Exercise Mitigates Endothelial Pyroptosis and Atherosclerosis by Downregulating NEAT1 Through N6-Methyladenosine Modifications

Abstract

BACKGROUND: The benefits of exercise on the cardiovascular system are widely recognized; however, the underlying mechanisms are unknown. Here, we report the effect of the long noncoding RNA NEAT1, which is regulated by exercise, on atherosclerosis development after N6-methyladenosine (m6A) modifications. METHODS: Using clinical cohorts and NEAT1 −/− mice, we determined the exercise-mediated expression and role of NEAT1 in atherosclerosis. To investigate the mechanism of epigenetic modification of NEAT1 regulated by exercise, we identified METTL14 (methyltransferase-like 14)—a key m6A modification enzyme under exercise—and found that METTL14 alters the expression and role of NEAT1 through m6A modification and elucidated the specific mechanism of METTL14 in vitro and in vivo. Finally, the NEAT1 downstream regulatory network was investigated. RESULTS: We found that NEAT1 expression was downregulated with exercise and that downregulation of NEAT1 was an important factor in the improvement of atherosclerosis with exercise. Exercise-mediated loss of function of NEAT1 can delay atherosclerosis. Mechanistically, we showed that exercise induced a significant downregulation of m6A modification and METTL14, which binds to the m6A sites of NEAT1 and promotes NEAT1 expression through subsequent YTHDC1 (YTH domain-containing 1) recognition to promote endothelial pyroptosis. Furthermore, NEAT1 induces endothelial pyroptosis by binding KLF4 (Kruppel-like factor 4) to promote the transcriptional activation of the key pyroptotic protein NLRP3, whereas exercise can attenuate NEAT1-mediated endothelial pyroptosis to improve atherosclerosis. CONCLUSIONS: Our study of NEAT1 provides new insights into the improvement of atherosclerosis by exercise. This finding demonstrates the role of exercise-mediated NEAT1 downregulation in atherosclerosis while expanding our understanding of the mechanisms by which exercise regulates long noncoding RNA function through epigenetic modifications.

NLRP3 inflammasome and pyroptosis in cardiovascular diseases and exercise intervention

“…A study found that voluntary wheel running, a natural type of aerobic exercise in the murine model could decrease the protein levels of the inflammasome components and markedly inhibit the caspase-1 activity in endothelial cells within the aorta of mice fed with a high-fat diet (HFD) (Lee et al, 2020). Recently, another study has demonstrated that exercise-induced a significant downregulation of m6A modification and methyltransferase-like 14 (Yang et al, 2023). This protein binds to the m6A sites of nuclear paraspeckle assembly transcript 1 (NEAT1) and promotes NEAT1 expression through subsequent YT521-B homology domain-containing 1, which transcriptionally promotes NLRP3 expression and endothelial pyroptosis (Yang et al, 2023).…”

“…Recently, another study has demonstrated that exercise-induced a significant downregulation of m6A modification and methyltransferase-like 14 (Yang et al, 2023). This protein binds to the m6A sites of nuclear paraspeckle assembly transcript 1 (NEAT1) and promotes NEAT1 expression through subsequent YT521-B homology domain-containing 1, which transcriptionally promotes NLRP3 expression and endothelial pyroptosis (Yang et al, 2023). As a result, exercise effectively inhibits NLRP3 expression and endothelial pyroptosis, preventing AS plaque formation (Yang et al, 2023).…”

“…This protein binds to the m6A sites of nuclear paraspeckle assembly transcript 1 (NEAT1) and promotes NEAT1 expression through subsequent YT521-B homology domain-containing 1, which transcriptionally promotes NLRP3 expression and endothelial pyroptosis (Yang et al, 2023). As a result, exercise effectively inhibits NLRP3 expression and endothelial pyroptosis, preventing AS plaque formation (Yang et al, 2023). In addition, it is widely recognized that fibroblast growth factor 21 (FGF21), a wellestablished negative risk factor for AS expressed in the aorta, exerts inhibitory effects on NLRP3 inflammasome activity, thereby attenuating aortic pyroptosis to prevent AS development .…”

Epigenetic regulation of diverse cell death modalities in cancer: a focus on pyroptosis, ferroptosis, cuproptosis, and disulfidptosis

“…Furthermore, down-regulation of METTL14 reduces its binding to the m6A site of NEAT1 and subsequently promotes NEAT1 expression through YTHDC1 recognition. In addition, NEAT1 promotes transcriptional activation of NLRP3 by binding to KLF4 (Kruppel-like factor 4), which ultimately promotes the pyroptosis of endothelial cells [ 90 ]. However, in the tissues of renal cell carcinoma (RCC), METTL14 regulates the expression of NEAT1 through another recognition protein YTHDF2.…”

Inhibition of METTL3 ameliorates doxorubicin-induced cardiotoxicity through suppression of TFRC-mediated ferroptosis

“…Notably, m 6 A modification is perceived to regulate a wide spectrum of RNA biology including splicing, nuclear export, translation, and mRNA stability and decoy, thereby influencing multiple biological processes, including stress responses, cell differentiation, and embryonic development [ 20 , 21 ]. Moreover, dysregulation of m 6 A has been reported in multiple types of cardiovascular diseases [ 22 ], including myocardial infarction [ 23 ], heart failure [ 24 ], cardiac hypertrophy [ 25 , 26 ], and atherosclerosis [ 27 , 28 ]. However, the etiological nature of m 6 A modification in DIC remains elusive.…”