Abstract
N6-methyladenosine (m6A) is one of the most important epigenetic regulation of RNAs, such as lncRNAs. However, the underlying regulatory mechanism of m6A in diabetic cardiomyopathy (DCM) is very limited. In this study, we sought to define the role of METTL14-mediated m6A modification in pyroptosis and DCM progression. DCM rat model was established and qRT-PCR, western blot, and immunohistochemistry (IHC) were used to detect the expression of METTL14 and TINCR. Gain-and-loss functional experiments were performed to define the role of METTL14-TINCR-NLRP3 axis in pyroptosis and DCM. RNA pulldown and RNA immunoprecipitation (RIP) assays were carried out to verify the underlying interaction. Our results showed that pyroptosis was tightly involved in DCM progression. METTL14 was downregulated in cardiomyocytes and hear tissues of DCM rat tissues. Functionally, METTL14 suppressed pyroptosis and DCM via downregulating lncRNA TINCR, which further decreased the expression of key pyroptosis-related protein, NLRP3. Mechanistically, METTL14 increased m6A methylation level of TINCR gene, resulting in its downregulation. Moreover, the m6A reader protein YTHDF2 was essential for m6A methylation and mediated the degradation of TINCR. Finally, TINCR positively regulated NLRP3 by increasing its mRNA stability. To conclude, our work revealed the novel role of METTL14-mediated m6A methylation and lncRNA regulation in pyroptosis and DCM, which could help extend our understanding the epigenetic regulation of pyroptosis in DCM progression.
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Background
Diabetic cardiomyopathy (DCM), a major cardiovascular complication of diabetes, is characterized by myocardial fibrosis, ventricular remodeling, and cardiac dysfunction [1]. DCM is closely associated with the occurrence of heart failure, making it the majority cause of death among patients with diabetes [2]. DCM influences heart healthy through various mechanisms, including changes in metabolism, abnormal subcellular composition, and damage of microvascular [3]. However, the detailed mechanism of DCM is not well known and remains elusive. Revealing the key genes involved in DCM and identifying the potential regulatory mechanism will provide therapeutic targets used for overcoming DCM.
Pyroptosis is characterized by rapid plasma membrane rupture, with the consequent release of intracellular contents and pro-inflammatory mediators, such as caspase-1 [4]. The main signaling pathway involved in pyroptosis is mediated by caspase-1 activation, resulting in the maturation process of IL-1β, IL-18, and gasdermin D (GSDMD) [5]. Previous studies widely reported the essential role of pyroptosis in cardiomyopathy, especially in DCM [6]. ** novel therapeutic strategies to overcome DCM.
Data availability
The analyzed data sets generated during the study are available from the corresponding author on reasonable request.
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Funding
This study is supported by the National Natural Science Foundation of China (No. 82000252, 81900345); Project From Health Department of Zhejiang Provincial (2021RC032); Medical and Health Science and Technology Plan Project of Shaoxing City (2020A13018).
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Authors and Affiliations
Contributions
LM, HL, FP and SW mainly designed and did the research. XH and JW collected and analyzed the data.
