Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression.

他汀类药物诱导斑块消退，其特征是人类巨噬细胞含量减少，但其潜在机制仍然是推测性的。研究具有人源化脂蛋白代谢的翻译 APOE*3-Leiden.CETP 小鼠模型，我们发现通过口服阿托伐他汀或饮食限制降低全身胆固醇可抑制单核细胞浸润，并逆转动脉粥样硬化斑块中的巨噬细胞积累。与目前的看法相反，（1）减少单核细胞流入（通过胸部屏蔽照射骨髓嵌合体中的细胞命运图研究），（2）增强巨噬细胞流出（通过荧光珠标记和转移研究），或 (3) 阿托伐他汀在鼠或人斑块中的积累（通过质谱法评估）可以充分解释所观察到的经过表型退化的斑块中巨噬细胞含量的减少。相反，巨噬细胞局部增殖的抑制主导了胆固醇降低的表型斑块消退：鼠主动脉和人颈动脉斑块中血清低密度脂蛋白胆固醇和脂质含量的水平越低，原位巨噬细胞增殖率就越低。我们的研究将巨噬细胞增殖确定为主要的周转决定因素和诱导斑块消退的有吸引力的目标。鼠主动脉和人颈动脉斑块中血清低密度脂蛋白胆固醇和脂质含量越低，原位巨噬细胞增殖率越低。我们的研究将巨噬细胞增殖确定为主要的周转决定因素和诱导斑块消退的有吸引力的目标。鼠主动脉和人颈动脉斑块中血清低密度脂蛋白胆固醇和脂质含量越低，原位巨噬细胞增殖率越低。我们的研究将巨噬细胞增殖确定为主要的周转决定因素和诱导斑块消退的有吸引力的目标。