In vivo miR-138-5p inhibition alleviates monocrotaline-induced pulmonary hypertension and normalizes pulmonary KCNK3 and SLC45A3 expression.
Administration, Inhalation
Animals
Antagomirs
/ administration & dosage
Arterial Pressure
Cell Proliferation
Cells, Cultured
Disease Models, Animal
Gene Expression Regulation
Humans
Male
MicroRNAs
/ antagonists & inhibitors
Monocrotaline
Monosaccharide Transport Proteins
/ genetics
Nerve Tissue Proteins
/ genetics
Potassium Channels, Tandem Pore Domain
/ genetics
Pulmonary Arterial Hypertension
/ genetics
Pulmonary Artery
/ metabolism
Rats, Wistar
Signal Transduction
Vascular Remodeling
KCNK3
PAH
Proliferation
SLC45A3
miR-138
Journal
Respiratory research
ISSN: 1465-993X
Titre abrégé: Respir Res
Pays: England
ID NLM: 101090633
Informations de publication
Date de publication:
16 Jul 2020
16 Jul 2020
Historique:
received:
22
04
2020
accepted:
06
07
2020
entrez:
18
7
2020
pubmed:
18
7
2020
medline:
10
6
2021
Statut:
epublish
Résumé
The pathogenesis of pulmonary arterial hypertension (PAH) involves many signalling pathways. MicroRNAs are potential candidates involved in simultaneously coordinating multiple genes under such multifactorial conditions. MiR-138-5p is overexpressed in pulmonary arterial smooth muscle cells (PASMCs) from PAH patients and in lungs from rats with monocrotaline-induced pulmonary hypertension (MCT-PH). MiR-138-5p is predicted to regulate the expression of the potassium channel KCNK3, whose loss is associated with the development and progression of PAH. We hypothesized that, in vivo, miR-138-5p inhibition would restore KCNK3 lung expression and subsequently alleviate PAH. Nebulization-based delivery of anti-miR-138-5p to rats with established MCT-PH significantly reduced the right ventricular systolic pressure and significantly improved the pulmonary arterial acceleration time (PAAT). These haemodynamic improvements were related to decrease pulmonary vascular remodelling, lung inflammation and pulmonary vascular cell proliferation in situ. In vivo inhibition of miR-138-5p restored KCNK3 mRNA expression and SLC45A3 protein expression in the lungs. We confirmed that in vivo inhibition of miR-138-5p reduces the development of PH in experimental MCT-PH. The possible curative mechanisms involve at least the normalization of lung KCNK3 as well as SLC45A3 expression.
Sections du résumé
BACKGROUND
BACKGROUND
The pathogenesis of pulmonary arterial hypertension (PAH) involves many signalling pathways. MicroRNAs are potential candidates involved in simultaneously coordinating multiple genes under such multifactorial conditions.
METHODS AND RESULTS
RESULTS
MiR-138-5p is overexpressed in pulmonary arterial smooth muscle cells (PASMCs) from PAH patients and in lungs from rats with monocrotaline-induced pulmonary hypertension (MCT-PH). MiR-138-5p is predicted to regulate the expression of the potassium channel KCNK3, whose loss is associated with the development and progression of PAH. We hypothesized that, in vivo, miR-138-5p inhibition would restore KCNK3 lung expression and subsequently alleviate PAH. Nebulization-based delivery of anti-miR-138-5p to rats with established MCT-PH significantly reduced the right ventricular systolic pressure and significantly improved the pulmonary arterial acceleration time (PAAT). These haemodynamic improvements were related to decrease pulmonary vascular remodelling, lung inflammation and pulmonary vascular cell proliferation in situ. In vivo inhibition of miR-138-5p restored KCNK3 mRNA expression and SLC45A3 protein expression in the lungs.
CONCLUSIONS
CONCLUSIONS
We confirmed that in vivo inhibition of miR-138-5p reduces the development of PH in experimental MCT-PH. The possible curative mechanisms involve at least the normalization of lung KCNK3 as well as SLC45A3 expression.
Identifiants
pubmed: 32678044
doi: 10.1186/s12931-020-01444-7
pii: 10.1186/s12931-020-01444-7
pmc: PMC7364627
doi:
Substances chimiques
Antagomirs
0
MIRN138 microRNA, human
0
MIRN138 microRNA, rat
0
MicroRNAs
0
Monosaccharide Transport Proteins
0
Nerve Tissue Proteins
0
Potassium Channels, Tandem Pore Domain
0
potassium channel subfamily K member 3
1HQ3YCN4GS
Monocrotaline
73077K8HYV
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
186Subventions
Organisme : Agence Nationale de la Recherche
ID : ANR-18-CE14-0023
Références
Oncotarget. 2017 May 26;8(43):74106-74118
pubmed: 29088771
Cardiovasc Res. 2018 May 1;114(6):880-893
pubmed: 29360952
Annu Rev Immunol. 2008;26:677-704
pubmed: 18173375
Stem Cells. 2014 Jun;32(6):1380-9
pubmed: 24497003
Mol Cancer. 2016 Dec 15;15(1):82
pubmed: 27978829
J Mol Cell Cardiol. 2018 May;118:208-224
pubmed: 29634917
Curr Opin Oncol. 2016 Jan;28(1):72-82
pubmed: 26569423
Circulation. 2016 Apr 5;133(14):1371-85
pubmed: 26912814
Adv Exp Med Biol. 2015;888:237-52
pubmed: 26663186
Am J Physiol Renal Physiol. 2000 Nov;279(5):F793-801
pubmed: 11053038
Mol Med Rep. 2018 Feb;17(2):3021-3027
pubmed: 29257242
Cancer Cell. 2015 Apr 13;27(4):450-61
pubmed: 25858804
Circulation. 2015 Jul 14;132(2):82-92
pubmed: 25951834
Eur Respir Rev. 2013 Dec;22(130):543-51
pubmed: 24293470
PLoS One. 2013 Nov 11;8(11):e78684
pubmed: 24244340
Anal Cell Pathol (Amst). 2015;2015:326385
pubmed: 26345623
Am J Respir Crit Care Med. 2017 Feb 15;195(4):515-529
pubmed: 27648837
Clin Genet. 2017 Mar;91(3):453-457
pubmed: 27649371
Mol Aspects Med. 2013 Apr-Jun;34(2-3):655-60
pubmed: 23506898
Chest. 2017 Apr;151(4):821-828
pubmed: 27884767
BMC Pulm Med. 2017 Apr 7;17(1):57
pubmed: 28388887
Eur Respir J. 2019 Jan 24;53(1):
pubmed: 30545976
Cell Oncol (Dordr). 2015 Jun;38(3):173-81
pubmed: 25875420
J Biol Chem. 2000 Sep 15;275(37):28398-405
pubmed: 10880510
J Exp Med. 2011 Mar 14;208(3):535-48
pubmed: 21321078
Biochem J. 2013 Jun 1;452(2):281-91
pubmed: 23485012
Genes Chromosomes Cancer. 2019 Apr;58(4):244-253
pubmed: 30578699
Biochem Biophys Res Commun. 2015 Aug 7;463(4):1159-64
pubmed: 26079878
J Hypertens. 2018 May;36(5):1164-1177
pubmed: 29369849
Circ Res. 2016 Mar 4;118(5):822-33
pubmed: 26838788
Circ Res. 2019 Sep 13;125(7):678-695
pubmed: 31347976
Circulation. 2015 Sep 1;132(9):834-47
pubmed: 26130118
Am J Physiol Lung Cell Mol Physiol. 2020 Jan 1;318(1):L10-L26
pubmed: 31553627
N Engl J Med. 2013 Jul 25;369(4):351-361
pubmed: 23883380
Am J Transl Res. 2019 Oct 15;11(10):6619-6631
pubmed: 31737212
Curr Pharm Des. 2020;25(43):4613-4621
pubmed: 31486753