RESULTS: By analyzing our data and human and mouse data from the Gene Expression Omnibus database, we found that Meg3 expression was reduced in humans and mice with cardiovascular disease, indicating its potential role in atherosclerosis. In Ldlr-/- mice fed a Western diet for 12 weeks, Meg3 silencing by chemically modified antisense oligonucleotides attenuated the formation of atherosclerotic lesions by 34.9% and 20.1% in male and female mice, respectively, revealed by en-face Oil Red O staining, which did not correlate with changes in plasma lipid profiles. Real-time quantitative PCR analysis of cellular senescence markers p21 and p16 revealed that Meg3 deficiency aggravates hepatic cellular senescence but not cellular senescence at aortic roots. Human Meg3 transgenic mice were generated to examine the role of Meg3 gain-of-function in the development of atherosclerosis induced by PCSK9 overexpression. Meg3 overexpression promotes atherosclerotic lesion formation by 29.2% in Meg3 knock-in mice independent of its effects on lipid profiles. Meg3 overexpression inhibits hepatic cellular senescence, while it promotes aortic cellular senescence likely by impairing mitochondrial function and delaying cell cycle progression.
CONCLUSIONS: Our data demonstrate that Meg3 promotes the formation of atherosclerotic lesions independent of its effects on plasma lipid profiles. In addition, Meg3 regulates cellular senescence in a tissue-specific manner during atherosclerosis. Thus, we demonstrated that Meg3 has multifaceted roles in cellular senescence and atherosclerosis.
结果:通过分析我们的数据以及来自基因表达综合数据库的人类和小鼠数据,我们发现Meg3在患有心血管疾病的人和小鼠中的表达降低,表明其在动脉粥样硬化中的潜在作用。在喂食西方饮食12周的Ldlr-/-小鼠中,通过化学修饰的反义寡核苷酸沉默Meg3使雄性和雌性小鼠动脉粥样硬化病变的形成减少了34.9%和20.1%,分别,通过正面油红O染色显示,这与血浆脂质谱的变化无关。细胞衰老标志物p21和p16的实时定量PCR分析显示,Meg3缺乏会加重肝细胞衰老,但不会加重主动脉根部的细胞衰老。产生人Meg3转基因小鼠以检查Meg3功能获得在PCSK9过表达诱导的动脉粥样硬化发展中的作用。Meg3过表达在Meg3敲入小鼠中促进动脉粥样硬化病变形成29.2%,而与其对血脂谱的影响无关。Meg3过表达抑制肝细胞衰老,而它可能通过损害线粒体功能和延迟细胞周期进程来促进主动脉细胞衰老。
结论:我们的数据表明Meg3促进动脉粥样硬化病变的形成,而不依赖于其对血浆脂质分布的影响。此外,Meg3在动脉粥样硬化期间以组织特异性方式调节细胞衰老。因此,我们证明Meg3在细胞衰老和动脉粥样硬化中具有多方面的作用.