Store-operated calcium entry via ORAI1 regulates doxorubicin-induced apoptosis and prevents cardiotoxicity in cardiac fibroblasts.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2022
2022
Historique:
received:
24
07
2022
accepted:
18
11
2022
entrez:
6
12
2022
pubmed:
7
12
2022
medline:
15
12
2022
Statut:
epublish
Résumé
Despite exhibiting cardiotoxicity, doxorubicin (DOX) is widely used for cancer treatments. Cardiac fibroblasts (CFs) are important in the pathogenesis of heart failure. This necessitates the study of the effect of DOX on CFs. The impairment of calcium (Ca2+) homeostasis is a common mechanism of heart failure. Store-operated Ca2+ entry (SOCE) is a receptor-regulated Ca2⁺ entry pathway that maintains calcium balance by sensing reduced calcium stores in the endoplasmic reticulum. ORAI1, a calcium channel protein and the most important component of SOCE, is highly expressed in human cardiac fibroblasts (HCFs). It is upregulated in CFs from failing ventricles. However, whether ORAI1 in HCFs is increased and/or plays a role in DOX-induced cardiotoxicity remains unknown. In this study, we aimed to elucidate the relationship between ORAI1/SOCE and DOX-induced heart failure. Induction of apoptosis by DOX was characterized in HCFs. Apoptosis and cell cycle analyses were performed by fluorescence-activated cell sorting (FACS). Reactive oxygen species (ROS) production was measured using fluorescence. YM-58483 was used as an ORAI1/SOCE inhibitor. ORAI1-knockdown cells were established by RNA interference. In vivo experiments were performed by intraperitoneally injecting YM-58483 and DOX into mice. We first demonstrated that DOX significantly increased the protein expression level of p53 in HCFs by western blotting. FACS analysis revealed that DOX increased early apoptosis and induced cell cycle arrest in the G2 phase in fibroblasts. DOX also increased ROS production. DOX significantly increased the expression level of ORAI1 in CFs. Both YM-58483 and ORAI1 gene knockdown attenuated DOX-induced apoptosis. Similarly, YM-58483 attenuated cell cycle arrest in the G2 phase, and ORAI1 knockdown attenuated DOX-induced ROS production in HCFs. In the animal experiment, YM-58483 attenuated DOX-induced apoptosis. In HCFs, ORAI1/SOCE regulates p53 expression and plays an important role in DOX-induced cardiotoxicity. ORAI1 may serve as a new target for preventing DOX-induced heart failure.
Identifiants
pubmed: 36472998
doi: 10.1371/journal.pone.0278613
pii: PONE-D-22-18663
pmc: PMC9725120
doi:
Substances chimiques
4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide
0
Calcium
SY7Q814VUP
Tumor Suppressor Protein p53
0
Doxorubicin
80168379AG
ORAI1 protein, human
0
ORAI1 Protein
0
Orai1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0278613Informations de copyright
Copyright: © 2022 Nemoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
J Mol Cell Cardiol. 2020 Feb;139:124-134
pubmed: 31958463
J Biochem Mol Toxicol. 2021 Sep;35(9):e22842
pubmed: 34273911
Eur J Pharmacol. 2018 Jan 5;818:241-253
pubmed: 29074412
J Am Coll Cardiol. 2014 Sep 2;64(9):938-45
pubmed: 25169180
J Mol Cell Cardiol. 2016 May;94:22-31
pubmed: 26996756
Microcirculation. 2013 May;20(4):330-6
pubmed: 23312019
Oxid Med Cell Longev. 2017;2017:1521020
pubmed: 29181122
Pharm Biol. 2016 Jul;54(7):1289-97
pubmed: 26440532
Phytomedicine. 2022 Jan 29;99:153964
pubmed: 35180677
Cancer. 2003 Jun 1;97(11):2869-79
pubmed: 12767102
J Histochem Cytochem. 2007 Jun;55(6):629-39
pubmed: 17312011
N Engl J Med. 2001 Mar 15;344(11):783-92
pubmed: 11248153
Toxicol Appl Pharmacol. 2018 Jun 1;348:1-13
pubmed: 29653124
PLoS One. 2019 Sep 12;14(9):e0221940
pubmed: 31513610
Front Pharmacol. 2021 Apr 15;11:603596
pubmed: 33935690
J Mol Cell Cardiol. 2004 Oct;37(4):837-46
pubmed: 15380674
Eur J Pharmacol. 2020 Jan 5;866:172818
pubmed: 31758940
Biol Open. 2017 Mar 15;6(3):326-332
pubmed: 28126709
PLoS One. 2014 Feb 21;9(2):e89292
pubmed: 24586666
Am J Physiol Lung Cell Mol Physiol. 2019 Jan 1;316(1):L216-L228
pubmed: 30358436
Eur Rev Med Pharmacol Sci. 2016 Jun;20(11):2435-42
pubmed: 27338072
Eur Heart J. 2016 Sep 21;37(36):2768-2801
pubmed: 27567406
Sci Rep. 2018 Apr 19;8(1):6277
pubmed: 29674727
Inflammation. 2017 Jun;40(3):778-787
pubmed: 28168659
Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H933-9
pubmed: 14766674
Life Sci. 1999;65(9):925-33
pubmed: 10465352
PLoS One. 2020 Sep 22;15(9):e0238856
pubmed: 32960902
ESC Heart Fail. 2020 Apr;7(2):588-603
pubmed: 31984667
Toxicol Lett. 2019 Jun 1;307:41-48
pubmed: 30817977
Eur J Pharmacol. 2007 Apr 10;560(2-3):225-33
pubmed: 17307161
Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19626-19634
pubmed: 31488712
Cardiovasc Res. 2014 Jul 1;103(1):81-9
pubmed: 24812279
Exp Mol Med. 2006 Oct 31;38(5):535-45
pubmed: 17079870
Physiol Rep. 2018 May;6(9):e13687
pubmed: 29722156
J Clin Invest. 1997 Jun 1;99(11):2635-43
pubmed: 9169493
Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1736-44
pubmed: 18263706
Mitochondrion. 2010 Nov;10(6):649-61
pubmed: 20601193
Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2606-13
pubmed: 16687611
Int Immunopharmacol. 2008 Dec 20;8(13-14):1787-92
pubmed: 18793756