Prolyl 4-Hydroxylase Domain Protein 3-Inhibited Smooth-Muscle-Cell Dedifferentiation Improves Cardiac Perivascular Fibrosis Induced by Obstructive Sleep Apnea.
Animals
Cardiomyopathies
/ etiology
Cell Dedifferentiation
/ genetics
Cell Hypoxia
/ genetics
Disease Models, Animal
Fibrosis
/ etiology
Gene Expression Regulation
/ genetics
Humans
Mice
Myocytes, Smooth Muscle
/ metabolism
Procollagen-Proline Dioxygenase
/ genetics
Sleep Apnea, Obstructive
/ complications
Journal
BioMed research international
ISSN: 2314-6141
Titre abrégé: Biomed Res Int
Pays: United States
ID NLM: 101600173
Informations de publication
Date de publication:
2019
2019
Historique:
received:
29
12
2018
revised:
10
04
2019
accepted:
02
06
2019
entrez:
27
7
2019
pubmed:
28
7
2019
medline:
9
1
2020
Statut:
epublish
Résumé
Intermittent hypoxia (IH) induced by obstructive sleep apnea (OSA) is a leading factor affecting cardiovascular fibrosis. Under IH condition, smooth muscle cells (SMAs) respond by dedifferentiation, which is associated with vascular remodelling. The expression of prolyl 4-hydroxylase domain protein 3 (PHD3) increases under hypoxia. However, the role of PHD3 in OSA-induced SMA dedifferentiation and cardiovascular fibrosis remains uncertain. We explored the mechanism of cardiovascular remodelling in C57BL/6 mice exposed to IH for 3 months and investigated the mechanism of PHD3 in improving the remodelling in vivo and vitro. In vivo remodelling showed that IH induced cardiovascular fibrosis via SMC dedifferentiation and that fibrosis improved when PHD3 was overexpressed. In vitro remodelling showed that IH induced SMA dedifferentiation, which secretes much collagen I. PHD3 overexpression in cultured SMCs reversed the dedifferentiation by degrading and inactivating HIF-1 OSA-induced cardiovascular fibrosis was associated with SMC dedifferentiation, and PHD3 overexpression may benefit its prevention by reversing the dedifferentiation. Therefore, PHD3 overexpression has therapeutic potential in disease treatment.
Sections du résumé
BACKGROUND
BACKGROUND
Intermittent hypoxia (IH) induced by obstructive sleep apnea (OSA) is a leading factor affecting cardiovascular fibrosis. Under IH condition, smooth muscle cells (SMAs) respond by dedifferentiation, which is associated with vascular remodelling. The expression of prolyl 4-hydroxylase domain protein 3 (PHD3) increases under hypoxia. However, the role of PHD3 in OSA-induced SMA dedifferentiation and cardiovascular fibrosis remains uncertain.
METHODS
METHODS
We explored the mechanism of cardiovascular remodelling in C57BL/6 mice exposed to IH for 3 months and investigated the mechanism of PHD3 in improving the remodelling in vivo and vitro.
RESULTS
RESULTS
In vivo remodelling showed that IH induced cardiovascular fibrosis via SMC dedifferentiation and that fibrosis improved when PHD3 was overexpressed. In vitro remodelling showed that IH induced SMA dedifferentiation, which secretes much collagen I. PHD3 overexpression in cultured SMCs reversed the dedifferentiation by degrading and inactivating HIF-1
CONCLUSION
CONCLUSIONS
OSA-induced cardiovascular fibrosis was associated with SMC dedifferentiation, and PHD3 overexpression may benefit its prevention by reversing the dedifferentiation. Therefore, PHD3 overexpression has therapeutic potential in disease treatment.
Identifiants
pubmed: 31346526
doi: 10.1155/2019/9174218
pmc: PMC6621170
doi:
Substances chimiques
PHD3 protein, mouse
EC 1.14.11.2
Procollagen-Proline Dioxygenase
EC 1.14.11.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9174218Références
J Appl Physiol (1985). 2001 Apr;90(4):1600-5
pubmed: 11247966
Am J Respir Crit Care Med. 2002 May 1;165(9):1217-39
pubmed: 11991871
Biochem Cell Biol. 2002;80(4):421-6
pubmed: 12234095
J Cell Sci. 2003 Apr 1;116(Pt 7):1319-26
pubmed: 12615973
Lancet. 2005 Mar 19-25;365(9464):1046-53
pubmed: 15781100
J Appl Physiol (1985). 2005 Nov;99(5):2028-35
pubmed: 16002771
Biochem J. 2007 Jan 1;401(1):217-26
pubmed: 16958618
Am J Respir Crit Care Med. 2008 Mar 1;177(5):544-54
pubmed: 18006889
Mol Biol Cell. 2008 May;19(5):2231-40
pubmed: 18337469
Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4745-50
pubmed: 18347341
Int J Cardiol. 2010 Feb 18;139(1):7-16
pubmed: 19505734
Cardiovasc Res. 2010 Oct 1;88(1):196-204
pubmed: 20498255
Eur Respir J. 2011 May;37(5):1137-43
pubmed: 20817711
Am J Respir Cell Mol Biol. 2011 Jul;45(1):154-62
pubmed: 20870895
Nat Rev Cardiol. 2010 Dec;7(12):677-85
pubmed: 21079639
Cardiovasc Res. 2012 Jul 15;95(2):156-64
pubmed: 22406749
Hypertens Res. 2012 Aug;35(8):811-8
pubmed: 22495609
J Cardiol. 2012 Nov;60(5):416-21
pubmed: 22867802
Nat Rev Cardiol. 2012 Dec;9(12):679-88
pubmed: 23007221
Biol Chem. 2013 Apr;394(4):449-57
pubmed: 23380539
Am J Epidemiol. 2013 May 1;177(9):1006-14
pubmed: 23589584
Oncogene. 2014 Apr 17;33(16):2053-64
pubmed: 23728336
Lancet. 2014 Feb 22;383(9918):736-47
pubmed: 23910433
Lancet Respir Med. 2013 Mar;1(1):61-72
pubmed: 24321805
J Biomed Res. 2014 Jan;28(1):40-6
pubmed: 24474962
Int J Cardiol. 2014 Mar 1;172(1):202-12
pubmed: 24485636
J Cell Physiol. 2014 Oct;229(10):1511-20
pubmed: 24615545
Am J Physiol Lung Cell Mol Physiol. 2014 Jul 15;307(2):L129-40
pubmed: 24838748
Biochim Biophys Acta. 2015 Apr;1849(4):448-53
pubmed: 24937434
Am J Respir Crit Care Med. 2014 Oct 15;190(8):958-61
pubmed: 25317468
Sleep. 2014 Nov 01;37(11):1757-65
pubmed: 25364071
Nat Commun. 2014 Nov 25;5:5582
pubmed: 25420773
Mol Cancer. 2015 Jul 30;14:143
pubmed: 26223520
Chest. 2016 Jun;149(6):1400-8
pubmed: 26836908
Circ Res. 2016 Feb 19;118(4):692-702
pubmed: 26892967
In Vitro Cell Dev Biol Anim. 2017 Jan;53(1):58-66
pubmed: 27632054
Cardiovasc Res. 2017 Apr 1;113(5):519-530
pubmed: 28165114
J Am Coll Cardiol. 2017 Feb 21;69(7):841-858
pubmed: 28209226
J Am Heart Assoc. 2017 Oct 19;6(10):null
pubmed: 29051216
N Engl J Med. 1993 Apr 29;328(17):1230-5
pubmed: 8464434