Stabilizing and inhibiting plaque formation is a key challenge for preventing and treating ischemic stroke. KDM1A-mediated histone modifications, which involved in the development of training immunity, ultimately exacerbate the outcomes of inflammation. Although lncRNAs can recruit KDM1A to participate in histone methylation modification and regulate inflammation, cell proliferation, and other biological processes, little is known about the role of KDM1A-lncRNA interaction during atherosclerosis. The present study sought to delineate the effect of the interaction between lnc_000048 and KDM1A on plaque rupture in carotid atherosclerosis, as well as the potential mechanism. Our results revealed that lnc_000048 reduced the activity of histone demethylase and activated MAP2K2 expression by interacting with KDM1A. Furthermore, upregulated lnc_000048 indirectly regulated ERK phosphorylation by MAP2K2 and eventually activated the inflammatory response through the MAPK pathway, which was involved in atherosclerosis. Importantly, our study using ApoE-/- mice confirmed the regulatory role of lnc_000048 in promoting inflammation and collagen degradation in atherosclerotic plaques. These results suggest that targeting the lnc_000048 /KDM1A/MAP2K2/ERK axis may be a promising strategy for preventing atherosclerosis.

稳定和抑制斑块形成是预防和治疗缺血性中风的关键挑战。KDM1A 介导的组蛋白修饰参与训练免疫力的发展，最终会加剧炎症的结果。尽管 lncRNA 可以招募 KDM1A 参与组蛋白甲基化修饰并调节炎症、细胞增殖和其他生物过程，但关于 KDM1A-lncRNA 相互作用在动脉粥样硬化过程中的作用知之甚少。本研究试图描述 lnc_000048 和 KDM1A 之间的相互作用对颈动脉粥样硬化斑块破裂的影响，以及潜在的机制。我们的结果表明，lnc_000048 通过与 KDM1A 相互作用降低组蛋白去甲基化酶的活性并激活 MAP2K2 表达。此外，上调 lnc_000048 通过 MAP2K2 间接调节 ERK 磷酸化，并最终通过 MAPK 通路激活炎症反应，该通路参与动脉粥样硬化。重要的是，我们使用 ApoE-/- 小鼠的研究证实了 lnc_000048 在促进动脉粥样硬化斑块中的炎症和胶原蛋白降解方面的调节作用。这些结果表明，靶向 lnc_000048 /KDM1A/MAP2K2/ERK 轴可能是预防动脉粥样硬化的有前途的策略。