Downregulation of FKBP5 Promotes Atrial Arrhythmogenesis.
animals
atrial fibrillation
electrophysiology
mice
Journal
Circulation research
ISSN: 1524-4571
Titre abrégé: Circ Res
Pays: United States
ID NLM: 0047103
Informations de publication
Date de publication:
23 06 2023
23 06 2023
Historique:
pmc-release:
23
06
2024
medline:
26
6
2023
pubmed:
8
5
2023
entrez:
8
5
2023
Statut:
ppublish
Résumé
Atrial fibrillation (AF), the most common arrhythmia, is associated with the downregulation of Right atrial samples from patients with AF were used to assess the protein levels of FKBP5. A cardiomyocyte-specific FKBP5 knockdown mouse model was established by crossbreeding FKBP5 protein levels were lower in the atrial lysates of patients with paroxysmal AF or long-lasting persistent (chronic) AF. Cardiomyocyte-specific knockdown mice exhibited increased AF inducibility and duration compared with control mice. Enhanced AF susceptibility in cardiomyocyte-specific knockdown mice was associated with the development of action potential alternans and spontaneous Ca This is the first study to demonstrate a role for the FKBP5-deficiency in atrial arrhythmogenesis and to establish FKBP5 as a negative regulator of hypoxia-inducible factor 1α in cardiomyocytes. Our results identify a potential molecular mechanism for the proarrhythmic NCX1 upregulation in chronic AF patients.
Sections du résumé
BACKGROUND
Atrial fibrillation (AF), the most common arrhythmia, is associated with the downregulation of
METHODS
Right atrial samples from patients with AF were used to assess the protein levels of FKBP5. A cardiomyocyte-specific FKBP5 knockdown mouse model was established by crossbreeding
RESULTS
FKBP5 protein levels were lower in the atrial lysates of patients with paroxysmal AF or long-lasting persistent (chronic) AF. Cardiomyocyte-specific knockdown mice exhibited increased AF inducibility and duration compared with control mice. Enhanced AF susceptibility in cardiomyocyte-specific knockdown mice was associated with the development of action potential alternans and spontaneous Ca
CONCLUSIONS
This is the first study to demonstrate a role for the FKBP5-deficiency in atrial arrhythmogenesis and to establish FKBP5 as a negative regulator of hypoxia-inducible factor 1α in cardiomyocytes. Our results identify a potential molecular mechanism for the proarrhythmic NCX1 upregulation in chronic AF patients.
Identifiants
pubmed: 37154033
doi: 10.1161/CIRCRESAHA.122.322213
pmc: PMC10330339
mid: NIHMS1894680
doi:
Substances chimiques
tacrolimus binding protein 5
EC 5.2.1.8
Heat-Shock Proteins
0
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
e1-e16Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL136389
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL166549
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL147108
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL163277
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL131517
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006348
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL089598
Pays : United States
Organisme : NIH HHS
ID : S10 OD032380
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL160992
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114356
Pays : United States
Commentaires et corrections
Type : CommentIn
Références
J Physiol. 2015 Mar 15;593(6):1361-82
pubmed: 25772291
Int J Mol Sci. 2019 Jun 04;20(11):
pubmed: 31167373
J Am Heart Assoc. 2018 Dec 4;7(23):e009972
pubmed: 30520673
Yonsei Med J. 2017 May;58(3):489-496
pubmed: 28332352
Int J Mol Sci. 2017 Dec 05;18(12):
pubmed: 29206196
J Biol Chem. 2011 Jan 7;286(1):290-8
pubmed: 21041301
Circ Res. 2020 Jun 19;127(1):73-90
pubmed: 32717176
J Physiol. 2017 Jun 15;595(12):4001-4008
pubmed: 28181690
PLoS One. 2010 Jul 22;5(7):e11717
pubmed: 20661446
Am J Med Sci. 2021 Mar;361(3):319-326
pubmed: 33541709
Neuropsychobiology. 2019;78(2):104-112
pubmed: 31071710
Int J Mol Sci. 2021 Sep 26;22(19):
pubmed: 34638717
Sci Rep. 2019 Feb 4;9(1):1389
pubmed: 30718782
Circ Res. 2014 Apr 25;114(9):1483-99
pubmed: 24763466
Curr Oncol Rep. 2019 Jan 22;21(1):6
pubmed: 30671662
J Mol Med (Berl). 2007 Dec;85(12):1309-15
pubmed: 18026917
Biophys J. 2010 Aug 4;99(3):755-64
pubmed: 20682252
Cell Death Differ. 2010 Jan;17(1):145-57
pubmed: 19696786
Stroke. 2011 Mar;42(3):754-63
pubmed: 21293012
Circ Res. 2020 Jun 19;127(1):51-72
pubmed: 32717172
Surg Obes Relat Dis. 2016 Sep - Oct;12(8):1560-1561
pubmed: 27444859
J Mol Cell Cardiol. 2012 May;52(5):1183-90
pubmed: 22406195
Circ Res. 2009 Oct 23;105(9):876-85
pubmed: 19762679
Cardiovasc Res. 2017 Dec 01;113(14):1743-1752
pubmed: 29016722
Circulation. 2012 May 1;125(17):2059-70
pubmed: 22456474
Adv Exp Med Biol. 2013;961:125-35
pubmed: 23224875
J Cardiovasc Electrophysiol. 1994 Nov;5(11):933-44
pubmed: 7889233
Curr Opin Pharmacol. 2011 Aug;11(4):308-13
pubmed: 21514887
Heart Rhythm. 2012 Oct;9(10):1698-705
pubmed: 22721857
Circ Res. 2001 Jul 6;89(1):20-5
pubmed: 11440973
J Psychiatr Res. 2018 Sep;104:227-234
pubmed: 30107269
Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11370-11379
pubmed: 31113877
Clin Chim Acta. 2019 Dec;499:4-12
pubmed: 31473195
Circ Heart Fail. 2013 May;6(3):572-83
pubmed: 23508759
J Neurochem. 2012 Jul;122(1):4-18
pubmed: 22548329
Cells. 2022 May 06;11(9):
pubmed: 35563877
Lancet. 2015 Jul 11;386(9989):154-62
pubmed: 25960110
Annu Rev Physiol. 2014;76:39-56
pubmed: 23988176
J Mol Cell Cardiol. 2021 Apr;153:111-122
pubmed: 33383036
Cardiovasc Diabetol. 2018 Apr 30;17(1):63
pubmed: 29712555
Cancer Cell. 2009 Sep 8;16(3):259-66
pubmed: 19732725
Eur J Med Chem. 2012 Mar;49:24-40
pubmed: 22305612
Circ Heart Fail. 2019 Feb;12(2):e005131
pubmed: 30744415
Pacing Clin Electrophysiol. 2006 Mar;29(3):290-5
pubmed: 16606397
Nat Chem Biol. 2015 Jan;11(1):33-7
pubmed: 25436518
Cardiovasc Res. 2002 Jan;53(1):192-201
pubmed: 11744028
Circ Res. 2012 Feb 3;110(3):465-70
pubmed: 22158709
Circulation. 2006 Aug 15;114(7):670-80
pubmed: 16894034
ACS Chem Biol. 2018 Aug 17;13(8):2288-2299
pubmed: 29893552
Circ J. 2010 Sep;74(9):1815-21
pubmed: 20631454
Am J Cardiol. 2017 Dec 1;120(11):1966-1973
pubmed: 28964382
Nat Rev Cardiol. 2017 Nov;14(11):637-653
pubmed: 28660894
Cardiovasc Pathol. 2010 Mar-Apr;19(2):102-11
pubmed: 19211267
Heart Rhythm. 2018 Nov;15(11):1717-1727
pubmed: 29908372
Int J Cardiol. 2015 Apr 1;184:190-197
pubmed: 25706326
Pflugers Arch. 2021 Mar;473(3):389-405
pubmed: 33511453
Nat Commun. 2017 Nov 23;8(1):1725
pubmed: 29170369
Circ Arrhythm Electrophysiol. 2020 Jun;13(6):e008179
pubmed: 32433891
Mol Ther. 2018 Jul 5;26(7):1735-1745
pubmed: 29843956
J Am Heart Assoc. 2021 Nov 2;10(21):e021101
pubmed: 34713710
Cancer Gene Ther. 2021 Sep;28(9):1058-1070
pubmed: 33664459
Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8348-53
pubmed: 15159550
Circulation. 2018 Nov 13;138(20):2227-2242
pubmed: 29802206
Cardiovasc Res. 2016 Sep;111(4):348-61
pubmed: 27229460
Circulation. 2014 Jan 14;129(2):145-156
pubmed: 24249718
Cardiovasc Res. 2021 Jun 16;117(7):1746-1759
pubmed: 33523143
J Physiol. 2013 Apr 15;591(8):2067-86
pubmed: 23401616
EMBO Rep. 2019 Jan;20(1):
pubmed: 30429208
Circ Res. 2019 Jan 18;124(2):256-262
pubmed: 30582449