Metabolic Health Research,The Netherlands Organization of Applied Scientific Research (TNO), Gaubius Laboratory, Leiden, The Netherlands; Department of CardiologyLeiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine,Leiden University Medical Center, Leiden, The Netherlands.
Metabolic Health Research,The Netherlands Organization of Applied Scientific Research (TNO), Gaubius Laboratory, Leiden, The Netherlands.
J Lipid Res. 2020 Mar;61(3):365-375. doi: 10.1194/jlr.RA119000419. Epub 2019 Dec 16.
Atherosclerosis-related CVD causes nearly 20 million deaths annually. Most patients are treated after plaques develop, so therapies must regress existing lesions. Current therapies reduce plaque volume, but targeting all apoB-containing lipoproteins with intensive combinations that include alirocumab or evinacumab, monoclonal antibodies against cholesterol-regulating proprotein convertase subtilisin/kexin type 9 and angiopoietin-like protein 3, may provide more benefit. We investigated the effect of such lipid-lowering interventions on atherosclerosis in APOE*3-Leiden.CETP mice, a well-established model for hyperlipidemia. Mice were fed a Western-type diet for 13 weeks and thereafter matched into a baseline group (euthanized at 13 weeks) and five groups that received diet alone (control) or with treatment [atorvastatin; atorvastatin and alirocumab; atorvastatin and evinacumab; or atorvastatin, alirocumab, and evinacumab (triple therapy)] for 25 weeks. We measured effects on cholesterol levels, plaque composition and morphology, monocyte adherence, and macrophage proliferation. All interventions reduced plasma total cholesterol (37% with atorvastatin to 80% with triple treatment; all < 0.001). Triple treatment decreased non-HDL-C to 1.0 mmol/l (91% difference from control; < 0.001). Atorvastatin reduced atherosclerosis progression by 28% versus control ( < 0.001); double treatment completely blocked progression and diminished lesion severity. Triple treatment regressed lesion size versus baseline in the thoracic aorta by 50% and the aortic root by 36% (both < 0.05 vs. baseline), decreased macrophage accumulation through reduced proliferation, and abated lesion severity. Thus, high-intensive cholesterol-lowering triple treatment targeting all apoB-containing lipoproteins regresses atherosclerotic lesion area and improves lesion composition in mice, making it a promising potential approach for treating atherosclerosis.
动脉粥样硬化相关的心血管疾病每年导致近 2000 万人死亡。大多数患者在斑块形成后接受治疗，因此治疗必须使现有病变消退。目前的治疗方法可减少斑块体积，但通过使用包含载脂蛋白 B 的脂蛋白的强化联合治疗，包括针对胆固醇调节蛋白前转化酶枯草溶菌素/激肽释放酶 9 和血管生成素样蛋白 3 的单克隆抗体阿里库单抗或依维莫司，可能会带来更多益处。我们研究了这种降脂干预措施对 APOE*3-Leiden.CETP 小鼠动脉粥样硬化的影响，该小鼠是高脂血症的一种成熟模型。小鼠喂食西方饮食 13 周，然后分为基线组（13 周时安乐死）和 5 个组，分别接受单纯饮食（对照组）或联合治疗[阿托伐他汀；阿托伐他汀联合阿里库单抗；阿托伐他汀联合依维莫司；或阿托伐他汀、阿里库单抗和依维莫司（三联治疗）]25 周。我们测量了对胆固醇水平、斑块组成和形态、单核细胞黏附和巨噬细胞增殖的影响。所有干预措施均降低了血浆总胆固醇（阿托伐他汀降低 37%，三联治疗降低 80%；均 < 0.001）。三联治疗将非高密度脂蛋白胆固醇降低至 1.0 mmol/L（与对照组相比差异为 91%；< 0.001）。与对照组相比，阿托伐他汀使动脉粥样硬化进展减少 28%（< 0.001）；双重治疗完全阻止了进展并减轻了病变严重程度。与基线相比，三联治疗使胸主动脉和主动脉根部的病变大小分别缩小 50%和 36%（均 < 0.05），通过减少增殖减少了巨噬细胞的积累，并减轻了病变严重程度。因此，针对所有载脂蛋白 B 脂蛋白的高强度降脂三联治疗可使小鼠的动脉粥样硬化病变面积消退，并改善病变组成，这是治疗动脉粥样硬化的一种很有前途的潜在方法。
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