METTL3 mediates Ang-II-induced cardiac hypertrophy through accelerating pri-miR-221/222 maturation in an m6A-dependent manner.
Cell Mol Biol Lett
; 27(1): 55, 2022 Jul 14.
Article
in En
| MEDLINE
| ID: mdl-35836108
ABSTRACT
BACKGROUND:
METTL3 is the core catalytic enzyme in m6A and is involved in a variety of cardiovascular diseases. However, whether and how METTL3 plays a role during angiotensin II (Ang-II)-induced myocardial hypertrophy is still unknown.METHODS:
Neonatal rat cardiomyocytes (NRCMs) and C57BL/6J mice were treated with Ang-II to induce myocardial hypertrophy. qRT-PCR and western blots were used to detect the expression of RNAs and proteins. Gene function was verified by knockdown and/or overexpression, respectively. Luciferase and RNA immunoprecipitation (RIP) assays were used to verify interactions among multiple genes. Wheat germ agglutinin (WGA), hematoxylin and eosin (H&E), and immunofluorescence were used to examine myocardial size. m6A methylation was detected by a colorimetric kit.RESULTS:
METTL3 and miR-221/222 expression and m6A levels were significantly increased in response to Ang-II stimulation. Knockdown of METTL3 or miR-221/222 could completely abolish the ability of NRCMs to undergo hypertrophy. The expression of miR-221/222 was positively regulated by METTL3, and the levels of pri-miR-221/222 that bind to DGCR8 or form m6A methylation were promoted by METTL3 in NRCMs. The effect of METTL3 knockdown on hypertrophy was antagonized by miR-221/222 overexpression. Mechanically, Wnt/ß-catenin signaling was activated during hypertrophy and restrained by METTL3 or miR-221/222 inhibition. The Wnt/ß-catenin antagonist DKK2 was directly targeted by miR-221/222, and the effect of miR-221/222 inhibitor on Wnt/ß-catenin was abolished after inhibition of DKK2. Finally, AAV9-mediated cardiac METTL3 knockdown was able to attenuate Ang-II-induced cardiac hypertrophy in mouse model.CONCLUSIONS:
Our findings suggest that METTL3 positively modulates the pri-miR221/222 maturation process in an m6A-dependent manner and subsequently activates Wnt/ß-catenin signaling by inhibiting DKK2, thus promoting Ang-II-induced cardiac hypertrophy. AAV9-mediated cardiac METTL3 knockdown could be a therapeutic for pathological myocardial hypertrophy.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Angiotensin II
/
MicroRNAs
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Cell Mol Biol Lett
Journal subject:
BIOLOGIA MOLECULAR
Year:
2022
Document type:
Article
Publication country:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
/
UK
/
UNITED KINGDOM