Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK.
Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore.
Nature. 2024 Oct;634(8033):457-465. doi: 10.1038/s41586-024-07993-x. Epub 2024 Sep 4.
Hyperlipidaemia is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Risk of cardiovascular events depends on cumulative lifetime exposure to low-density lipoprotein cholesterol (LDL-C) and, independently, on the time course of exposure to LDL-C, with early exposure being associated with a higher risk. Furthermore, LDL-C fluctuations are associated with ASCVD outcomes. However, the precise mechanisms behind this increased ASCVD risk are not understood. Here we find that early intermittent feeding of mice on a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to the WD, despite similar cumulative circulating LDL-C levels. We find that early intermittent hyperlipidaemia alters the number and homeostatic phenotype of resident-like arterial macrophages. Macrophage genes with altered expression are enriched for genes linked to human ASCVD in genome-wide association studies. We show that LYVE1 resident macrophages are atheroprotective, and identify biological pathways related to actin filament organization, of which alteration accelerates atherosclerosis. Using the Young Finns Study, we show that exposure to cholesterol early in life is significantly associated with the incidence and size of carotid atherosclerotic plaques in mid-adulthood. In summary, our results identify early intermittent exposure to cholesterol as a strong determinant of accelerated atherosclerosis, highlighting the importance of optimal control of hyperlipidaemia early in life, and providing insights into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat ASCVD.
高脂血症是动脉粥样硬化性心血管疾病（ASCVD）的一个主要危险因素。心血管事件的风险取决于低密度脂蛋白胆固醇（LDL-C）的终生累积暴露，并且独立于 LDL-C 的暴露时间过程，早期暴露与更高的风险相关。此外，LDL-C 波动与 ASCVD 结局相关。然而，这种 ASCVD 风险增加的确切机制尚不清楚。在这里，我们发现与晚期连续暴露于高脂西方饮食（WD）相比，早期间歇性喂养 WD 的小鼠会加速动脉粥样硬化，尽管累积循环 LDL-C 水平相似。我们发现，早期间歇性高脂血症改变了类似于动脉巨噬细胞的常驻巨噬细胞的数量和体内平衡表型。基因表达改变的巨噬细胞基因富含与全基因组关联研究中人类 ASCVD 相关的基因。我们表明，LYVE1 常驻巨噬细胞具有抗动脉粥样硬化作用，并确定了与肌动蛋白丝组织相关的生物学途径，其改变会加速动脉粥样硬化。通过 Young Finns 研究，我们表明，生命早期暴露于胆固醇与中年时颈动脉粥样硬化斑块的发生和大小显著相关。总之，我们的结果表明，早期间歇性暴露于胆固醇是加速动脉粥样硬化的一个重要决定因素，突出了在生命早期控制高脂血症的重要性，并提供了对潜在生物学机制的深入了解。这些知识对于设计有效的治疗策略来对抗 ASCVD 至关重要。
