Hardaway Brian D, Fidler Trevor P, Tavallaie Mojdeh, Avrampou Kleopatra, Hsu Cheng-Chieh, Schiavone Sandra, Xiao Tong, Wang Nan, Tall Alan R
Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
bioRxiv. 2025 Jul 30:2025.07.23.666334. doi: 10.1101/2025.07.23.666334.
BACKGROUND -: Clonal hematopoiesis (CH) has emerged as an important risk factor for atherosclerotic cardiovascular disease (ACVD). Mouse studies have established a causal role of CH in atherosclerosis progression and have defined macrophage inflammatory responses as a key underlying mechanism. We undertook the present study to assess the hypothesis that ongoing inflammation would impede atherosclerosis regression in ( ) CH mice.
METHODS AND RESULTS -: Chimeric or control bone marrow was transplanted into mice and, following 13-16 weeks of Western diet-induced atherosclerosis progression, cholesterol was lowered either moderately (to 200-300 mg/dl) or markedly (to 100 mg/dl). With moderate cholesterol lowering there was impaired regression in CH mice compared to controls. However, with marked cholesterol lowering, regression was similar in CH and control mice.Two mechanisms of low-density lipoprotein (LDL) lowering-induced suppression of inflammation in plaques were implicated: 1) reversal of increased proliferation, DNA damage and Absent in Melanoma 2 (AIM2) inflammasome activation specifically in macrophages and 2) markedly increased macrophage triggering receptor expressed on myeloid cells 2 (TREM2), c-myc expressing macrophages in both and control mice.
CONCLUSIONS -: Aggressive LDL lowering reverses inflammasome activation and induces pro-resolving changes in macrophages in CH, halting atherosclerosis progression and promoting features of plaque stabilization. These findings suggest that aggressive LDL cholesterol lowering could effectively reverse ACVD risk in individuals with clonal hematopoiesis.
克隆性造血（CH）已成为动脉粥样硬化性心血管疾病（ACVD）的重要危险因素。小鼠研究已证实CH在动脉粥样硬化进展中具有因果作用，并将巨噬细胞炎症反应确定为关键的潜在机制。我们进行了本研究，以评估持续炎症会阻碍（ ）CH小鼠动脉粥样硬化消退这一假说。
将嵌合的 或对照 骨髓移植到 小鼠体内，在西式饮食诱导动脉粥样硬化进展13 - 16周后，将胆固醇适度降低（至200 - 300 mg/dl）或显著降低（至100 mg/dl）。与对照组相比，适度降低胆固醇时，CH小鼠的消退受损。然而，显著降低胆固醇时，CH小鼠和对照小鼠的消退相似。低密度脂蛋白（LDL）降低诱导斑块炎症抑制涉及两种机制：1）特别是在 巨噬细胞中，增殖增加、DNA损伤和黑色素瘤缺失2（AIM2）炎性小体激活的逆转；2）在 和对照小鼠中，髓系细胞2（TREM2）、表达c - myc的巨噬细胞上表达的巨噬细胞触发受体显著增加。
积极降低LDL可逆转炎性小体激活，并诱导CH小鼠巨噬细胞发生促消退变化，阻止动脉粥样硬化进展并促进斑块稳定特征。这些发现表明，积极降低LDL胆固醇可有效逆转具有克隆性造血个体的ACVD风险。
