Abstract：
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.
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 chemoattractant protein 1 (Mcp-1), interleukin (IL)-1β, 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-1β, 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.
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.
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 chemoattractant protein 1 (Mcp-1), interleukin (IL)-1β, 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-1β, 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.
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.
摘要：
目的：乳糖化，最近发现的翻译后修饰（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了乳酸化,是否参与了运动诱导的动脉粥样硬化性心血管疾病(ASCVD)的减弱,目前尚不清楚.目的探讨运动诱导的乳酸化对ASCVD的影响及机制。
结果：使用高脂饮食诱导的ASCVD载脂蛋白缺陷小鼠模型，我们发现运动训练促进Mecp2赖氨酸的乳酸化（Mecp2k271la）；它还降低了血管细胞粘附分子1（Vcam-1）的表达，细胞间粘附分子1（Icam-1），单核细胞趋化蛋白1（Mcp-1），白细胞介素（IL）-1β，IL-6，并增加小鼠主动脉组织中内皮型一氧化氮合酶（Enos）的水平。为了探索潜在的机制，小鼠主动脉内皮细胞（MAECs）进行RNA测序和CHIP-qPCR，这证实了Mecp2k271la通过与染色质结合抑制了表观调节蛋白（Ereg）的表达，证明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的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-1β的表达，ECs中的IL-6和Enos，这反过来又促进了动脉粥样硬化的消退。此外,通过体内外源性乳酸给药增加Mecp2k271la的水平也抑制了ECs中Ereg的表达和MAPK活性，导致抑制动脉粥样硬化进展。
结论：总之，这项研究提供了运动和乳酸修饰之间的机械联系，为运动诱发的PTM的抗动脉粥样硬化作用提供了新的见解。
结果：使用高脂饮食诱导的ASCVD载脂蛋白缺陷小鼠模型，我们发现运动训练促进Mecp2赖氨酸的乳酸化（Mecp2k271la）；它还降低了血管细胞粘附分子1（Vcam-1）的表达，细胞间粘附分子1（Icam-1），单核细胞趋化蛋白1（Mcp-1），白细胞介素（IL）-1β，IL-6，并增加小鼠主动脉组织中内皮型一氧化氮合酶（Enos）的水平。为了探索潜在的机制，小鼠主动脉内皮细胞（MAECs）进行RNA测序和CHIP-qPCR，这证实了Mecp2k271la通过与染色质结合抑制了表观调节蛋白（Ereg）的表达，证明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的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-1β的表达，ECs中的IL-6和Enos，这反过来又促进了动脉粥样硬化的消退。此外,通过体内外源性乳酸给药增加Mecp2k271la的水平也抑制了ECs中Ereg的表达和MAPK活性，导致抑制动脉粥样硬化进展。
结论：总之，这项研究提供了运动和乳酸修饰之间的机械联系，为运动诱发的PTM的抗动脉粥样硬化作用提供了新的见解。
