Epigenetic control of LncRNA NEAT1 enables cardiac fibroblast pyroptosis and cardiac fibrosis

Cardiac fibroblasts (CFs) are the main orchestrators of extracellular matrix (ECM) remodeling after left ventricular (LV) pressure overload and leading to fibrosis and diastolic dysfunction (Kalyanasundaram et al., 2021). Recent studies indicated that CFs pyroptosis is implicated in cardiac fibrosis (Shi et al., 2021). The nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome is an inflammatory complex existing in CFs pyroptosis (Nazir et al., 2017). NLRP3 activation promotes the secretion of the inflammatory cytokine interleukin-18/1β (IL-18/1β) and induces cell pyroptosis (de Almeida et al., 2015). Mechanistically, cell pyroptosis is driven by two main signaling pathways-one mediated by caspase-1 and the other by caspase-4/5/11 (Ruhl et al., 2018). Besides, some roles of long noncoding RNAs (lncRNAs) in cell pyroptosis have been recently studied (Zhang et al., 2020). Nevertheless, detailed reports on lncRNAs regulating CFs pyroptosis biology and describing their implication in cardiac fibrosis are still missing.

LncRNAs exhibit a variety of biological functions through transcriptional and post-transcriptional regulation of target genes (Quinn and Chang, 2016). It is well documented that lncRNAs can fold into structural units and form complexes with proteins to regulate different functions, including cell pyroptosis (Xu et al., 2020)and differentiation (Frank et al., 2019). LncRNA NEAT1 is explicitly localized to nuclear bodies, called paraspeckles, which are irregularly shaped compartments in the interchromatin of the nucleus and are involved in the development of the mammary gland (Zhang et al., 2019). Reports suggest that lncRNA NEAT1 plays a role in various developmental and disease scenarios, including fibrotic disease (Kaucsar et al., 2022). However, the functional studies of lncRNA NEAT1 regulating CFs pyroptosis are not as advanced.

Recent discoveries have marked lncRNAs as new important players regulated by DNA methylation (Lu et al., 2020). DNA methylation accomplished by the joint action of three S-adenosylmethionine (SAM)-dependent DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) plays a critical role in fibrosis disease (Dixon et al., 2021). For example, dysregulation of DNA methylation in the promoter of H19 during calcific aortic valve disease promotes an osteogenic program by interfering with the expression of NOTCH1 (Hadji et al., 2016). However, it was not clear whether DNA methylation-related dysregulation of lncRNA NEAT1 occurs during CFs pyroptosis and cardiac fibrosis.

In this work, we discovered that the down-regulation of lncRNA NEAT1 regulated by DNMT3A facilitates CFs pyroptosis via the NLRP3 axis. We propose that this novel DNA methylation regulatory mechanism may underlie the lncRNA NEAT1 dynamics associated with CFs pyroptosis and cardiac fibrosis.

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