title: Three-dimensional structure of the intercalated disc reveals plicate domain and gap junction remodeling in heart failure.
abstract: The intercalated disc (ICD) orchestrates electrochemical and mechanical communication between neighboring cardiac myocytes, properties that are perturbed in heart failure (HF). Although structural data from transmission electron microscopy two-dimensional images have provided valuable insights into the domains forming the ICD, there are currently no three-dimensional (3D) reconstructions for an entire ICD in healthy or diseased hearts. Here, we aimed to understand the link between changes in protein expression in an ovine tachypacing-induced HF model and ultrastructural remodeling of the ICD by determining the 3D intercalated disc architecture using serial block face scanning electron microscopy. In the failing myocardium there is no change to the number of ICDs within the left ventricle, but there is an almost doubling of the number of discs with a surface area of <1.0 × 10(8)μm(2) in comparison to control. The 3D reconstructions further revealed that there is remodeling of the plicate domains and gap junctions with vacuole formation around and between the contributing membranes that form the ICDs in HF. Biochemical analysis revealed upregulation of proteins involved in stabilizing the adhesive and mechanical properties consistent with the morphological changes. Our studies here have shown that in tachypacing-induced HF mechanical stresses are associated with both structural and molecular alterations. To our knowledge, these data together provide novel, to our knowledge, insights as to how remodeling at the molecular and structural levels leads to impaired intercellular communication.
authors: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
authors: Christian
authors: C
authors: Pinali
authors: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
authors: Hayley J
authors: HJ
authors: Bennett
authors: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
authors: J Bernard
authors: JB
authors: Davenport
authors: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
authors: Jessica L
authors: JL
authors: Caldwell
authors: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors: Tobias
authors: T
authors: Starborg
authors: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
authors: Andrew W
authors: AW
authors: Trafford
authors: Institute of Cardiovascular Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom. Electronic address: ashraf.kitmitto@manchester.ac.uk.
authors: Ashraf
authors: A
authors: Kitmitto
mesh_terms: D000818:Animals; D017629:Gap Junctions / Q000378:metabolism / Q000648:ultrastructure*; D006333:Heart Failure / Q000473:pathology* / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology / Q000648:ultrastructure; D021621:Imaging, Three-Dimensional; D007365:Intercellular Junctions / Q000648:ultrastructure*; D008929:Mitochondria, Heart / Q000648:ultrastructure; D011506:Proteins / Q000378:metabolism; D012756:Sheep; D015854:Up-Regulation; D014617:Vacuoles / Q000648:ultrastructure
chemical_list: D011506:Proteins
references: J Mol Cell Cardiol. 1999 Feb;31(2):319-31
references: 10093045
references: Circ Res. 1999 Nov 26;85(11):1046-55
references: 10571536
references: Circ Res. 2000 Aug 18;87(4):316-22
references: 10948066
references: J Mol Cell Cardiol. 2001 Feb;33(2):219-31
references: 11162128
references: Biochemistry. 2001 Dec 11;40(49):14898-906
references: 11732910
references: Anat Rec. 1975 Oct;183(2):243-57
references: 1200401
references: J Cell Sci. 2003 Mar 1;116(Pt 5):875-85
references: 12571285
references: J Biophys Biochem Cytol. 1960 Oct;8:305-18
references: 13708707
references: J Mol Cell Cardiol. 2004 Jan;36(1):101-10
references: 14734052
references: Circ Res. 2004 Mar 19;94(5):585-91
references: 15031271
references: Cardiovasc Res. 2004 May 1;62(2):426-36
references: 15094362
references: J Comput Chem. 2004 Oct;25(13):1605-12
references: 15264254
references: Circ Res. 2004 Oct 1;95(7):717-25
references: 15345654
references: Dev Dyn. 2005 May;233(1):201-12
references: 15765519
references: Heart Fail Rev. 2000 Oct;5(3):251-7
references: 16228908
references: Eur J Cell Biol. 2006 Feb;85(2):69-82
references: 16406610
references: Mol Biol Cell. 2006 Apr;17(4):2091-100
references: 16481394
references: Eur Heart J. 2006 Aug;27(15):1847-54
references: 16774985
references: Tissue Cell. 2006 Dec;38(6):417-20
references: 17049576
references: J Membr Biol. 2007 Aug;218(1-3):13-28
references: 17661127
references: Heart Rhythm. 2007 Sep;4(9):1196-205
references: 17765621
references: Cardiovasc Res. 2008 Oct 1;80(1):9-19
references: 18519446
references: Heart Rhythm. 2008 Aug;5(8):1178-85
references: 18675229
references: Heart Rhythm. 2009 Aug;6(8 Suppl):S62-5
references: 19541548
references: Circ Heart Fail. 2009 Sep;2(5):482-9
references: 19808379
references: Circulation. 1991 Feb;83(2):504-14
references: 1991369
references: J Physiol. 2011 Mar 15;589(Pt 6):1367-82
references: 21242250
references: Front Biosci (Landmark Ed). 2012 Jan 01;17:1035-50
references: 22201789
references: Circulation. 2012 Apr 17;125(15):1835-47
references: 22412072
references: Nat Methods. 2012 Jul;9(7):671-5
references: 22930834
references: Anal Biochem. 2013 Feb 15;433(2):105-11
references: 23085117
references: Cell Mol Life Sci. 2014 Jan;71(1):165-81
references: 23708682
references: Biochim Biophys Acta. 2013 Dec;1832(12):2414-24
references: 24036209
references: Circ Res. 2013 Nov 8;113(11):1219-30
references: 24044951
references: Int J Cardiol. 1990 Feb;26(2):137-73
references: 2406208
references: Cardiovasc Res. 2014 Apr 1;102(1):24-34
references: 24413773
references: Circ Arrhythm Electrophysiol. 2014 Dec;7(6):1198-204
references: 25313260
references: Circ Res. 1989 Nov;65(5):1458-62
references: 2619820
references: Circ Res. 1989 Mar;64(3):563-74
references: 2645060
references: Circ Res. 1989 Jul;65(1):22-42
references: 2736737
references: Biophys Rev. 2009 Mar;1(1):43
references: 28510153
references: Int Rev Cytol. 1988;113:101-43
references: 2976409
references: Tissue Cell. 1985;17(5):605-48
references: 3904080
references: Basic Res Cardiol. 1985;80 Suppl 2:35-40
references: 4062835
references: Tissue Cell. 1982;14(1):25-37
references: 7089964
references: Circulation. 1993 Sep;88(3):864-75
references: 8394786
references: J Struct Biol. 1996 Jan-Feb;116(1):71-6
references: 8742726