Decrease of Pdzrn3 is required for heart maturation and protects against heart failure.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
07 01 2022
07 01 2022
Historique:
received:
08
06
2021
accepted:
24
11
2021
entrez:
8
1
2022
pubmed:
9
1
2022
medline:
24
2
2022
Statut:
epublish
Résumé
Heart failure is the final common stage of most cardiopathies. Cardiomyocytes (CM) connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between CM. Yet no factor on its own is known to coordinate CM polarized organization. We have previously shown that PDZRN3, an ubiquitine ligase E3 expressed in various tissues including the heart, mediates a branch of the Planar cell polarity (PCP) signaling involved in tissue patterning, instructing cell polarity and cell polar organization within a tissue. PDZRN3 is expressed in the embryonic mouse heart then its expression dropped significantly postnatally corresponding with heart maturation and CM polarized elongation. A moderate CM overexpression of Pdzrn3 (Pdzrn3 OE) during the first week of life, induced a severe eccentric hypertrophic phenotype with heart failure. In models of pressure-overload stress heart failure, CM-specific Pdzrn3 knockout showed complete protection against degradation of heart function. We reported that Pdzrn3 signaling induced PKC ζ expression, c-Jun nuclear translocation and a reduced nuclear ß catenin level, consistent markers of the planar non-canonical Wnt signaling in CM. We then show that subcellular localization (intercalated disk) of junction proteins as Cx43, ZO1 and Desmoglein 2 was altered in Pdzrn3 OE mice, which provides a molecular explanation for impaired CM polarization in these mice. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of CM, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.
Identifiants
pubmed: 34996942
doi: 10.1038/s41598-021-03795-7
pii: 10.1038/s41598-021-03795-7
pmc: PMC8742099
doi:
Substances chimiques
beta Catenin
0
PDZRN3 protein, mouse
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Protein Kinase C
EC 2.7.11.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8Subventions
Organisme : Agence National de la Recherche ANR -16-CE17-0001-01
ID : ANR -16-CE17-0001-01
Informations de copyright
© 2022. The Author(s).
Références
Balse, E. et al. Dynamic of ion channel expression at the plasma membrane of cardiomyocytes. Physiol. Rev. 92, 1317–1358 (2012).
pubmed: 22811429
doi: 10.1152/physrev.00041.2011
Le Garrec, J.-F. et al. Quantitative analysis of polarity in 3D reveals local cell coordination in the embryonic mouse heart. Development 140, 395–404 (2013).
pubmed: 23250213
doi: 10.1242/dev.087940
Yang, Y. & Mlodzik, M. Wnt-frizzled/planar cell polarity signaling: Cellular orientation by facing the wind (Wnt). Annu. Rev. Cell Dev. Biol. 31, 623–646 (2015).
pubmed: 26566118
pmcid: 4673888
doi: 10.1146/annurev-cellbio-100814-125315
Pandur, P., Lasche, M., Eisenberg, L. M. & Kuhl, M. Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis. Nature 418, 636–641 (2002).
pubmed: 12167861
doi: 10.1038/nature00921
Nagy, I. et al. Wnt-11 signalling controls ventricular myocardium development by patterning N-cadherin and beta-catenin expression. Cardiovasc. Res. 85, 100–109 (2010).
pubmed: 19622544
doi: 10.1093/cvr/cvp254
Henderson, D. J. et al. Cardiovascular defects associated with abnormalities in midline development in the Loop-tail mouse mutant. Circ. Res. 89, 6–12 (2001).
pubmed: 11440971
doi: 10.1161/hh1301.092497
Leung, C., Lu, X., Liu, M. & Feng, Q. Rac1 signaling is critical to cardiomyocyte polarity and embryonic heart development. J. Am. Heart Assoc. 3, e001271 (2014).
pubmed: 25315346
pmcid: 4323834
doi: 10.1161/JAHA.114.001271
Sewduth, R. N. et al. The ubiquitin ligase PDZRN3 is required for vascular morphogenesis through Wnt/planar cell polarity signalling. Nat. Commun. 5, 4832 (2014).
pubmed: 25198863
doi: 10.1038/ncomms5832
Sewduth, R. N. et al. PDZRN3 destabilizes endothelial cell-cell junctions through a PKCzeta-containing polarity complex to increase vascular permeability. Sci. Signaling 10, 464 (2017).
doi: 10.1126/scisignal.aag3209
Ho, H. et al. Mechanisms of Wnt5a-ror signaling in development and disease. FASEB J. 34, 1–1 (2020).
Chhabra, E. S. & Higgs, H. N. The many faces of actin: Matching assembly factors with cellular structures. Nat. Cell Biol. 9, 1110–1121 (2007).
pubmed: 17909522
doi: 10.1038/ncb1007-1110
Gottardi, C. J., Arpin, M., Fanning, A. S. & Louvard, D. The junction-associated protein, zonula occludens-1, localizes to the nucleus before the maturation and during the remodeling of cell-cell contacts. Proc. Natl. Acad. Sci. 93, 10779–10784 (1996).
pubmed: 8855257
pmcid: 38232
doi: 10.1073/pnas.93.20.10779
Yoshida, M. et al. Alterations in adhesion junction precede gap junction remodelling during the development of heart failure in cardiomyopathic hamsters. Cardiovasc. Res. 92, 95–105 (2011).
pubmed: 21693625
doi: 10.1093/cvr/cvr182
Krusche, C. A. et al. Desmoglein 2 mutant mice develop cardiac fibrosis and dilation. Basic Res. Cardiol. 106, 617–633 (2011).
pubmed: 21455723
pmcid: 3105238
doi: 10.1007/s00395-011-0175-y
Schlipp, A. et al. Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function. Cardiovasc. Res. 104, 245–257 (2014).
pubmed: 25213555
doi: 10.1093/cvr/cvu206
Porrello, E. R. & Olson, E. N. A neonatal blueprint for cardiac regeneration. Stem Cell Res. 13, 556–570 (2014).
pubmed: 25108892
pmcid: 4316722
doi: 10.1016/j.scr.2014.06.003
Heineke, J. & Molkentin, J. D. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat. Rev. Mol. Cell Biol. 7, 589–600 (2006).
pubmed: 16936699
doi: 10.1038/nrm1983
Hoshijima, M. & Chien, K. R. Mixed signals in heart failure: Cancer rules. J. Clin. Invest. 109, 849–855 (2002).
pubmed: 11927610
pmcid: 150934
doi: 10.1172/JCI0215380
Nomura, S. et al. Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure. Nat. Commun. 9, 4435 (2018).
pubmed: 30375404
pmcid: 6207673
doi: 10.1038/s41467-018-06639-7
Gessert, S. & Kühl, M. The multiple phases and faces of wnt signaling during cardiac differentiation and development. Circ. Res. 107, 186–199 (2010).
pubmed: 20651295
doi: 10.1161/CIRCRESAHA.110.221531
Jeong, M.-H. et al. Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling. Proc. Natl. Acad. Sci. USA 114, E1345–E1354 (2017).
pubmed: 28154134
pmcid: 5338397
doi: 10.1073/pnas.1615105114
Mazzotta, S. et al. Distinctive roles of canonical and noncanonical wnt signaling in human embryonic cardiomyocyte development. Stem Cell Rep. 7, 764–776 (2016).
doi: 10.1016/j.stemcr.2016.08.008
Malekar, P. et al. Wnt signaling is critical for maladaptive cardiac hypertrophy and accelerates myocardial remodeling. Hypertension 55, 939–945 (2010).
pubmed: 20177000
doi: 10.1161/HYPERTENSIONAHA.109.141127
Haq, S. et al. Stabilization of beta-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth. Proc. Natl. Acad. Sci. USA. 100, 4610–4615 (2003).
pubmed: 12668767
pmcid: 153603
doi: 10.1073/pnas.0835895100
Blankesteijn, W. M., van de Schans, V. A., ter Horst, P. & Smits, J. F. The Wnt/frizzled/GSK-3 beta pathway: S novel therapeutic target for cardiac hypertrophy. Trends Pharmacol. Sci. 29, 175–180 (2008).
pubmed: 18342376
doi: 10.1016/j.tips.2008.01.003
Qu, J. et al. Cardiac-specific haploinsufficiency of beta-catenin attenuates cardiac hypertrophy but enhances fetal gene expression in response to aortic constriction. J. Mol. Cell. Cardiol. 43, 319–326 (2007).
pubmed: 17673255
pmcid: 2084259
doi: 10.1016/j.yjmcc.2007.06.006
Petrich, B. G. et al. Targeted activation of c-Jun N-terminal kinase in vivo induces restrictive cardiomyopathy and conduction defects. J. Biol. Chem. 279, 15330–15338 (2004).
pubmed: 14742426
doi: 10.1074/jbc.M314142200
Abdul-Ghani, M. et al. Wnt11 promotes cardiomyocyte development by caspase-mediated suppression of canonical wnt signals. Mol. Cell. Biol. 31, 163–178 (2011).
pubmed: 21041481
doi: 10.1128/MCB.01539-09
Toyofuku, T. et al. Direct association of the gap junction protein connexin-43 with ZO-1 in cardiac myocytes. J. Biol. Chem. 273, 12725–12731 (1998).
pubmed: 9582296
doi: 10.1074/jbc.273.21.12725
Barker, R. J., Price, R. L. & Gourdie, R. G. Increased association of ZO-1 with connexin43 during remodeling of cardiac gap junctions. Circ. Res. 90, 317–324 (2002).
pubmed: 11861421
doi: 10.1161/hh0302.104471
Laing, J. G., Tadros, P. N., Westphale, E. M. & Beyer, E. C. Degradation of connexin43 gap junctions involves both the proteasome and the lysosome. Exp. Cell Res. 236, 482–492 (1997).
pubmed: 9367633
doi: 10.1006/excr.1997.3747
Danik, S. B. et al. Modulation of cardiac gap junction expression and arrhythmic susceptibility. Circ. Res. 95, 1035–1041 (2004).
pubmed: 15499029
pmcid: 2956442
doi: 10.1161/01.RES.0000148664.33695.2a
Gutstein, D. E. et al. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ. Res. 88, 333–339 (2001).
pubmed: 11179202
pmcid: 3630465
doi: 10.1161/01.RES.88.3.333
van Rijen, H. V. M. et al. Slow conduction and enhanced anisotropy increase the propensity for ventricular tachyarrhythmias in adult mice with induced deletion of connexin43. Circulation 109, 1048–1055 (2004).
pubmed: 14967725
doi: 10.1161/01.CIR.0000117402.70689.75
Saffitz, J. E. Arrhythmogenic cardiomyopathy and abnormalities of cell-to-cell coupling. Heart Rhythm 6, S62–S65 (2009).
pubmed: 19541548
doi: 10.1016/j.hrthm.2009.03.003
Eshkind, L. Loss of desmoglein 2 suggests essential functions for early embryonic development and proliferation of embryonal stem cells. Eur. J. Cell Biol. 81, 592–598 (2002).
pubmed: 12494996
doi: 10.1078/0171-9335-00278
Maron, B. J. et al. Contemporary definitions and classification of the cardiomyopathies: An American Heart Association Scientific Statement From the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 113, 1807–1816 (2006).
pubmed: 16567565
doi: 10.1161/CIRCULATIONAHA.106.174287
Debus, J. D. et al. In vitro analysis of arrhythmogenic cardiomyopathy associated desmoglein-2 (DSG2) mutations reveals diverse glycosylation patterns. J. Mol. Cell. Cardiol. 129, 303–313 (2019).
pubmed: 30885746
doi: 10.1016/j.yjmcc.2019.03.014
Gutstein, D. E. The organization of adherens junctions and desmosomes at the cardiac intercalated disc is independent of gap junctions. J. Cell Sci. 116, 875–885 (2003).
pubmed: 12571285
doi: 10.1242/jcs.00258
Nekrasova, O. E. et al. Desmosomal cadherins utilize distinct kinesins for assembly into desmosomes. J. Cell Biol. 195, 1185–1203 (2011).
pubmed: 22184201
pmcid: 3246898
doi: 10.1083/jcb.201106057
Ehler, E. et al. Alterations at the intercalated disk associated with the absence of muscle LIM protein. J. Cell Biol. 153, 763–772 (2001).
pubmed: 11352937
pmcid: 2192386
doi: 10.1083/jcb.153.4.763
Ferreira-Cornwell, M. C. et al. Remodeling the intercalated disc leads to cardiomyopathy in mice misexpressing cadherins in the heart. J. Cell Sci. 115, 1623–1634 (2002).
pubmed: 11950881
doi: 10.1242/jcs.115.8.1623
Phillips, H. M. et al. Disruption of planar cell polarity signaling results in congenital heart defects and cardiomyopathy attributable to early cardiomyocyte disorganization. Circ. Res. 101, 137–145 (2007).
pubmed: 17556662
doi: 10.1161/CIRCRESAHA.106.142406
Bruce, A. F., Rothery, S., Dupont, E. & Severs, N. J. Gap junction remodelling in human heart failure is associated with increased interaction of connexin43 with ZO-1. Cardiovasc. Res. 77, 757–765 (2008).
pubmed: 18056766
doi: 10.1093/cvr/cvm083
Laing, J. G., Saffitz, J. E., Steinberg, T. H. & Yamada, K. A. Diminished zonula occludens-1 expression in the failing human heart. Cardiovasc. Pathol. 16, 159–164 (2007).
pubmed: 17502245
doi: 10.1016/j.carpath.2007.01.004
Kostin, S. Zonula occludens-1 and connexin 43 expression in the failing human heart. J. Cell Mol. Med. 11, 892–895 (2007).
pubmed: 17760848
pmcid: 3823265
doi: 10.1111/j.1582-4934.2007.00063.x
Sepp, R., Severs, N. J. & Gourdie, R. G. Altered patterns of cardiac intercellular junction distribution in hypertrophic cardiomyopathy. Heart 76, 412–417 (1996).
pubmed: 8944586
pmcid: 484572
doi: 10.1136/hrt.76.5.412
Severs, N. J., Bruce, A. F., Dupont, E. & Rothery, S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc. Res. 80, 9–19 (2008).
pubmed: 18519446
pmcid: 2533424
doi: 10.1093/cvr/cvn133
Hong, T.-T. et al. BIN1 is reduced and Cav12 trafficking is impaired in human failing cardiomyocytes. Heart Rhythm 9, 812–820 (2012).
pubmed: 22138472
doi: 10.1016/j.hrthm.2011.11.055
Smyth, J. W. et al. Limited forward trafficking of connexin 43 reduces cell-cell coupling in stressed human and mouse myocardium. J. Clin. Invest. 120, 266–279 (2010).
pubmed: 20038810
doi: 10.1172/JCI39740
Sohal, D. S. et al. Temporally regulated and tissue-specific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible cre protein. Circ. Res. 89, 20–25 (2001).
pubmed: 11440973
doi: 10.1161/hh1301.092687
https://fr.freedownloadmanager.org/Windows-PC/LabChart.html .
https://imagej.net/Fiji . Accessed 24 Jan 2020.
https://www.bruker.com/.../infrared-and-raman/opus-spectroscopy-software/downloads.html .
Hackett, M. J. et al. Subcellular biochemical investigation of Purkinje neurons using synchrotron radiation Fourier transform infrared spectroscopic imaging with a focal plane array detector. ACS Chem. Neurosci. 4, 1071–1080 (2013).
pubmed: 23638613
pmcid: 3715895
doi: 10.1021/cn4000346
https://www.graphpad.com/scientific-software/prism/ (2020).