Molecular remodeling of Cx43, but not structural remodeling, promotes arrhythmias in an arrhythmogenic canine model of nonischemic heart failure.
Action Potentials
Animals
Connexin 43
/ metabolism
Disease Models, Animal
Dogs
Electric Conductivity
Female
Fibrosis
Gap Junctions
/ metabolism
Heart Conduction System
/ physiopathology
Heart Failure
/ complications
Heart Ventricles
/ metabolism
Male
Phosphorylation
Tachycardia, Ventricular
/ complications
Ventricular Dysfunction, Left
/ complications
Ventricular Fibrillation
/ complications
Ventricular Function, Left
Conduction velocity
Dephosphorylation
Fibrosis
Heart failure
connexin43 remodeling
Journal
Journal of molecular and cellular cardiology
ISSN: 1095-8584
Titre abrégé: J Mol Cell Cardiol
Pays: England
ID NLM: 0262322
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
10
03
2021
revised:
30
04
2021
accepted:
21
05
2021
pubmed:
29
5
2021
medline:
29
1
2022
entrez:
28
5
2021
Statut:
ppublish
Résumé
Both gap junctional remodeling and interstitial fibrosis have been linked to impaired electrical conduction velocity (CV) and fatal ventricular arrhythmias in nonischemic heart failure (HF). However, the arrhythmogenic role of the ventricular gap junctional Cx43 in nonischemic HF remains in debate. Here, we assessed this in a newly developed arrhythmogenic canine model of nonischemic HF. Nonischemic HF was induced in canines by combined aortic valve insufficiency and aortic constriction. Left ventricular (LV) myocardium from HF dogs showed similar pathological changes to that of humans. HF dogs had reduced LV function, widened QRS complexes, and spontaneous nonsustained ventricular tachycardia. CV was measured in intact LV epicardium with high-density grid mapping. Total (Cx43-T) and nonphosphorylated Cx43 (Cx43-NP) and histological interstitial fibrosis were assessed from these mapped LV tissues. Longitudinal CV, which was slowed in HF (49 ± 1 vs. 65 ± 2 cm/s in Ctl), was positively correlated with reduced total junctional Cx43 and negatively correlated with markedly increased junctional Cx43-NP (2-fold) in HF. Cx43 dephosphorylation in HF was associated with enhanced colocalization of PP2A at the level of Cx43. Unchanged action potential upstroke and transverse CV were associated with unaltered Cx43 lateralization and interstitial fibrosis in the nonischemic HF canine LV. Our unique arrhythmogenic canine model of HF resembles human nonischemic HF (prior to the end stage). Cx43 remodeling occurs prior to the structural remodeling (with lack of fibrosis) in HF and it is crucial in slowed CV and ventricular arrhythmia development. Our findings suggest that altered Cx43 alone is arrhythmogenic and modulation of Cx43 has the anti-arrhythmic therapeutic potential for HF patients.
Sections du résumé
BACKGROUND
Both gap junctional remodeling and interstitial fibrosis have been linked to impaired electrical conduction velocity (CV) and fatal ventricular arrhythmias in nonischemic heart failure (HF). However, the arrhythmogenic role of the ventricular gap junctional Cx43 in nonischemic HF remains in debate. Here, we assessed this in a newly developed arrhythmogenic canine model of nonischemic HF.
METHODS AND RESULTS
Nonischemic HF was induced in canines by combined aortic valve insufficiency and aortic constriction. Left ventricular (LV) myocardium from HF dogs showed similar pathological changes to that of humans. HF dogs had reduced LV function, widened QRS complexes, and spontaneous nonsustained ventricular tachycardia. CV was measured in intact LV epicardium with high-density grid mapping. Total (Cx43-T) and nonphosphorylated Cx43 (Cx43-NP) and histological interstitial fibrosis were assessed from these mapped LV tissues. Longitudinal CV, which was slowed in HF (49 ± 1 vs. 65 ± 2 cm/s in Ctl), was positively correlated with reduced total junctional Cx43 and negatively correlated with markedly increased junctional Cx43-NP (2-fold) in HF. Cx43 dephosphorylation in HF was associated with enhanced colocalization of PP2A at the level of Cx43. Unchanged action potential upstroke and transverse CV were associated with unaltered Cx43 lateralization and interstitial fibrosis in the nonischemic HF canine LV.
CONCLUSION
Our unique arrhythmogenic canine model of HF resembles human nonischemic HF (prior to the end stage). Cx43 remodeling occurs prior to the structural remodeling (with lack of fibrosis) in HF and it is crucial in slowed CV and ventricular arrhythmia development. Our findings suggest that altered Cx43 alone is arrhythmogenic and modulation of Cx43 has the anti-arrhythmic therapeutic potential for HF patients.
Identifiants
pubmed: 34048725
pii: S0022-2828(21)00106-1
doi: 10.1016/j.yjmcc.2021.05.012
pmc: PMC8963384
mid: NIHMS1788237
pii:
doi:
Substances chimiques
Connexin 43
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
72-81Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL073966
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL113640
Pays : United States
Organisme : NHLBI NIH HHS
ID : R21 HL097268
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL146744
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA024769
Pays : United States
Informations de copyright
Copyright © 2021. Published by Elsevier Ltd.
Références
Circulation. 1995 Aug 15;92(4):1034-48
pubmed: 7543829
Front Cardiovasc Med. 2016 Mar 02;3:5
pubmed: 26973841
J Pharmacol Toxicol Methods. 2006 Jan-Feb;53(1):11-9
pubmed: 15886026
Circulation. 2005 Oct 18;112(16):2386-96
pubmed: 16203911
Biophys J. 1983 Oct;44(1):9-26
pubmed: 6626682
Circ Res. 2004 Oct 1;95(7):717-25
pubmed: 15345654
Circ Res. 2010 Apr 2;106(6):1153-63
pubmed: 20167932
J Mol Cell Cardiol. 2018 Jan;114:105-115
pubmed: 29146153
PLoS One. 2014 Aug 20;9(8):e105379
pubmed: 25140699
Circ Res. 2018 Mar 16;122(6):821-835
pubmed: 29352041
J Cardiovasc Electrophysiol. 2002 Sep;13(9):865-70
pubmed: 12380923
Circulation. 2004 Nov 16;110(20):3161-7
pubmed: 15533856
Am J Physiol. 1989 Aug;257(2 Pt 2):H681-9
pubmed: 2764148
Circulation. 2003 Jul 8;108(1):54-9
pubmed: 12821550
J Mol Cell Cardiol. 2005 Mar;38(3):475-83
pubmed: 15733907
J Am Coll Cardiol. 2002 Jan 2;39(1):116-23
pubmed: 11755296
Pharmacol Rev. 2017 Oct;69(4):396-478
pubmed: 28931622
J Mol Cell Cardiol. 2001 Feb;33(2):359-71
pubmed: 11162139
Am J Physiol Heart Circ Physiol. 2007 Aug;293(2):H1223-30
pubmed: 17434978
Cardiovasc Res. 2011 Oct 1;92(1):106-14
pubmed: 21727092
Neth Heart J. 2010 Oct;18(10):509-15
pubmed: 20978597
Circ Res. 1997 May;80(5):673-81
pubmed: 9130448
Biochim Biophys Acta. 2012 Aug;1818(8):2020-9
pubmed: 21839722
Circ Res. 1992 Feb;70(2):438-44
pubmed: 1310450
Am J Cardiol. 2014 May 15;113(10):1697-704
pubmed: 24698466
Circulation. 2012 Apr 17;125(15):1835-47
pubmed: 22412072
J Clin Invest. 1993 Jul;92(1):122-40
pubmed: 8325977
Basic Res Cardiol. 1992;87 Suppl 2:115-29
pubmed: 1299206
Prog Biophys Mol Biol. 2019 Jul;144:41-50
pubmed: 30241906
Am J Physiol Heart Circ Physiol. 2004 Oct;287(4):H1762-70
pubmed: 15205174
Circulation. 1996 Aug 1;94(3):384-9
pubmed: 8759080
Circulation. 1998 Dec 1;98(22):2404-14
pubmed: 9832485
Eur J Biochem. 1996 May 15;238(1):1-27
pubmed: 8665925
Circ Res. 2005 Jan 7;96(1):54-63
pubmed: 15576650
Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1164-73
pubmed: 18065522
J Clin Invest. 1997 Apr 15;99(8):1991-8
pubmed: 9109444
Circ Res. 1997 Nov;81(5):727-41
pubmed: 9351447
J Mol Cell Cardiol. 2017 Jun;107:52-57
pubmed: 28478048
J Am Coll Cardiol. 2012 Sep 18;60(12):1103-10
pubmed: 22883636
Cardiovasc Res. 2013 Mar 1;97(3):589-97
pubmed: 23241357
Heart Rhythm. 2008 Aug;5(8):1178-85
pubmed: 18675229
Heart Fail Rev. 2015 Nov;20(6):731-49
pubmed: 26423909
Circulation. 1985 Oct;72(4):681-5
pubmed: 2863012
Cardiovasc Res. 2010 Mar 1;85(4):751-62
pubmed: 19880431
Circ Res. 2001 Jun 8;88(11):1159-67
pubmed: 11397782
J Vis Exp. 2015 Mar 23;(97):
pubmed: 25867896
Biochim Biophys Acta Biomembr. 2018 Jan;1860(1):83-90
pubmed: 28414037
Cardiovasc Res. 2002 May;54(2):361-79
pubmed: 12062341
IEEE Trans Biomed Eng. 1998 May;45(5):563-71
pubmed: 9581054
J Cardiovasc Electrophysiol. 1995 Jun;6(6):498-510
pubmed: 7551319
J Pharmacol Methods. 1989 Nov;22(3):207-17
pubmed: 2586115
PLoS One. 2014 Aug 08;9(8):e104357
pubmed: 25105669
Int J Cardiol. 2017 Feb 1;228:881-885
pubmed: 27889555
Circ Res. 2004 Nov 12;95(10):1035-41
pubmed: 15499029