Exercise Mitigates Endothelial Pyroptosis and Atherosclerosis by Downregulating NEAT1 Through N6-Methyladenosine Modifications
Exercise Mitigates Endothelial Pyroptosis and Atherosclerosis by Downregulating NEAT1 Through N6-Methyladenosine Modifications
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DOI：
10.1161/atvbaha.123.319251
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发表时间：
2023-04
期刊：
影响因子：
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通讯作者：
Qingyuan Yang;Shiliang Chen;Xingyi Wang;Xinyu Yang;Liangqi Chen;Tuo Huang;Yang Zheng;Xianghui Zhe
中科院分区：
文献类型：
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作者：
Qingyuan Yang;Shiliang Chen;Xingyi Wang;Xinyu Yang;Liangqi Chen;Tuo Huang;Yang Zheng;Xianghui Zhe
背景：运动对心血管系统的益处已被广泛认可;然而，其潜在机制尚不清楚。在这里，我们报告的影响，长的非编码RNA NEAT 1（核paraspeckle装配转录1），这是由运动调节，动脉粥样硬化的发展后，N6-甲基腺苷（m6 A）的修改。方法：使用临床队列和NEAT 1 −/−小鼠，我们确定了NEAT 1在动脉粥样硬化中的运动介导的表达和作用。为了探讨运动调节NEAT 1表观遗传修饰的机制，我们鉴定了运动条件下关键的m6 A修饰酶-最后，研究了NEAT 1下游调控网络。结果如下：我们发现NEAT 1的表达随着运动而下调，并且NEAT 1的下调是运动改善动脉粥样硬化的重要因素。糖尿病介导的NEAT 1功能丧失可延迟动脉粥样硬化。从机制上讲，我们发现运动诱导m6 A修饰和胃L14的显著下调，胃L14结合NEAT 1的m6 A位点，并通过随后的YTHDC 1（含YTH结构域1）识别促进NEAT 1表达，从而促进内皮细胞焦亡。此外，NEAT 1通过结合KLF 4（Kruppel样因子4）来促进关键性热凋亡蛋白NLRP 3（NOD样受体热蛋白结构域相关蛋白3）的转录激活来诱导内皮细胞热凋亡，而运动可以减弱NEAT 1介导的内皮细胞热凋亡以改善动脉粥样硬化。结论：我们对NEAT 1的研究为运动改善动脉粥样硬化提供了新的见解。这一发现证明了运动介导的NEAT 1下调在动脉粥样硬化中的作用，同时扩大了我们对运动通过表观遗传修饰调节长链非编码RNA功能的机制的理解。
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 (nuclear paraspeckle assembly transcript 1), 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 (NOD-like receptor thermal protein domain-associated protein 3), 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.