sep 13;44(36):11986-96
references.pmid: 16142896
references.citation: J Cardiovasc Pharmacol. 2000 Jan;35(1):84-92
references.pmid: 10630737
references.citation: Front Biosci (Landmark Ed). 2009 Jan 01;14:4436-43
references.pmid: 19273361
references.citation: Biochim Biophys Acta. 2006 Mar;1757(3):166-72
references.pmid: 16624252
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4759-64
references.pmid: 16537391
references.citation: J Mol Cell Cardiol. 2009 Jan;46(1):86-92
references.pmid: 18977358
references.citation: N Engl J Med. 2007 Sep 13;357(11):1121-35
references.pmid: 17855673
references.citation: Trends Pharmacol Sci. 2005 Apr;26(4):190-5
references.pmid: 15808343
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10764-9
references.pmid: 19528654
references.citation: J Exp Med. 2007 Sep 3;204(9):2089-102
references.pmid: 17682069
references.citation: Cardiovasc Res. 2007 Jul 15;75(2):283-90
references.pmid: 17466959
references.citation: J Card Fail. 2008 May;14(4):320-6
references.pmid: 18474345
references.citation: J Biol Chem. 2002 Oct 11;277(41):38079-86
references.pmid: 12154090
references.citation: Am J Cardiol. 2008 Jun 2;101(11A):22E-25E
references.pmid: 18514622
references.citation: Biochim Biophys Acta. 2006 May-Jun;1757(5-6):535-42
references.pmid: 16615992