title: Targeted deletion of NF-kappaB p50 diminishes the cardioprotection of histone deacetylase inhibition.
abstract: We have recently demonstrated that the inhibition of histone deacetylases (HDAC) protects the heart against ischemia-reperfusion (I/R) injury. The mechanism by which HDAC inhibition confers myocardial protection remains unknown. The purpose of this study is to investigate whether the disruption of NF-kappaB p50 would eliminate the protective effects of HDAC inhibition. Wild-type and NF-kappaB p50-deficient mice were treated with trichostatin A (TSA; 0.1 mg/kg ip), a potent inhibitor of HDACs. Twenty-four hours later, the hearts were perfused in Langendorff model and subjected to 30 min of ischemia and 30 min of reperfusion. Inhibition of HDACs by TSA in wild-type mice produced marked improvements in left ventricular end-diastolic pressure, left ventricular rate pressure product, and the reduction of infarct size compared with non-TSA-treated group. TSA-induced cardioprotection in wild-type animals was absent with genetic deletion of NF-kappaB p50 subunit. Notably, Western blot displayed a significant increase in nuclear NF-kappaB p50 and the immunoprecipitation demonstrated a remarkable acetylation of NF-kappaB p50 at lysine residues following HDAC inhibition. EMSA exhibited a subsequent increase in NF-kappaB DNA binding activity. Luciferase assay demonstrated an activation of NF-kappaB by HDAC inhibition. The pretreatment of H9c2 cardiomyoblasts with TSA (50 nmol/l) decreased cell necrosis and increased in cell viability in simulated ischemia. The resistance of H9c2 cardiomyoblasts to simulated ischemia by HDAC inhibition was eliminated by genetic knockdown of NF-kappaB p50 with transfection of NF-kappaB p50 short interfering RNA but not scrambled short interfering RNA. These results suggest that NF-kappaB p50 acetylation and activation play a pivotal role in HDAC inhibition-induced cardioprotection.
authors.affiliation: Department of Medicine, Brown Medical School, Brown University, Providence, Rhode Island, USA.
authors.forename: L X
authors.initials: LX
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: G
authors.initials: G
authors.lastname: Cheng
authors.forename: T L
authors.initials: TL
authors.lastname: Guo
authors.forename: Y E
authors.initials: YE
authors.lastname: Chin
authors.forename: P Y
authors.initials: PY
authors.lastname: Liu
authors.forename: T C
authors.initials: TC
authors.lastname: Zhao
mesh_terms: D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects* / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052002:NF-kappa B p50 Subunit / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D009336:Necrosis / Q000517:prevention & control; D034741:RNA, Small Interfering / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D052002:NF-kappa B p50 Subunit; D034741:RNA, Small Interfering; C012589:trichostatin A; D004247:DNA; D006655:Histone Deacetylases
references.citation: Basic Res Cardiol. 2004 Sep;99(5):338-50
references.pmid: 15309413
references.citation: FASEB J. 2008 Oct;22(10):3549-60
references.pmid: 18606865
references.citation: Nat Med. 2005 Jan;11(1):71-6
references.pmid: 15619634
references.citation: Am J Physiol. 1999 Feb;276(2):H543-52
references.pmid: 9950856
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4868-73
references.pmid: 10220385
references.citation: Drug Metab Dispos. 2004 Oct;32(10):1132-8
references.pmid: 15269190
references.citation: J Immunol. 2003 Dec 15;171(12):6581-8
references.pmid: 14662860
references.citation: Circulation. 2006 Jun 6;113(22):2579-88
references.pmid: 16735673
references.citation: Nature. 2000 Jan 6;403(6765):41-5
references.pmid: 10638745
references.citation: J Neurochem. 2004 Jun;89(6):1358-67
references.pmid: 15189338
references.citation: J Biol Chem. 2003 Aug 1;278(31):28930-7
references.pmid: 12761226
references.citation: Circulation. 1986 Nov;74(5):1124-36
references.pmid: 3769170
references.citation: Annu Rev Cell Biol. 1994;10:405-55
references.pmid: 7888182
references.citation: J Biol Chem. 1999 Apr 23;274(17):11713-20
references.pmid: 10206986
references.citation: Cardiovasc Res. 2002 Aug 15;55(3):520-5
references.pmid: 12160948
references.citation: FEBS Lett. 1998 Jun 16;429(3):365-9
references.pmid: 9662450
references.citation: Trends Genet. 2003 May;19(5):286-93
references.pmid: 12711221
references.citation: Cardiovasc Res. 2007 Dec 1;76(3):473-81
references.pmid: 17884027
references.citation: J Biol Chem. 2002 Jul 19;277(29):26217-24
references.pmid: 12011070
references.citation: Am J Physiol Heart Circ Physiol. 2007 Aug;293(2):H968-77
references.pmid: 17400721
references.citation: Circ Res. 1999 May 14;84(9):1095-109
references.pmid: 10325247
references.citation: Cell. 2000 Oct 13;103(2):263-71
references.pmid: 11057899
references.citation: J Mol Cell Cardiol. 2002 Mar;34(3):263-77
references.pmid: 11945020
references.citation: Biochemistry. 1998 Dec 22;37(51):17637-41
references.pmid: 9922128
references.citation: Circ Res. 2009 Mar 13;104(5):699-706
references.pmid: 19168865
references.citation: Nature. 1999 Sep 9;401(6749):188-93
references.pmid: 10490031
references.citation: Circulation. 2006 Jan 3;113(1):51-9
references.pmid: 16380549
references.citation: Am J Physiol Heart Circ Physiol. 2000 Oct;279(4):H1679-89
references.pmid: 11009455
references.citation: Cell. 1996 Oct 4;87(1):13-20
references.pmid: 8858144
references.citation: FASEB J. 2003 May;17(8):923-5
references.pmid: 12670879
references.citation: Mol Cell Biol. 2000 Jul;20(13):4505-12
references.pmid: 10848577
references.citation: Bioessays. 2000 Sep;22(9):836-45
references.pmid: 10944586
references.citation: Mol Cell Biol. 1999 Nov;19(11):7816-27
references.pmid: 10523670
references.citation: Science. 2001 Aug 31;293(5535):1653-7
references.pmid: 11533489
references.citation: Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H434-41
references.pmid: 12793983
references.citation: Curr Cancer Drug Targets. 2004 Mar;4(2):205-18
references.pmid: 15032670
references.citation: J Pharmacol Exp Ther. 2006 Jun;317(3):1106-13
references.pmid: 16489128
references.citation: Cardiovasc Res. 2008 Dec 1;80(3):416-24
references.pmid: 18697792
references.citation: Mol Cell Biol. 2001 Oct;21(20):7065-77
references.pmid: 11564889
references.citation: J Biol Chem. 1990 Oct 5;265(28):17174-9
references.pmid: 2211619
references.citation: Circ Res. 2001 Nov 9;89(10):915-22
references.pmid: 11701619
references.citation: Nat Med. 1997 Aug;3(8):894-9
references.pmid: 9256281
references.citation: Nature. 1997 Sep 18;389(6648):251-60
references.pmid: 9305837
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3519-24
references.pmid: 9520398
references.citation: J Mol Cell Cardiol. 2006 Jun;40(6):775-82
references.pmid: 16678846