PDF(Pubmed)
Abstract：
UNASSIGNED: Thromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions is the global leading cause of death. The most common and effective means to reduce these major adverse cardiovascular events, including myocardial infarction and stroke, is aggressive lipid lowering via a combination of drugs and dietary modifications. However, we know little regarding the effects of reducing dietary lipids on the composition and stability of advanced atherosclerotic lesions, the mechanisms that regulate these processes, and what therapeutic approaches might augment the benefits of lipid lowering.
UNASSIGNED: Smooth muscle cell lineage-tracing Apoe-/- mice were fed a high-cholesterol Western diet for 18 weeks and then a zero-cholesterol standard laboratory diet for 12 weeks before treating them with an IL (interleukin)-1β or control antibody for 8 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of smooth muscle cell and other lesion cells by smooth muscle cell lineage tracing combined with single-cell RNA sequencing, cytometry by time-of-flight, and immunostaining plus high-resolution confocal microscopic z-stack analysis.
UNASSIGNED: Lipid lowering by switching Apoe-/- mice from a Western diet to a standard laboratory diet reduced LDL cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden, as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1β antibody treatment after diet-induced reductions in lipids resulted in multiple detrimental changes including increased plaque burden and brachiocephalic artery lesion size, as well as increasedintraplaque hemorrhage, necrotic core area, and senescence as compared with IgG control antibody-treated mice. Furthermore, IL-1β antibody treatment upregulated neutrophil degranulation pathways but downregulated smooth muscle cell extracellular matrix pathways likely important for the protective fibrous cap.
UNASSIGNED: Taken together, IL-1β appears to be required for the maintenance of standard laboratory diet-induced reductions in plaque burden and increases in multiple indices of plaque stability.
UNASSIGNED: Smooth muscle cell lineage-tracing Apoe-/- mice were fed a high-cholesterol Western diet for 18 weeks and then a zero-cholesterol standard laboratory diet for 12 weeks before treating them with an IL (interleukin)-1β or control antibody for 8 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of smooth muscle cell and other lesion cells by smooth muscle cell lineage tracing combined with single-cell RNA sequencing, cytometry by time-of-flight, and immunostaining plus high-resolution confocal microscopic z-stack analysis.
UNASSIGNED: Lipid lowering by switching Apoe-/- mice from a Western diet to a standard laboratory diet reduced LDL cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden, as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1β antibody treatment after diet-induced reductions in lipids resulted in multiple detrimental changes including increased plaque burden and brachiocephalic artery lesion size, as well as increasedintraplaque hemorrhage, necrotic core area, and senescence as compared with IgG control antibody-treated mice. Furthermore, IL-1β antibody treatment upregulated neutrophil degranulation pathways but downregulated smooth muscle cell extracellular matrix pathways likely important for the protective fibrous cap.
UNASSIGNED: Taken together, IL-1β appears to be required for the maintenance of standard laboratory diet-induced reductions in plaque burden and increases in multiple indices of plaque stability.
摘要：
■继发于晚期动脉粥样硬化病变破裂或侵蚀的血栓栓塞事件是全球主要死亡原因。减少这些主要不良心血管事件的最常见和最有效的手段，包括心肌梗塞和中风,是通过药物和饮食调整的组合积极降脂。然而,我们对降低膳食脂质对晚期动脉粥样硬化病变的组成和稳定性的影响知之甚少，调节这些过程的机制，以及哪些治疗方法可能会增加降脂的好处。
■平滑肌细胞谱系追踪Apoe-/-小鼠喂食高胆固醇西方饮食18周，然后喂食零胆固醇标准实验室饮食12周，然后用IL（白介素）-1β或对照抗体治疗8周。我们评估了病变大小和重塑指数，以及主动脉和头臂动脉病变的细胞组成，斑块稳定性指数，总体斑块负荷，通过平滑肌细胞谱系追踪结合单细胞RNA测序，以及平滑肌细胞和其他病变细胞的表型转变，通过飞行时间进行细胞计数，免疫染色和高分辨率共聚焦显微镜z-stack分析。
■通过将Apoe-/-小鼠从西方饮食转换为标准实验室饮食来降低血脂，使LDL胆固醇水平降低了70％，并产生了多种有益效果，包括降低了总的主动脉斑块负担。以及减少斑块内出血和坏死核心区。然而,与预期相反,饮食诱导的脂质减少后IL-1β抗体治疗导致多种有害变化，包括斑块负荷增加和头臂动脉病变大小，以及斑块内出血增加，坏死核心区域,和衰老与IgG对照抗体处理的小鼠相比。此外，IL-1β抗体治疗上调中性粒细胞脱颗粒途径，但下调平滑肌细胞细胞外基质途径可能对保护性纤维帽很重要。
■放在一起，IL-1β似乎是维持标准实验室饮食诱导的斑块负荷减少和斑块稳定性多个指标增加所必需的。
■平滑肌细胞谱系追踪Apoe-/-小鼠喂食高胆固醇西方饮食18周，然后喂食零胆固醇标准实验室饮食12周，然后用IL（白介素）-1β或对照抗体治疗8周。我们评估了病变大小和重塑指数，以及主动脉和头臂动脉病变的细胞组成，斑块稳定性指数，总体斑块负荷，通过平滑肌细胞谱系追踪结合单细胞RNA测序，以及平滑肌细胞和其他病变细胞的表型转变，通过飞行时间进行细胞计数，免疫染色和高分辨率共聚焦显微镜z-stack分析。
■通过将Apoe-/-小鼠从西方饮食转换为标准实验室饮食来降低血脂，使LDL胆固醇水平降低了70％，并产生了多种有益效果，包括降低了总的主动脉斑块负担。以及减少斑块内出血和坏死核心区。然而,与预期相反,饮食诱导的脂质减少后IL-1β抗体治疗导致多种有害变化，包括斑块负荷增加和头臂动脉病变大小，以及斑块内出血增加，坏死核心区域,和衰老与IgG对照抗体处理的小鼠相比。此外，IL-1β抗体治疗上调中性粒细胞脱颗粒途径，但下调平滑肌细胞细胞外基质途径可能对保护性纤维帽很重要。
■放在一起，IL-1β似乎是维持标准实验室饮食诱导的斑块负荷减少和斑块稳定性多个指标增加所必需的。
