The mir-200 family regulates key pathogenic events in ascending aortas of individuals with bicuspid aortic valves.
Aorta
/ metabolism
Aortic Aneurysm
/ genetics
Aortic Valve
/ abnormalities
Bicuspid Aortic Valve Disease
Epithelial-Mesenchymal Transition
/ genetics
Female
Gene Expression Regulation
Heart Valve Diseases
/ pathology
Humans
Male
MicroRNAs
/ genetics
Proteomics
Signal Transduction
Zinc Finger E-box Binding Homeobox 2
/ genetics
Zinc Finger E-box-Binding Homeobox 1
/ genetics
aortic aneurysm
bicuspid aortic valve
microRNA
Journal
Journal of internal medicine
ISSN: 1365-2796
Titre abrégé: J Intern Med
Pays: England
ID NLM: 8904841
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
pubmed:
4
10
2018
medline:
22
11
2019
entrez:
4
10
2018
Statut:
ppublish
Résumé
An individual with a bicuspid aortic valve (BAV) runs a substantially higher risk of developing aneurysm in the ascending aorta compared to the normal population with tricuspid aortic valves (TAV). Aneurysm formation in patients with BAV and TAV is known to be distinct at the molecular level but the underlying mechanisms are undefined. Here, we investigated the still incompletely described role of microRNAs (miRNAs), important post-transcriptional regulators of gene expression, in such aortic disease of patients with BAV as compared with TAV. Using a system biology approach, based on data obtained from proteomic analysis of non-dilated aortas from BAV and TAV patients, we constructed a gene-interaction network of regulatory microRNAs associated with the observed differential protein signature. The miR-200 family was the highest ranked miRNA, hence potentially having the strongest effect on the signalling network associated with BAV. Further, qRT-PCR and ChIP analyses showed lower expression of miR-200c, higher expression of miR-200 target genes, ZEB1/ZEB2 transcription factors, and higher chromatin occupancy of the miR-200c promoter by ZEB1/ZEB2 in BAV patients, indicating a miR-200c/ZEBs negative feedback loop and induction of endothelial/epithelial mesenchymal transition (EndMT/EMT). We propose that a miR-200-dependent process of EndMT/EMT is a plausible biological mechanism rendering the BAV ascending aorta more prone to aneurysm development. Although initially supported by a miR-200c/ZEB feedback loop, this process is most probably advanced by cooperation of other miRNAs.
Sections du résumé
BACKGROUND
An individual with a bicuspid aortic valve (BAV) runs a substantially higher risk of developing aneurysm in the ascending aorta compared to the normal population with tricuspid aortic valves (TAV). Aneurysm formation in patients with BAV and TAV is known to be distinct at the molecular level but the underlying mechanisms are undefined. Here, we investigated the still incompletely described role of microRNAs (miRNAs), important post-transcriptional regulators of gene expression, in such aortic disease of patients with BAV as compared with TAV.
METHODS AND RESULTS
Using a system biology approach, based on data obtained from proteomic analysis of non-dilated aortas from BAV and TAV patients, we constructed a gene-interaction network of regulatory microRNAs associated with the observed differential protein signature. The miR-200 family was the highest ranked miRNA, hence potentially having the strongest effect on the signalling network associated with BAV. Further, qRT-PCR and ChIP analyses showed lower expression of miR-200c, higher expression of miR-200 target genes, ZEB1/ZEB2 transcription factors, and higher chromatin occupancy of the miR-200c promoter by ZEB1/ZEB2 in BAV patients, indicating a miR-200c/ZEBs negative feedback loop and induction of endothelial/epithelial mesenchymal transition (EndMT/EMT).
CONCLUSION
We propose that a miR-200-dependent process of EndMT/EMT is a plausible biological mechanism rendering the BAV ascending aorta more prone to aneurysm development. Although initially supported by a miR-200c/ZEB feedback loop, this process is most probably advanced by cooperation of other miRNAs.
Identifiants
pubmed: 30280445
doi: 10.1111/joim.12833
pmc: PMC6488227
mid: NIHMS1013365
doi:
Substances chimiques
MIRN200 microRNA, human
0
MicroRNAs
0
Zinc Finger E-box Binding Homeobox 2
0
Zinc Finger E-box-Binding Homeobox 1
0
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
102-114Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL138437
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL122596
Pays : United States
Organisme : NCATS NIH HHS
ID : UH3 TR002073
Pays : United States
Organisme : NCATS NIH HHS
ID : UH2 TR002073
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL124021
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2018 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Références
Biomed Res Int. 2015;2015:831641
pubmed: 26221607
Cancer Cell. 2013 Feb 11;23(2):186-99
pubmed: 23410973
Cancer Lett. 2014 Mar 28;344(2):166-73
pubmed: 24262661
J Biol Chem. 2011 Jul 22;286(29):25992-6002
pubmed: 21596753
EMBO J. 2014 Jul 17;33(14):1565-81
pubmed: 24920580
Mol Med. 2011;17(11-12):1365-73
pubmed: 21968790
Biochim Biophys Acta. 2016 Apr;1862(4):733-740
pubmed: 26876948
Sci Rep. 2016 Oct 25;6:35712
pubmed: 27779199
J Pathol. 2014 Feb;232(3):319-29
pubmed: 24122292
Am J Cancer Res. 2011;1(7):897-912
pubmed: 22016835
Int J Mol Sci. 2017 Nov 22;18(11):
pubmed: 29165337
N Engl J Med. 2014 May 15;370(20):1920-9
pubmed: 24827036
Plant Methods. 2007 Sep 24;3:11
pubmed: 17892552
Cancer Manag Res. 2014 Apr 25;6:205-16
pubmed: 24812525
Cell Biol Int. 2013 Jul;37(7):669-74
pubmed: 23483606
Front Physiol. 2017 Jun 16;8:429
pubmed: 28670289
Sci Rep. 2016 Feb 18;6:21117
pubmed: 26887353
Trends Cell Biol. 2008 Aug;18(8):357-9
pubmed: 18585040
Cell Div. 2017 Aug 29;12:6
pubmed: 28855958
J Am Coll Cardiol. 2014 Aug 26;64(8):832-9
pubmed: 25145529
Circulation. 2012 Apr 10;125(14):1795-808
pubmed: 22492947
PLoS One. 2012;7(4):e35440
pubmed: 22514743
Clin Exp Metastasis. 2011 Jan;28(1):27-38
pubmed: 21069438
J Transl Med. 2017 Apr 11;15(1):76
pubmed: 28399937
Oncotarget. 2015 Nov 10;6(35):38139-50
pubmed: 26497367
EMBO Rep. 2008 Jun;9(6):582-9
pubmed: 18483486
Genes Dev. 2008 Apr 1;22(7):894-907
pubmed: 18381893
Nat Cell Biol. 2009 Dec;11(12):1487-95
pubmed: 19935649
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15805-10
pubmed: 17890317
Nat Rev Mol Cell Biol. 2014 Mar;15(3):178-96
pubmed: 24556840
J Clin Invest. 2014 Aug;124(8):3514-28
pubmed: 24960162
Circ Res. 2011 Sep 2;109(6):649-57
pubmed: 21778427
Oncol Rep. 2016 Oct;36(4):2108-16
pubmed: 27498672
Adv Biol Regul. 2015 Jan;57:10-6
pubmed: 25482988
Cell Mol Life Sci. 2012 Oct;69(20):3429-56
pubmed: 22945800
J Cell Physiol. 2017 Nov;232(11):2938-2945
pubmed: 28112397
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Sci Rep. 2018 Feb 9;8(1):2777
pubmed: 29426841
Int J Cancer. 2013 Feb 15;132(4):745-54
pubmed: 22753312
Int J Mol Sci. 2013 Jul 12;14(7):14647-58
pubmed: 23857059
Proc Natl Acad Sci U S A. 1983 Jun;80(12):3734-7
pubmed: 6407019
Genome Biol. 2010;11(5):R53
pubmed: 20482850
Development. 2001 May;128(9):1531-8
pubmed: 11290292
Arterioscler Thromb Vasc Biol. 2011 Mar;31(3):691-7
pubmed: 21148425
PLoS One. 2014 Nov 19;9(11):e113700
pubmed: 25409297
PLoS One. 2008 Mar 12;3(3):e1798
pubmed: 18335064
J Intern Med. 2019 Jan;285(1):102-114
pubmed: 30280445
EMBO Rep. 2010 Sep;11(9):670-7
pubmed: 20706219
Cell. 2004 Sep 3;118(5):649-63
pubmed: 15339668
Elife. 2015 Aug 12;4:
pubmed: 26267216