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METTL14 aggravates pyroptosis in diabetic cardiomyopathy by promoting m6A modification of NLRP3
Zhao Hua1, Fangjie Zhong2, Chaofen Xu2
1Department of Endocrine, Nanming District, Gui Yang Sixth Hospital, No. 42, Fuyuan South Road, Nanming District, Guiyang City, 550005, Guizhou Province, China. gylyhuazhao@126.com.
Abstract:
Diabetic cardiomyopathy (DCM) is an irreversible chronic cardiovascular complication of diabetes with a high mortality rate. This study aimed to explore the role of methyltransferase-like 14 (METTL14)-mediated m6A modification in DCM. Here, DCM mouse models and high glucose (HG)-induced H9C2 cell models were employed. Cell phenotype was assessed using CCK-8 assay, lactate dehydrogenase (LDH) assay, Western blot, and flow cytometry. The underlying mechanism was investigated using quantitative real-time PCR (qPCR), methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and dual-luciferase reporter assay. The results showed that METTL14 was upregulated in vitro and in vivo. Downregulation of METTL14 inhibited pyroptosis and myocardial damage. Mechanistically, METTL14 enhanced NLRP3 stability through m6A modification of NLRP3. Moreover, the m6A reader protein YTHDF1 (YTH N6-methyladenosine RNA-binding protein 1) mediated NLRP3 upregulation. This study revealed a novel mechanism by which METTL14-mediated m6A methylation regulates DCM progression, providing a potential therapeutic target for DCM.
Insights
Methyltransferase-like 14 (METTL14) promotes diabetic cardiomyopathy (DCM) by enhancing NLRP3 stability via m6A modification. Inhibiting METTL14 may offer a new therapeutic strategy for treating this serious diabetes complication.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiology
Background:
- Diabetic cardiomyopathy (DCM) is a severe complication of diabetes, leading to high mortality.
- The molecular mechanisms underlying DCM progression require further elucidation.
Purpose of the Study:
- To investigate the role of methyltransferase-like 14 (METTL14) and its mediated m6A modification in diabetic cardiomyopathy.
- To explore the potential of targeting METTL14 as a therapeutic strategy for DCM.
Main Methods:
- Established diabetic cardiomyopathy (DCM) mouse models and high glucose-induced H9C2 cell models.
- Utilized cell assays (CCK-8, LDH), Western blot, flow cytometry, qPCR, MeRIP, RIP, and dual-luciferase reporter assays.
- Investigated the interaction between METTL14, m6A modification, NLRP3, and YTHDF1.
Main Results:
- METTL14 expression was significantly upregulated in both in vitro and in vivo DCM models.
- Downregulation of METTL14 effectively inhibited pyroptosis and reduced myocardial damage.
- METTL14 promotes NLRP3 stability and upregulation through m6A modification, with YTHDF1 acting as a key reader protein.
Conclusions:
- METTL14-mediated m6A modification plays a crucial role in regulating diabetic cardiomyopathy progression.
- The METTL14/m6A/NLRP3 pathway represents a novel mechanism contributing to DCM.
- Targeting METTL14 offers a promising therapeutic avenue for managing diabetic cardiomyopathy.
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