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http://purl.uniprot.org/citations/35836108http://www.w3.org/2000/01/rdf-schema#comment"

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/β-catenin signaling was activated during hypertrophy and restrained by METTL3 or miR-221/222 inhibition. The Wnt/β-catenin antagonist DKK2 was directly targeted by miR-221/222, and the effect of miR-221/222 inhibitor on Wnt/β-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/β-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."xsd:string
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http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/author"Chen X."xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/author"Ji Z."xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/author"Su Y."xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/author"Zhang R."xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/author"Yang M."xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/author"Yao Y."xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/author"Qu Y."xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/author"Ma G."xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/author"Zuo W."xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/author"Hao C."xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/date"2022"xsd:gYear
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/name"Cell Mol Biol Lett"xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/pages"55"xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/title"METTL3 mediates Ang-II-induced cardiac hypertrophy through accelerating pri-miR-221/222 maturation in an m6A-dependent manner."xsd:string
http://purl.uniprot.org/citations/35836108http://purl.uniprot.org/core/volume"27"xsd:string
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