Transient Introduction of miR-294 in the Heart Promotes Cardiomyocyte Cell Cycle Reentry After Injury.
cell cycle
embryonic stem cells
microRNAs
myocardial infarction
myocardium
Journal
Circulation research
ISSN: 1524-4571
Titre abrégé: Circ Res
Pays: United States
ID NLM: 0047103
Informations de publication
Date de publication:
21 06 2019
21 06 2019
Historique:
pubmed:
10
4
2019
medline:
4
4
2020
entrez:
10
4
2019
Statut:
ppublish
Résumé
Embryonic heart is characterized of rapidly dividing cardiomyocytes required to build a working myocardium. Cardiomyocytes retain some proliferative capacity in the neonates but lose it in adulthood. Consequently, a number of signaling hubs including microRNAs are altered during cardiac development that adversely impacts regenerative potential of cardiac tissue. Embryonic stem cell cycle miRs are a class of microRNAs exclusively expressed during developmental stages; however, their effect on cardiomyocyte proliferation and heart function in adult myocardium has not been studied previously. To determine whether transient reintroduction of embryonic stem cell cycle miR-294 promotes cardiomyocyte cell cycle reentry enhancing cardiac repair after myocardial injury. miR-294 is expressed in the heart during development, prenatal stages, lost in the neonate, and adult heart confirmed by qRT-PCR and in situ hybridization. Neonatal ventricular myocytes treated with miR-294 showed elevated expression of Ki67, p-histone H3, and Aurora B confirmed by immunocytochemistry compared with control cells. miR-294 enhanced oxidative phosphorylation and glycolysis in Neonatal ventricular myocytes measured by seahorse assay. Mechanistically, miR-294 represses Wee1 leading to increased activity of the cyclin B1/CDK1 complex confirmed by qRT-PCR and immunoblot analysis. Next, a doxycycline-inducible AAV9-miR-294 vector was delivered to mice for activating miR-294 in myocytes for 14 days continuously after myocardial infarction. miR-294-treated mice significantly improved left ventricular functions together with decreased infarct size and apoptosis 8 weeks after MI. Myocyte cell cycle reentry increased in miR-294 hearts analyzed by Ki67, pH3, and AurB (Aurora B kinase) expression parallel to increased small myocyte number in the heart. Isolated adult myocytes from miR-294 hearts showed increased 5-ethynyl-2'-deoxyuridine+ cells and upregulation of cell cycle markers and miR-294 targets 8 weeks after MI. Ectopic transient expression of miR-294 recapitulates developmental signaling and phenotype in cardiomyocytes promoting cell cycle reentry that leads to augmented cardiac function in mice after myocardial infarction.
Identifiants
pubmed: 30964391
doi: 10.1161/CIRCRESAHA.118.314223
pmc: PMC6586499
mid: NIHMS1526733
doi:
Substances chimiques
MIRN294 microRNA, mouse
0
MicroRNAs
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
14-25Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL126186
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL091983
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL137850
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL134608
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL135117
Pays : United States
Organisme : American Heart Association-American Stroke Association
ID : 15SDG25550038
Pays : United States
Commentaires et corrections
Type : CommentIn
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