AAV1.SERCA2a Gene Therapy Reverses Pulmonary Fibrosis by Blocking the STAT3/FOXM1 Pathway and Promoting the SNON/SKI Axis.
Animals
DNA-Binding Proteins
/ metabolism
Dependovirus
/ genetics
Disease Models, Animal
Fibroblasts
/ metabolism
Forkhead Box Protein M1
/ metabolism
Gene Expression
Genetic Therapy
Genetic Vectors
/ genetics
Humans
Intracellular Signaling Peptides and Proteins
/ metabolism
Proto-Oncogene Proteins
/ metabolism
Pulmonary Fibrosis
/ genetics
STAT3 Transcription Factor
/ metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases
/ genetics
Signal Transduction
SERCA2a
TGF-β signaling
adeno-associated virus
bleomycin
gene therapy
pulmonary fibrosis
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
05 02 2020
05 02 2020
Historique:
received:
27
06
2019
revised:
08
11
2019
accepted:
11
11
2019
pubmed:
28
12
2019
medline:
29
12
2020
entrez:
28
12
2019
Statut:
ppublish
Résumé
Inhibition of pulmonary fibrosis (PF) by restoring sarco/endoplasmic reticulum calcium ATPase 2a isoform (SERCA2a) expression using targeted gene therapy may be a potentially powerful new treatment approach for PF. Here, we found that SERCA2a expression was significantly decreased in lung samples from patients with PF and in the bleomycin (BLM) mouse model of PF. In the BLM-induced PF model, intratracheal aerosolized adeno-associated virus serotype 1 (AAV1) encoding for human SERCA2a (AAV1.hSERCA2a) reduces lung fibrosis and associated vascular remodeling. SERCA2a gene therapy also decreases right ventricular pressure and hypertrophy in both prevention and curative protocols. In vitro, we observed that SERCA2a overexpression inhibits fibroblast proliferation, migration, and fibroblast-to-myofibroblast transition induced by transforming growth factor β (TGF-β1). Thus, pro-fibrotic gene expression is prevented by blocking nuclear factor κB (NF-κB)/interleukin-6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3) activation. This effect is signaled toward an inhibitory mechanism of small mother against decapentaplegic (SMAD)/TGF-β signaling through the repression of OTU deubiquitinase, ubiquitin aldehyde binding 1 (OTUB1) and Forkhead box M1 (FOXM1). Interestingly, this cross-inhibition leads to an increase of SKI and SnoN expression, an auto-inhibitory feedback loop of TGF-β signaling. Collectively, our results demonstrate that SERCA2a gene transfer attenuates bleomycin (BLM)-induced PF by blocking the STAT3/FOXM1 pathway and promoting the SNON/SKI Axis. Thus, SERCA2a gene therapy may be a potential therapeutic target for PF.
Identifiants
pubmed: 31879190
pii: S1525-0016(19)30553-2
doi: 10.1016/j.ymthe.2019.11.027
pmc: PMC7001085
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Forkhead Box Protein M1
0
Intracellular Signaling Peptides and Proteins
0
Proto-Oncogene Proteins
0
SKIL protein, human
0
STAT3 Transcription Factor
0
SKI protein, human
126648-96-2
Sarcoplasmic Reticulum Calcium-Transporting ATPases
EC 3.6.3.8
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
394-410Subventions
Organisme : NHLBI NIH HHS
ID : P50 HL112324
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL119046
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL117505
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007824
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128072
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL135093
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133554
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL129814
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL131404
Pays : United States
Organisme : NHLBI NIH HHS
ID : K01 HL135474
Pays : United States
Informations de copyright
Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.
Références
Cell. 2002 Nov 1;111(3):357-67
pubmed: 12419246
Circulation. 2013 Jul 30;128(5):512-23
pubmed: 23804254
Nat Immunol. 2004 Jan;5(1):45-54
pubmed: 14661020
Antioxid Redox Signal. 2011 Apr 1;14(7):1245-59
pubmed: 20836702
Am J Respir Cell Mol Biol. 2012 Jun;46(6):757-64
pubmed: 22268139
Am J Respir Crit Care Med. 2015 Jul 15;192(2):e3-19
pubmed: 26177183
Respiration. 2014;88(6):487-99
pubmed: 25359084
Respiration. 2011;82(3):294-304
pubmed: 21677422
J Clin Pathol. 1988 Apr;41(4):467-70
pubmed: 3366935
EMBO Mol Med. 2012 Sep;4(9):939-51
pubmed: 22684844
Am J Pathol. 2012 Apr;180(4):1340-55
pubmed: 22387320
Am J Respir Cell Mol Biol. 2013 Dec;49(6):1093-101
pubmed: 23885794
Int J Rheumatol. 2011;2011:721608
pubmed: 21941555
Am J Respir Cell Mol Biol. 2011 Jul;45(1):1-15
pubmed: 21057104
Nat Commun. 2013;4:2519
pubmed: 24071738
Kidney Int. 2016 Dec;90(6):1285-1297
pubmed: 27616741
J Clin Invest. 2014 Feb;124(2):564-79
pubmed: 24382352
Cell Mol Life Sci. 2016 Apr;73(7):1439-55
pubmed: 26762302
Chest. 2006 Mar;129(3):746-52
pubmed: 16537877
Eur Respir J. 2015 Oct;46(4):1113-30
pubmed: 26424523
Am J Respir Cell Mol Biol. 2015 Oct;53(4):450-8
pubmed: 25664495
Oncogene. 2016 Mar 17;35(11):1433-44
pubmed: 26148240
J Cell Physiol. 2019 Jun;234(6):9052-9064
pubmed: 30378114
J Am Coll Cardiol. 2016 May 3;67(17):2032-46
pubmed: 27126531
Mol Biol Cell. 2018 Jan 15;29(2):84-95
pubmed: 29142074
Respirology. 2009 Sep;14(7):917-33
pubmed: 19740254
Proc Am Thorac Soc. 2008 Apr 15;5(3):334-7
pubmed: 18403329
Chem Biol Drug Des. 2018 Apr;91(4):933-941
pubmed: 29250925
Clinicoecon Outcomes Res. 2018 Feb 22;10:127-137
pubmed: 29503576
FASEB J. 2016 Jan;30(1):129-40
pubmed: 26324850
Nat Struct Mol Biol. 2013 Sep;20(9):1033-9
pubmed: 23955022
Chest. 2007 Mar;131(3):657-663
pubmed: 17356077
J Am Soc Nephrol. 2003 Dec;14(12):3167-77
pubmed: 14638915
Am J Respir Crit Care Med. 2007 Oct 1;176(7):636-43
pubmed: 17585107
Proc Am Thorac Soc. 2006 Nov;3(8):696-702
pubmed: 17065376
Oncogene. 2017 May 25;36(21):3059-3066
pubmed: 27893707
Int J Mol Sci. 2018 Aug 05;19(8):null
pubmed: 30081609
Arthritis Res Ther. 2018 Mar 15;20(1):46
pubmed: 29544542
Toxicol Res. 2010 Sep;26(3):217-22
pubmed: 24278527
Am J Physiol Lung Cell Mol Physiol. 2002 Mar;282(3):L585-93
pubmed: 11839555
Respir Res. 2018 Feb 06;19(1):24
pubmed: 29409529
Oncogene. 2005 May 12;24(21):3397-408
pubmed: 15735721
J Biol Chem. 2014 Apr 4;289(14):9952-60
pubmed: 24550394
Small. 2013 Nov 25;9(22):3799-811
pubmed: 23650105
Proc Am Thorac Soc. 2012 Jul;9(3):111-6
pubmed: 22802283
Int J Biochem Cell Biol. 2008;40(3):362-82
pubmed: 17936056
PLoS One. 2013;8(2):e55794
pubmed: 23418461
Front Med (Lausanne). 2018 Mar 20;5:43
pubmed: 29616220
Front Pharmacol. 2017 Jul 14;8:461
pubmed: 28769795
Mucosal Immunol. 2014 May;7(3):684-93
pubmed: 24172847
Oncogene. 2016 Aug 18;35(33):4422
pubmed: 27345395
Curr Opin Genet Dev. 2004 Feb;14(1):65-70
pubmed: 15108807
Thorax. 2018 Jun;73(6):519-529
pubmed: 29440315
Cytokine. 2011 Mar;53(3):327-33
pubmed: 21185199
Mol Cell Biol. 1990 May;10(5):2327-34
pubmed: 2183031
Mayo Clin Proc. 2014 Aug;89(8):1130-42
pubmed: 24867394
Am J Respir Crit Care Med. 2013 Sep 15;188(6):733-48
pubmed: 24032382
Am J Respir Cell Mol Biol. 2008 May;38(5):566-71
pubmed: 18096870
Arthritis Res Ther. 2017 May 31;19(1):112
pubmed: 28569204
Cancer Res. 2010 May 15;70(10):4204-13
pubmed: 20460516
Methods Mol Biol. 2017;1627:27-42
pubmed: 28836192
Am J Respir Crit Care Med. 2003 Sep 1;168(5):538-42
pubmed: 12773325
Respir Res. 2015 Aug 20;16:99
pubmed: 26289430