Exercise-induced endothelial Mecp2 lactylation suppresses atherosclerosis via the Ereg/MAPK signalling pathway
Exercise-induced endothelial Mecp2 lactylation suppresses atherosclerosis via the Ereg/MAPK signalling pathway
复制标题
运动诱导的内皮细胞Mecp2乳酸化通过Ereg/MAPK信号通路抑制动脉粥样硬化
DOI：
10.1016/j.atherosclerosis.2023.05.009
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发表时间：
2023-05-26
期刊：
影响因子：
5.3
通讯作者：
Yu, Bo
中科院分区：
文献类型：
--
作者：
Wang, Yanan;Chen, Liangqi;Yu, Bo
背景和目的：乳酸酰化是最近发现的一种翻译后修饰（PTM），在多种生理和病理过程的调节中起着核心作用。众所周知，运动可以预防心血管疾病。然而，运动产生的乳酸是否改变乳酸化并参与运动诱导的动脉粥样硬化性心血管疾病（ASCVD）的衰减仍不清楚。本研究的目的是探讨运动诱导的乳酸化对ASCVD的影响及其机制。方法与结果：通过高脂饮食诱导的ASCVD载脂蛋白缺失小鼠模型，我们发现运动训练促进Mecp2赖氨酸乳酸化（Mecp2k271la）；降低血管细胞黏附分子1 （Vcam-1）、细胞间黏附分子1 （Icam-1）、单核细胞化学引诱蛋白1 （Mcp-1）、白细胞介素(IL)-1和β的表达；IL-6，提高小鼠主动脉组织内皮型一氧化氮合酶（Enos）水平。为了探索其潜在机制，我们对小鼠主动脉内皮细胞（MAECs）进行了rna测序和CHIP-qPCR，证实Mecp2k271la通过与其染色质结合抑制表调节蛋白（epiregulin, Ereg）的表达，表明Ereg是Mecp2k271la的关键下游分子。此外，Ereg通过调节表皮生长因子受体磷酸化水平，改变丝裂原活化蛋白激酶（MAPK）信号通路，从而影响Vcam-1、Icam-1、Mcp-1、IL-1和β的表达；， IL-6和Enos，进而促进动脉粥样硬化的消退。此外，体内通过外源性乳酸给药增加Mecp2k271la的水平也会抑制ECs中Ereg的表达和MAPK的活性，从而抑制动脉粥样硬化的进展。结论：总之，本研究提供了运动与乳酸化修饰之间的机制联系，为运动诱导的PTM的抗动脉粥样硬化作用提供了新的见解。
Background and aims: Lactylation, a recently identified post-translational modification (PTM), plays a central role in the regulation of multiple physiological and pathological processes. Exercise is known to provide protection against cardiovascular disease. However, whether exercise-generated lactate changes lactylation and is involved in the exercise-induced attenuation of atherosclerotic cardiovascular disease (ASCVD) remains unclear. The purpose of this study was to investigate the effects and mechanisms of exercise-induced lactylation on ASCVD. Methods and Results: Using the high-fat diet-induced apolipoprotein-deficient mouse model of ASCVD, we found that exercise training promoted Mecp2 lysine lactylation (Mecp2k271la); it also decreased the expression of vascular cell adhesion molecule 1 (Vcam-1), intercellular adhesion molecule 1 (Icam-1), monocyte chemo-attractant protein 1 (Mcp-1), interleukin (IL)-1 & beta;, IL-6, and increased the level of endothelial nitric oxide synthase (Enos) in the aortic tissue of mice. To explore the underlying mechanisms, mouse aortic endothelial cells (MAECs) were subjected to RNA-sequencing and CHIP-qPCR, which confirmed that Mecp2k271la repressed the expression of epiregulin (Ereg) by binding to its chromatin, demonstrating Ereg as a key downstream molecule for Mecp2k271la. Furthermore, Ereg altered the mitogen-activated protein kinase (MAPK) signalling pathway through regulating the phosphorylation level of epidermal growth factor receptor, thereby affecting the expression of Vcam-1, Icam-1, Mcp-1, IL-1 & beta;, IL-6, and Enos in ECs, which in turn promoted the regression of atherosclerosis. In addition, increasing the level of Mecp2k271la by exogenous lactate administration in vivo also inhibits the expression of Ereg and the MAPK activity in ECs, resulting in repressed atherosclerotic progression. Conclusions: In summary, this study provides a mechanistic link between exercise and lactylation modification, offering new insight into the anti-atherosclerotic effects of exercise-induced PTM.