title: Anthrax lethal toxin induces acute diastolic dysfunction in rats through disruption of the phospholamban signaling network.
abstract: BACKGROUND
  Anthrax lethal toxin (LT), secreted by Bacillus anthracis, causes severe cardiac dysfunction by unknown mechanisms. LT specifically cleaves the docking domains of MAPKK (MEKs); thus, we hypothesized that LT directly impairs cardiac function through dysregulation of MAPK signaling mechanisms.
  
  
  RESULTS
  In a time-course study of LT toxicity, echocardiography revealed acute diastolic heart failure accompanied by pulmonary regurgitation and left atrial dilation in adult Sprague-Dawley rats at time points corresponding to dysregulated JNK, phospholamban (PLB) and protein phosphatase 2A (PP2A) myocardial signaling. Using isolated rat ventricular myocytes, we identified the MEK7-JNK1-PP2A-PLB signaling axis to be important for regulation of intracellular calcium (Ca(2+)(i)) handling, PP2A activation and targeting of PP2A-B56α to Ca(2+)(i) handling proteins, such as PLB. Through a combination of gain-of-function and loss-of-function studies, we demonstrated that over-expression of MEK7 protects against LT-induced PP2A activation and Ca(2+)(i) dysregulation through activation of JNK1. Moreover, targeted phosphorylation of PLB-Thr(17) by Akt improved sarcoplasmic reticulum Ca(2+)(i) release and reuptake during LT toxicity. Co-immunoprecipitation experiments further revealed the pivotal role of MEK7-JNK-Akt complex formation for phosphorylation of PLB-Thr(17) during acute LT toxicity.
  
  
  CONCLUSIONS
  Our findings support a cardiogenic mechanism of LT-induced diastolic dysfunction, by which LT disrupts JNK1 signaling and results in Ca(2+)(i) dysregulation through diminished phosphorylation of PLB by Akt and increased dephosphorylation of PLB by PP2A. Integration of the MEK7-JNK1 signaling module with Akt represents an important stress-activated signalosome that may confer protection to sustain cardiac contractility and maintain normal levels of Ca(2+)(i) through PLB-T(17) phosphorylation.
authors.affiliation: Division of Molecular Cardiology, Cardiovascular Research Institute, College of Medicine, Texas A&M University System Health Science Center, Temple, TX, USA.
authors.forename: Honey B
authors.initials: HB
authors.lastname: Golden
authors.forename: Linley E
authors.initials: LE
authors.lastname: Watson
authors.forename: Damir
authors.initials: D
authors.lastname: Nizamutdinov
authors.forename: Hao
authors.initials: H
authors.lastname: Feng
authors.forename: Fnu
authors.initials: F
authors.lastname: Gerilechaogetu
authors.forename: Hind
authors.initials: H
authors.lastname: Lal
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Verma
authors.forename: Swagoto
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Donald M
authors.initials: DM
authors.lastname: Foster
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Dillmann
authors.forename: David E
authors.initials: DE
authors.lastname: Dostal
mesh_terms: D000208:Acute Disease; D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D054144:Heart Failure, Diastolic / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000099211:Phospholamban
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002135:Calcium-Binding Proteins; D000099211:Phospholamban; C030325:anthrax toxin
keywords: Akt; Anthrax lethal toxin; Diastolic dysfunction; JNK1/2; Phospholamban
references.citation: Infect Immun. 2005 Dec;73(12):8275-81
references.pmid: 16299324
references.citation: Am J Physiol Heart Circ Physiol. 2011 Mar;300(3):H1108-18
references.pmid: 21217068
references.citation: JAMA. 2002 Feb 20;287(7):858-62
references.pmid: 11851577
references.citation: Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1183-92
references.pmid: 16603688
references.citation: J Mol Cell Cardiol. 2008 Dec;45(6):770-8
references.pmid: 18926830
references.citation: J Clin Invest. 2003 Sep;112(5):670-82
references.pmid: 12952916
references.citation: Biochem J. 2000 Dec 15;352 Pt 3:739-45
references.pmid: 11104681
references.citation: Methods. 2000 Jul;21(3):221-30
references.pmid: 10873476
references.citation: Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H109-19
references.pmid: 17416611
references.citation: J Infect Dis. 2007 Feb 15;195(4):572-80
references.pmid: 17230417
references.citation: Methods Mol Biol. 2012;843:205-14
references.pmid: 22222535
references.citation: Science. 1998 May 1;280(5364):734-7
references.pmid: 9563949
references.citation: Circulation. 2011 Sep 6;124(10):1151-9
references.pmid: 21844073
references.citation: J Infect Dis. 2005 Jun 1;191(11):1881-8
references.pmid: 15871122
references.citation: FEMS Immunol Med Microbiol. 2009 Jul;56(2):129-42
references.pmid: 19416348
references.citation: Cardiovasc Res. 2008 Oct 1;80(1):47-54
references.pmid: 18599478
references.citation: J Mol Cell Cardiol. 2003 Dec;35(12):1385-94
references.pmid: 14654364
references.citation: Science. 2002 Sep 20;297(5589):2048-51
references.pmid: 12202685
references.citation: Gene Ther. 2006 Jan;13(1):8-19
references.pmid: 16094411
references.citation: J Mol Cell Cardiol. 2007 Aug;43(2):137-47
references.pmid: 17583725
references.citation: Toxins (Basel). 2011 Jun;3(6):721-36
references.pmid: 22069736
references.citation: Circ Res. 2005 Dec 9;97(12):1332-41
references.pmid: 16293788
references.citation: J Biol Chem. 2009 Oct 9;284(41):28180-28187
references.pmid: 19696029
references.citation: J Am Soc Echocardiogr. 2004 Feb;17(2):161-7
references.pmid: 14752491
references.citation: J Immunol. 2008 Mar 15;180(6):4139-47
references.pmid: 18322225
references.citation: Nat Struct Mol Biol. 2004 Jan;11(1):60-6
references.pmid: 14718924
references.citation: PLoS Pathog. 2009 May;5(5):e1000456
references.pmid: 19478875
references.citation: JAMA. 2001 Nov 28;286(20):2554-9
references.pmid: 11722269
references.citation: Cardiovasc Res. 2009 Apr 1;82(1):67-76
references.pmid: 19201758
references.citation: Mol Pharmacol. 2008 Nov;74(5):1453-62
references.pmid: 18703669
references.citation: Biochem J. 2004 Mar 1;378(Pt 2):569-77
references.pmid: 14616089
references.citation: Mol Aspects Med. 2009 Dec;30(6):439-55
references.pmid: 19638283
references.citation: Am J Pathol. 2005 Jun;166(6):1871-81
references.pmid: 15920171
references.citation: Biochem Biophys Res Commun. 2006 Aug 4;346(3):700-6
references.pmid: 16774736
references.citation: J Infect Dis. 2010 Dec 15;202(12):1885-96
references.pmid: 21067373
references.citation: PLoS One. 2007 May 23;2(5):e466
references.pmid: 17520025
references.citation: Front Biosci. 2007 May 01;12:4670-5
references.pmid: 17485403
references.citation: Nat Rev Immunol. 2008 Oct;8(10):776-87
references.pmid: 18802444
references.citation: Am J Pathol. 2005 Nov;167(5):1309-20
references.pmid: 16251415
references.citation: Biochem Biophys Res Commun. 1998 Jul 30;248(3):706-11
references.pmid: 9703991
references.citation: Basic Res Cardiol. 2011 Sep;106(5):801-14
references.pmid: 21533831
references.citation: Eur J Cell Biol. 2011 Jun-Jul;90(6-7):536-44
references.pmid: 21333379