title: Lysine deacetylation in ischaemic preconditioning: the role of SIRT1.
abstract: OBJECTIVE
  Acute ischaemic preconditioning (IPC) induces protection against cardiac ischaemia-reperfusion (IR) via post-translational modification of key proteins. Lysine (Lys) acetylation is an important regulator of protein function, but this type of modification has not been studied in the context of IPC. We investigated Lys acetylation in IPC and its upstream regulation by SIRT1.
  
  
  RESULTS
  Hearts from C57BL/6 mice were Langendorff-perfused and subjected to IPC and IR injury. Mice were exposed to IPC by in vivo coronary artery occlusion. An isolated cardiomyocyte model of IPC was also developed. Lys acetylation was measured by western blotting, and pharmacological modulators of Lys acetylation were tested. More Lys deacetylation was observed in IPC, in the Langendorff, in vivo, and cellular IPC models; this was concurrent with an increase in SIRT1 activity measured by p53 Lys₃₇₉ deacetylation. IPC was not accompanied by changes in SIRT1 protein level, but evidence was obtained for SIRT1 modification by Small Ubiquitin-like Modifier (SUMOylation) in IPC. Furthermore, the specific SIRT1 inhibitor splitomicin reversed both IPC-mediated Lys deacetylation and IPC-induced cardioprotection. Inhibition of nicotinamide phosphoribosyltransferase (Nampt, an important enzyme which regulates SIRT1 activity by maintaining availability of the substrate NAD(+)) also blocked both IPC-induced deacetylation and cardioprotection.
  
  
  CONCLUSIONS
  Lys deacetylation occurs during IPC and an elevation in SIRT1 activity plays a role in this phenomenon. Inhibition of SIRT1, either directly or by restricting the availability of its substrate NAD(+), inhibits IPC. Together these data suggest a role for SIRT1-mediated Lys deacetylation in the mechanism of acute IPC.
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 604, Rochester, NY 14642, USA. sergiy_nadtochiy@urmc.rochester.edu
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Nadtochiy
authors.forename: Emily
authors.initials: E
authors.lastname: Redman
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
mesh_terms: D000107:Acetylation; D000818:Animals; D004195:Disease Models, Animal; D019157:Ischemic Preconditioning, Myocardial; D008239:Lysine / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D009243:NAD; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D008239:Lysine
references.citation: Circ Res. 2005 Aug 19;97(4):329-36
references.pmid: 16037573
references.citation: Physiol Rev. 2008 Apr;88(2):581-609
references.pmid: 18391174
references.citation: Science. 2009 May 22;324(5930):1076-80
references.pmid: 19461003
references.citation: J Mol Cell Cardiol. 2009 Jun;46(6):960-8
references.pmid: 19339206
references.citation: Circ Res. 2009 Apr 10;104(7):879-86
references.pmid: 19265035
references.citation: Chem Biol Drug Des. 2009 Dec;74(6):619-24
references.pmid: 19843076
references.citation: Int J Biochem Cell Biol. 2009 Jan;41(1):185-98
references.pmid: 18804549
references.citation: Nature. 2007 Nov 29;450(7170):712-6
references.pmid: 18046409
references.citation: Am J Physiol. 1999 Sep;277(3):H874-84
references.pmid: 10484406
references.citation: J Biol Chem. 2010 Mar 12;285(11):8375-82
references.pmid: 20089851
references.citation: J Biol Chem. 2004 Jul 9;279(28):28873-9
references.pmid: 15126506
references.citation: Circulation. 1986 Nov;74(5):1124-36
references.pmid: 3769170
references.citation: Recent Pat Cardiovasc Drug Discov. 2007 Jun;2(2):133-8
references.pmid: 18221111
references.citation: Science. 2004 Mar 26;303(5666):2011-5
references.pmid: 14976264
references.citation: EMBO J. 2004 Jun 16;23(12):2369-80
references.pmid: 15152190
references.citation: Cardiovasc Res. 2007 Dec 1;76(3):473-81
references.pmid: 17884027
references.citation: Biochem J. 2003 Mar 15;370(Pt 3):737-49
references.pmid: 12429021
references.citation: J Biol Chem. 2004 Dec 3;279(49):50754-63
references.pmid: 15381699
references.citation: Free Radic Biol Med. 2009 Jun 15;46(12):1589-97
references.pmid: 19303434
references.citation: Biochim Biophys Acta. 2006 Feb;1762(2):223-31
references.pmid: 16278076
references.citation: J Neurochem. 2009 Apr;109(1):257-67
references.pmid: 19200349
references.citation: J Biol Chem. 2007 Nov 23;282(47):34356-64
references.pmid: 17901049
references.citation: J Biol Chem. 2010 Mar 12;285(11):8340-51
references.pmid: 20061378
references.citation: Nature. 2009 Jul 30;460(7255):587-91
references.pmid: 19641587
references.citation: Nature. 2009 Apr 23;458(7241):1056-60
references.pmid: 19262508
references.citation: Cell. 2001 Oct 19;107(2):149-59
references.pmid: 11672523
references.citation: Antioxid Redox Signal. 2006 Nov-Dec;8(11-12):2101-9
references.pmid: 17034353
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3374-9
references.pmid: 18296641
references.citation: Antioxid Redox Signal. 2010 Oct 1;13(7):1023-32
references.pmid: 20392170
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Feb;292(2):L567-76
references.pmid: 17041012
references.citation: Biochem J. 2006 May 1;395(3):611-8
references.pmid: 16436046
references.citation: Science. 2008 Sep 12;321(5895):1493-5
references.pmid: 18787169
references.citation: Am J Physiol Heart Circ Physiol. 2003 Sep;285(3):H1220-8
references.pmid: 12763745
references.citation: Cancer Res. 2003 Nov 1;63(21):7436-42
references.pmid: 14612543
references.citation: Cardiovasc Res. 2002 Apr;54(1):140-51
references.pmid: 12062370
references.citation: Pharmacol Res. 2010 Jul;62(1):35-41
references.pmid: 20026274
references.citation: Nat Cell Biol. 2007 Nov;9(11):1253-62
references.pmid: 17934453
references.citation: J Mol Cell Cardiol. 2009 Jun;46(6):804-10
references.pmid: 19285082
references.citation: Circ Res. 2007 Nov 26;101(11):1155-63
references.pmid: 17916778
references.citation: J Biol Chem. 2003 Dec 26;278(52):52773-82
references.pmid: 14534292
references.citation: Cardiovasc Res. 2004 Feb 15;61(3):610-9
references.pmid: 14962491
references.citation: PLoS One. 2008;3(12):e4020
references.pmid: 19107194
references.citation: Nat Protoc. 2006;1(4):1872-8
references.pmid: 17487171
references.citation: Mol Med. 2001 Jun;7(6):406-17
references.pmid: 11474134
references.citation: J Mol Cell Cardiol. 2000 Jun;32(6):961-71
references.pmid: 10888250
references.citation: Biochemistry. 2004 Aug 3;43(30):9877-87
references.pmid: 15274642
references.citation: J Mol Cell Cardiol. 2007 Apr;42(4):812-25
references.pmid: 17350035
references.citation: Mol Cell Biol. 2006 Jan;26(1):28-38
references.pmid: 16354677
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14447-52
references.pmid: 18794531
references.citation: Circ Res. 2009 Oct 23;105(9):830-41
references.pmid: 19850949
references.citation: FASEB J. 2010 Sep;24(9):3145-59
references.pmid: 20385619
references.citation: J Mol Cell Cardiol. 2009 Jun;46(6):858-66
references.pmid: 19118560
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15113-8
references.pmid: 11752457
references.citation: Circ Res. 2009 Aug 28;105(5):481-91
references.pmid: 19661458
references.citation: J Mol Cell Cardiol. 2004 Dec;37(6):1195-203
references.pmid: 15572049
references.citation: Science. 2009 Jun 5;324(5932):1289-93
references.pmid: 19498162
references.citation: Circ Res. 2007 May 25;100(10):1512-21
references.pmid: 17446436
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14855-60
references.pmid: 17785417
references.citation: EMBO J. 2005 Mar 9;24(5):1021-32
references.pmid: 15692560
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10764-9
references.pmid: 19528654
references.citation: Mol Cell Biol. 2009 Aug;29(15):4116-29
references.pmid: 19470756
references.citation: J Biol Chem. 2005 Dec 30;280(52):43121-30
references.pmid: 16207712
references.citation: Am J Respir Crit Care Med. 2008 Apr 15;177(8):861-70
references.pmid: 18174544
references.citation: Can J Physiol Pharmacol. 2009 Apr;87(4):275-86
references.pmid: 19370081
references.citation: Am J Physiol Heart Circ Physiol. 2005 Feb;288(2):H971-6
references.pmid: 15358610
references.citation: EMBO J. 2002 May 15;21(10):2383-96
references.pmid: 12006491