Duality of Nrf2 in iron-overload cardiomyopathy.


Journal

Haematologica
ISSN: 1592-8721
Titre abrégé: Haematologica
Pays: Italy
ID NLM: 0417435

Informations de publication

Date de publication:
01 05 2023
Historique:
received: 30 08 2022
medline: 3 5 2023
pubmed: 27 1 2023
entrez: 26 1 2023
Statut: epublish

Résumé

Cardiomyopathy deeply affects quality of life and mortality of patients with b-thalassemia or with transfusion-dependent myelodysplastic syndromes. Recently, a link between Nrf2 activity and iron metabolism has been reported in liver ironoverload murine models. Here, we studied C57B6 mice as healthy control and nuclear erythroid factor-2 knockout (Nrf2-/-) male mice aged 4 and 12 months. Eleven-month-old wild-type and Nrf2-/- mice were fed with either standard diet or a diet containing 2.5% carbonyl-iron (iron overload [IO]) for 4 weeks. We show that Nrf2-/- mice develop an age-dependent cardiomyopathy, characterized by severe oxidation, degradation of SERCA2A and iron accumulation. This was associated with local hepcidin expression and increased serum non-transferrin-bound iron, which promotes maladaptive cardiac remodeling and interstitial fibrosis related to overactivation of the TGF-b pathway. When mice were exposed to IO diet, the absence of Nrf2 was paradoxically protective against further heart iron accumulation. Indeed, the combination of prolonged oxidation and the burst induced by IO diet resulted in activation of the unfolded protein response (UPR) system, which in turn promotes hepcidin expression independently from heart iron accumulation. In the heart of Hbbth3/+ mice, a model of b-thalassemia intermedia, despite the activation of Nrf2 pathway, we found severe protein oxidation, activation of UPR system and cardiac fibrosis independently from heart iron content. We describe the dual role of Nrf2 when aging is combined with IO and its novel interrelation with UPR system to ensure cell survival. We open a new perspective for early and intense treatment of cardiomyopathy in patients with b-thalassemia before the appearance of heart iron accumulation.

Identifiants

pubmed: 36700398
doi: 10.3324/haematol.2022.281995
pmc: PMC10153524
doi:

Substances chimiques

Hepcidins 0
Iron E1UOL152H7
NF-E2-Related Factor 2 0
Nfe2l2 protein, mouse 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1335-1348

Références

Blood. 2019 Jan 17;133(3):252-265
pubmed: 30404812
J Mol Cell Cardiol. 2018 Jan;114:20-28
pubmed: 29055654
Am J Nephrol. 2016;44(5):368-378
pubmed: 27771699
BMC Cardiovasc Disord. 2019 Nov 6;19(1):245
pubmed: 31694552
Cardiovasc Res. 2020 Apr 1;116(5):1021-1031
pubmed: 31373602
Front Cell Dev Biol. 2021 Oct 01;9:721795
pubmed: 34660582
Acta Neuropathol Commun. 2021 May 3;9(1):81
pubmed: 33941276
Life Sci. 2020 Aug 15;255:117838
pubmed: 32450168
J Cardiol. 2020 Mar;75(3):219-227
pubmed: 31699567
Nat Metab. 2019 May;1(5):519-531
pubmed: 31276102
Crit Rev Oncol Hematol. 2014 Jul;91(1):64-73
pubmed: 24529413
Curr Opin Rheumatol. 2012 Nov;24(6):663-8
pubmed: 22918530
Free Radic Biol Med. 2017 Nov;112:376-386
pubmed: 28801243
Blood. 2018 Feb 22;131(8):899-910
pubmed: 29237594
Cell Death Dis. 2020 Mar 13;11(3):186
pubmed: 32170070
Am J Hematol. 2015 Apr;90(4):310-3
pubmed: 25557851
Free Radic Biol Med. 2021 May 1;167:218-231
pubmed: 33741451
J Mol Cell Cardiol. 2015 Jul;84:143-53
pubmed: 25935309
Antioxid Redox Signal. 2015 Dec 1;23(16):1284-97
pubmed: 26058667
Antioxid Redox Signal. 2018 Dec 10;29(17):1756-1773
pubmed: 28793787
Oxid Med Cell Longev. 2013;2013:985210
pubmed: 24205432
Am J Hematol. 2009 Jan;84(1):29-33
pubmed: 19006228
Front Cell Dev Biol. 2021 Aug 25;9:669188
pubmed: 34513823
Exp Biol Med (Maywood). 2017 Jun;242(11):1126-1135
pubmed: 28485683
Circulation. 2011 Feb 8;123(5):504-14
pubmed: 21262993
Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1843-50
pubmed: 19592468
Mol Genet Metab. 2014 Jul;112(3):224-8
pubmed: 24857410
Front Physiol. 2016 Mar 15;7:93
pubmed: 27014091
J Cereb Blood Flow Metab. 2014 Mar;34(3):425-32
pubmed: 24301296
Circ Res. 2011 Mar 4;108(5):629-42
pubmed: 21372294
Science. 2009 Aug 14;325(5942):877-80
pubmed: 19679815
Theriogenology. 2019 Jan 15;124:9-17
pubmed: 30321755
Cardiovasc Res. 2011 May 1;90(2):315-24
pubmed: 21245055
Am J Hematol. 2020 Feb;95(2):188-197
pubmed: 31737919
J Biol Chem. 2010 Apr 30;285(18):13721-35
pubmed: 20194497
Expert Opin Ther Targets. 2009 Jul;13(7):785-94
pubmed: 19530984
Exp Cell Res. 2016 Dec 10;349(2):282-290
pubmed: 27816607
PLoS One. 2012;7(9):e44899
pubmed: 23028668
Lancet Haematol. 2018 May;5(5):e201-e210
pubmed: 29628397
Diabetes Metab J. 2017 Feb;41(1):10-19
pubmed: 28236381
Heart Fail Clin. 2017 Jul;13(3):417-426
pubmed: 28602363
Front Physiol. 2021 May 25;12:665622
pubmed: 34122136
Circulation. 2011 Nov 15;124(20):2253-63
pubmed: 22083147
Am J Hematol. 2021 Jan;96(1):110-127
pubmed: 32945012
Physiol Genomics. 2018 Feb 1;50(2):77-97
pubmed: 29187515
Circulation. 1990 Jul;82(1):88-94
pubmed: 2364528
J Card Fail. 2010 Nov;16(11):888-900
pubmed: 21055653
Basic Res Cardiol. 2013 Jul;108(4):360
pubmed: 23740218
J Cell Physiol. 2014 Oct;229(10):1503-10
pubmed: 24648278
Endocrinology. 2007 Jun;148(6):2663-8
pubmed: 17363462
Science. 2004 Dec 17;306(5704):2090-3
pubmed: 15514116
Biochim Biophys Acta. 2013 Jul;1832(7):940-7
pubmed: 23201247
Exp Mol Med. 2017 Nov 10;49(11):e389
pubmed: 29123254
Circ Res. 2004 Jun 25;94(12):1543-53
pubmed: 15217919
Circulation. 2013 Mar 26;127(12):1317-29
pubmed: 23446829
Free Radic Biol Med. 2015 Dec;89:906-17
pubmed: 26475037
Eur Heart J. 2020 Jul 21;41(28):2681-2695
pubmed: 30903157
Ann N Y Acad Sci. 2010 Aug;1202:1-9
pubmed: 20712765
Antioxid Redox Signal. 2018 Jan 1;28(1):1-14
pubmed: 28793778
Am J Physiol Heart Circ Physiol. 2006 Jan;290(1):H128-36
pubmed: 16155100
Am J Physiol. 1999 Aug;277(2):H584-94
pubmed: 10444483
Diabetes. 2017 Feb;66(2):529-542
pubmed: 27903744
Physiol Rev. 2013 Oct;93(4):1721-41
pubmed: 24137020
Front Pharmacol. 2021 Jul 07;12:683156
pubmed: 34305596
Curr Mol Med. 2018;18(10):661-671
pubmed: 30714521
Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2672-2680
pubmed: 30692261
Braz J Med Biol Res. 2017 Apr 13;50(5):e5742
pubmed: 28423119
Aging (Albany NY). 2020 Mar 17;12(6):4836-4865
pubmed: 32182211
J Biol Chem. 2002 Apr 5;277(14):12343-50
pubmed: 11805088
Sci Rep. 2015 Dec 07;5:18132
pubmed: 26638758

Auteurs

Enrica Federti (E)

Department of Medicine, University of Verona and AOUI Verona, Verona.

Francesca Vinchi (F)

Iron Research Laboratory, Lindsley Kimball Research Institute, New York Blood Center, New York, NY, USA; Dept. of Pathology and Laboratory Medicine, Weill Cornell Medicine.

Iana Iatcenko (I)

Department of Medicine, University of Verona and AOUI Verona, Verona.

Alessandra Ghigo (A)

Department Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center "Guido Tarrone", University of Torino, Torino.

Alessandro Matte (A)

Department of Medicine, University of Verona and AOUI Verona, Verona.

Serge Cedrick Mbiandjeu Toya (SCM)

Department of Medicine, University of Verona and AOUI Verona, Verona.

Angela Siciliano (A)

Department of Medicine, University of Verona and AOUI Verona, Verona.

Deborah Chiabrando (D)

Department Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center "Guido Tarrone", University of Torino, Torino.

Emanuela Tolosano (E)

Department Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center "Guido Tarrone", University of Torino, Torino.

Steven Zebulon Vance (SZ)

Iron Research Laboratory, Lindsley Kimball Research Institute, New York Blood Center, New York, NY.

Veronica Riccardi (V)

Department of Medicine, University of Verona and AOUI Verona, Verona.

Immacolata Andolfo (I)

Department of Molecular Medicine and Medical Biotechnologies, Federico II University of Naples; CEINGE - Biotecnologie Avanzate, Naples.

Manuela Iezzi (M)

Department of Medicine and Aging Science, "G. d'Annunzio" University of Chieti, Chieti.

Alessia Lamolinara (A)

Department of Medicine and Aging Science, "G. d'Annunzio" University of Chieti, Chieti.

Achille Iolascon (A)

Department of Molecular Medicine and Medical Biotechnologies, Federico II University of Naples; CEINGE - Biotecnologie Avanzate, Naples.

Lucia De Franceschi (L)

Department of Medicine, University of Verona and AOUI Verona, Verona. lucia.defranceschi@univr.it.

Articles similaires

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female
Humans United States Aged Cross-Sectional Studies Medicare Part C
1.00
Humans Yoga Low Back Pain Female Male
Humans Meals Time Factors Female Adult

Classifications MeSH