Cell-specific ablation of Hsp47 defines the collagen-producing cells in the injured heart
Animals
Cell Line
Collagen
/ metabolism
Disease Models, Animal
Endothelial Cells
/ metabolism
Fibrosis
Gene Expression Profiling
HSP47 Heat-Shock Proteins
/ genetics
Heart Ventricles
/ cytology
Humans
Male
Mice
Muscle, Skeletal
/ cytology
Muscular Dystrophies, Limb-Girdle
/ genetics
Myocardial Infarction
/ etiology
Myocytes, Cardiac
/ metabolism
Myofibroblasts
/ metabolism
Primary Cell Culture
Rats
Sarcoglycans
/ genetics
Ventricular Remodeling
Cardiovascular disease
Collagens
Fibrosis
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
08 08 2019
08 08 2019
Historique:
entrez:
9
8
2019
pubmed:
9
8
2019
medline:
1
9
2020
Statut:
epublish
Résumé
Collagen production in the adult heart is thought to be regulated by the fibroblast, although cardiomyocytes and endothelial cells also express multiple collagen mRNAs. Molecular chaperones are required for procollagen biosynthesis, including heat shock protein 47 (Hsp47). To determine the cell types critically involved in cardiac injury–induced fibrosis theHsp47 gene was deleted in cardiomyocytes, endothelial cells, or myofibroblasts. Deletion ofHsp47 from cardiomyocytes during embryonic development or adult stages, or deletion from adult endothelial cells, did not affect cardiac fibrosis after pressure overload injury. However, myofibroblast-specific ablation of Hsp47; blocked fibrosis and deposition of collagens type I, III, and V following pressure overload as well as significantly reduced cardiac hypertrophy. Fibroblast-specific Hsp47-deleted mice showed lethality after myocardial infarction injury, with ineffective scar formation and ventricular wall rupture. Similarly, only myofibroblast-specific deletion of Hsp47reduced fibrosis and disease in skeletal muscle in a mouse model of muscular dystrophy. Mechanistically, deletion of Hsp47 from myofibroblasts reduced mRNA expression of fibrillar collagens and attenuated their proliferation in the heart without affecting paracrine secretory activity of these cells. The results show that myofibroblasts are the primary mediators of tissue fibrosis and scar formation in the injured adult heart, which unexpectedly affects cardiomyocyte hypertrophy.
Identifiants
pubmed: 31393098
doi: 10.1172/jci.insight.128722
pii: 128722
pmc: PMC6693833
doi:
pii:
Substances chimiques
HSP47 Heat-Shock Proteins
0
Sarcoglycans
0
Serpinh1 protein, mouse
0
Sgcd protein, mouse
0
Collagen
9007-34-5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e128722Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR071301
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142217
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM063483
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
© 2019 Khalil et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Déclaration de conflit d'intérêts
The authors have declared that no conflict of interest exists.
Références
Kidney Int. 2000 Feb;57(2):619-31
pubmed: 10652040
Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1196-201
pubmed: 10655507
Nephrol Dial Transplant. 2000 Apr;15(4):529-35
pubmed: 10727549
Cardiovasc Res. 2000 May;46(2):250-6
pubmed: 10773228
Nat Genet. 2000 May;25(1):25-9
pubmed: 10802651
J Cell Sci. 2000 Jul;113 ( Pt 14):2535-44
pubmed: 10862711
J Cell Biol. 2000 Sep 18;150(6):1499-506
pubmed: 10995453
Circ Res. 2001 Jul 6;89(1):20-5
pubmed: 11440973
Cardiovasc Res. 2002 Jul;55(1):76-82
pubmed: 12062710
Hypertension. 2003 Jul;42(1):88-95
pubmed: 12756220
Eur Heart J. 1992 Sep;13 Suppl D:24-32
pubmed: 1396856
Annu Rev Med. 2004;55:373-94
pubmed: 14746527
J Biol Chem. 2004 Apr 9;279(15):15524-30
pubmed: 14749328
Semin Cell Dev Biol. 2003 Oct;14(5):275-82
pubmed: 14986857
J Biol Chem. 2004 Jun 18;279(25):26192-200
pubmed: 15082723
Circulation. 2004 Sep 7;110(10):1263-8
pubmed: 15313958
Circ Res. 2005 Feb 4;96(2):261-8
pubmed: 15618538
Mol Biol Cell. 2006 May;17(5):2346-55
pubmed: 16525016
Am J Physiol Cell Physiol. 2007 Aug;293(2):C661-9
pubmed: 17475662
Circ Res. 2007 Aug 3;101(3):313-21
pubmed: 17569887
Circ Res. 1991 Mar;68(3):734-44
pubmed: 1835909
Dev Biol. 1991 Mar;144(1):107-18
pubmed: 1847345
Cardiovasc Res. 2009 Feb 15;81(3):509-18
pubmed: 18762556
Development. 1991 Apr;111(4):945-53
pubmed: 1879363
Genesis. 2009 Feb;47(2):107-14
pubmed: 19165827
Cell Tissue Res. 2010 Jan;339(1):247-57
pubmed: 19693541
J Mol Cell Cardiol. 2010 Mar;48(3):474-82
pubmed: 19729019
Respir Med. 2010 Jun;104(6):895-901
pubmed: 20129768
Nucleic Acids Res. 2010 Jul;38(Web Server issue):W755-62
pubmed: 20513647
Circ Res. 1991 Jul;69(1):116-22
pubmed: 2054929
Cell Mol Biol Lett. 2010 Dec;15(4):551-63
pubmed: 20683677
J Cell Sci. 2012 Mar 1;125(Pt 5):1118-28
pubmed: 22492985
Am J Physiol Renal Physiol. 2012 Sep;303(5):F757-65
pubmed: 22718885
FASEB J. 2012 Dec;26(12):4925-36
pubmed: 22919069
Fibrogenesis Tissue Repair. 2012 Sep 03;5(1):15
pubmed: 22943504
Mol Cell Biol. 2012 Nov;32(22):4523-33
pubmed: 22949508
J Cell Biol. 2013 May 13;201(4):499-510
pubmed: 23671309
Hum Mol Genet. 2014 Oct 15;23(20):5452-63
pubmed: 24876160
Genet Mol Res. 2014 Dec 18;13(4):10787-802
pubmed: 25526199
Mol Cell Biol. 2015 Jun;35(12):2154-64
pubmed: 25870108
J Am Coll Cardiol. 1989 Jun;13(7):1637-52
pubmed: 2656824
Circ Res. 2016 Feb 5;118(3):400-9
pubmed: 26635390
Nat Commun. 2015 Dec 16;6:10084
pubmed: 26670661
Curr Pathobiol Rep. 2016 Mar;4(1):11-18
pubmed: 27171595
Nat Commun. 2016 Jul 22;7:12260
pubmed: 27447449
Nucleic Acids Res. 2017 Jan 4;45(D1):D331-D338
pubmed: 27899567
Nat Commun. 2017 Mar 22;8:14913
pubmed: 28327610
Circulation. 2017 Aug 8;136(6):549-561
pubmed: 28356446
Physiol Genomics. 2017 Aug 1;49(8):416-429
pubmed: 28698228
J Clin Invest. 2017 Oct 2;127(10):3770-3783
pubmed: 28891814
Nat Commun. 2017 Sep 28;8(1):712
pubmed: 28959037
Matrix Biol. 2019 Jan;75-76:43-57
pubmed: 29247693
J Clin Invest. 2018 May 1;128(5):2127-2143
pubmed: 29664017
Circulation. 2018 Sep 4;138(10):1012-1024
pubmed: 29666070
Nat Rev Cardiol. 2018 Jul;15(7):379
pubmed: 29713010
Arterioscler Thromb Vasc Biol. 2018 Nov;38(11):2550-2561
pubmed: 30354251
JCI Insight. 2018 Nov 15;3(22):
pubmed: 30429366
Circ Res. 2018 Dec 7;123(12):1285-1297
pubmed: 30566042
Nat Commun. 2019 Jan 8;10(1):76
pubmed: 30622267
J Cell Physiol. 1988 Jul;136(1):43-53
pubmed: 3294238
Biochem Biophys Res Commun. 1988 May 31;153(1):428-34
pubmed: 3377793
Proc Natl Acad Sci U S A. 1976 Jul;73(7):2361-4
pubmed: 59926
Mol Cell Biol. 1984 Aug;4(8):1483-92
pubmed: 6548546
Ann N Y Acad Sci. 1995 Mar 27;752:387-93
pubmed: 7755282
J Cell Biochem. 1994 Dec;56(4):518-26
pubmed: 7890810
J Clin Invest. 1994 Dec;94(6):2481-8
pubmed: 7989606
J Mol Cell Cardiol. 1994 Mar;26(3):279-92
pubmed: 8028011
J Biol Chem. 1993 Aug 25;268(24):18226-33
pubmed: 8349698
J Cell Biol. 1996 Apr;133(2):469-83
pubmed: 8609177
Dev Dyn. 1998 Mar;211(3):248-55
pubmed: 9520112
J Biol Chem. 1998 Apr 17;273(16):9637-43
pubmed: 9545296
Arterioscler Thromb Vasc Biol. 1998 May;18(5):717-22
pubmed: 9598829
Virchows Arch. 1998 May;432(5):455-60
pubmed: 9645446