title: Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias.
abstract: Millions of people suffer a myocardial infarction (MI) every year, and those who survive have increased risk of arrhythmias and sudden cardiac death. Recent clinical studies have identified sympathetic denervation as a predictor of increased arrhythmia susceptibility. Chondroitin sulfate proteoglycans present in the cardiac scar after MI prevent sympathetic reinnervation by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ). Here we show that the absence of PTPσ, or pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) beginning 3 days after injury, restores sympathetic innervation to the scar and markedly reduces arrhythmia susceptibility. Using optical mapping we observe increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation and Ca(2+) mishandling following MI. Sympathetic reinnervation prevents these changes and renders hearts remarkably resistant to induced arrhythmias.
authors: Department of Physiology and Pharmacology, Neuroscience Graduate Program, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors: R T
authors: RT
authors: Gardner
authors: Department of Pharmacology, University of California, Davis, California 95616, USA.
authors: L
authors: L
authors: Wang
authors: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors: B T
authors: BT
authors: Lang
authors: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors: J M
authors: JM
authors: Cregg
authors: Department of Physiology and Pharmacology, Neuroscience Graduate Program, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors: C L
authors: CL
authors: Dunbar
authors: Department of Neurology, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors: W R
authors: WR
authors: Woodward
authors: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors: J
authors: J
authors: Silver
authors: Department of Pharmacology, University of California, Davis, California 95616, USA.
authors: C M
authors: CM
authors: Ripplinger
authors: Department of Physiology and Pharmacology, Neuroscience Graduate Program, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors: B A
authors: BA
authors: Habecker
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism; D004562:Electrocardiography; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000188:drug therapy*; D010455:Peptides / Q000627:therapeutic use*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism
chemical_list: D010455:Peptides; D011943:Receptors, Adrenergic, beta; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D002118:Calcium
references: J Neurochem. 2012 Jan;120(2):239-47
references: 22007720
references: Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H614-21
references: 16963611
references: Circulation. 1997 Sep 16;96(6):1914-22
references: 9323081
references: Circulation. 1987 Jan;75(1):131-8
references: 3791599
references: Nat Genet. 1999 Mar;21(3):330-3
references: 10080191
references: N Engl J Med. 2002 Mar 21;346(12):877-83
references: 11907286
references: Circulation. 1992 Mar;85(3):1175-88
references: 1371431
references: Clin Physiol. 2000 Sep;20(5):366-73
references: 10971548
references: Nature. 2013 Oct 17;502(7471):372-6
references: 24077098
references: Cell Tissue Res. 2006 Jun;324(3):475-88
references: 16496177
references: Trends Pharmacol Sci. 2011 Mar;32(3):174-80
references: 21316769
references: Circ Res. 2014 Apr 25;114(9):1410-21
references: 24568740
references: J Neurosci. 2013 Apr 24;33(17):7175-83
references: 23616527
references: J Am Coll Cardiol. 2014 Jan 21;63(2):141-9
references: 24076296
references: J Mol Cell Cardiol. 2011 Mar;50(3):510-21
references: 21145895
references: Exp Physiol. 2010 Feb;95(2):304-14
references: 19880537
references: Curr Opin Pharmacol. 2014 Apr;15:107-14
references: 24632325
references: J Am Coll Cardiol. 2010 Jun 15;55(24):2769-77
references: 20538172
references: Nat Med. 2007 May;13(5):604-12
references: 17417650
references: J Biol Chem. 2013 May 31;288(22):16017-30
references: 23564460
references: Circ Res. 2007 Jun 22;100(12):1755-64
references: 17495227
references: Am J Physiol Heart Circ Physiol. 2010 Jun;298(6):H1652-60
references: 20190098
references: Circ Res. 2004 Jul 9;95(1):76-83
references: 15166093
references: N Engl J Med. 2005 May 12;352(19):1951-8
references: 15888695
references: Exp Neurol. 2013 Nov;249:111-9
references: 24013014
references: Annu Rev Physiol. 2008;70:23-49
references: 17988210
references: Ann N Y Acad Sci. 2006 Oct;1080:216-34
references: 17132786
references: J Am Coll Cardiol. 1989 Nov 15;14(6):1519-26
references: 2809013
references: J Mol Cell Cardiol. 2003 Feb;35(2):153-63
references: 12606256
references: Circulation. 1983 Apr;67(4):787-96
references: 6825234
references: Circulation. 2000 Aug 15;102(7):742-7
references: 10942741
references: Circ Res. 2013 Feb 15;112(4):689-97
references: 23295832
references: Circ Res. 2000 Apr 14;86(7):816-21
references: 10764417
references: Am J Physiol Heart Circ Physiol. 2004 Jun;286(6):H2229-36
references: 14726300
references: J Am Coll Cardiol. 2011 Sep 20;58(13):1309-24
references: 21920259
references: Annu Rev Physiol. 2000;62:25-50
references: 10845083
references: Circulation. 2010 Sep 28;122(13):1265-71
references: 20837894
references: Heart Rhythm. 2006 Jun;3(6):728-36
references: 16731479
references: Brain Res. 2006 Dec 8;1124(1):142-54
references: 17084822
references: Cardiovasc Res. 1995 Aug;30(2):270-80
references: 7585815
references: Basic Res Cardiol. 2004 Jul;99(4):279-87
references: 15221346
references: Am J Physiol Heart Circ Physiol. 2012 May 1;302(9):H1838-46
references: 22345568
references: Heart Rhythm. 2014 Mar;11(3):360-6
references: 24291775
references: J Cardiovasc Electrophysiol. 2002 Nov;13(11):1141-9
references: 12475106
references: Circulation. 2000 Apr 25;101(16):1960-9
references: 10779463
references: J Nucl Med. 2010 Aug;51(8):1241-9
references: 20679471
references: Circulation. 1997 Jul 1;96(1):183-91
references: 9236433
references: IEEE Trans Biomed Eng. 1998 May;45(5):563-71
references: 9581054
references: Circ Arrhythm Electrophysiol. 2011 Aug;4(4):478-85
references: 21665983
references: J Clin Invest. 2005 Sep;115(9):2305-15
references: 16138184
references: J Am Coll Cardiol. 1999 Aug;34(2):325-33
references: 10440140
references: Eur Heart J. 2004 Aug;25(15):1341-62
references: 15288162
references: Circ Res. 2012 May 25;110(11):1454-64
references: 22539768
references: N Engl J Med. 2005 Jun 23;352(25):2581-8
references: 15972864
references: Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20541-6
references: 21059915