From the Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark (E.D.B., C.C., L.B.N.); Roche Innovation Center Copenhagen, Hoersholm, Denmark (M.W.L.); and Departments of Biomedical Sciences (C.C., L.B.N.) and Clinical Medicine (L.B.N.), University of Copenhagen, Copenhagen, Denmark.
Circ Res. 2015 Nov 6;117(11):933-42. doi: 10.1161/CIRCRESAHA.115.307182. Epub 2015 Sep 10.
Plasma cholesterol lowering is beneficial in patients with atherosclerosis. However, it is unknown how it affects entry and degradation of low-density lipoprotein (LDL) particles in the lesioned arterial wall.
We studied the effect of lipid-lowering therapy on LDL permeability and degradation of LDL particles in atherosclerotic aortas of mice by measuring the accumulation of iodinated LDL particles in the arterial wall.
Cholesterol-fed, LDL receptor-deficient mice were treated with either an anti-Apob antisense oligonucleotide or a mismatch control antisense oligonucleotide once a week for 1 or 4 weeks before injection with preparations of iodinated LDL particles. The anti-Apob antisense oligonucleotide reduced plasma cholesterol by ≈90%. The aortic LDL permeability and degradation rates of newly entered LDL particles were reduced by ≈50% and ≈85% already after 1 week of treatment despite an unchanged pool size of aortic iodinated LDL particles. In contrast, the size, foam cell content, and aortic pool size of iodinated LDL particles of aortic atherosclerotic plaques were not reduced until after 4 weeks of treatment with the anti-Apob antisense oligonucleotide.
Improved endothelial barrier function toward the entry of plasma LDL particles and diminished aortic degradation of the newly entered LDL particles precede plaque regression.
血浆胆固醇降低对动脉粥样硬化患者有益。然而，目前尚不清楚它如何影响受损动脉壁中低密度脂蛋白（LDL）颗粒的进入和降解。
我们通过测量动脉壁中碘化 LDL 颗粒的积累，研究降脂治疗对载脂蛋白 B 反义寡核苷酸治疗的 LDL 通透性和 LDL 颗粒在动脉粥样硬化主动脉中的降解的影响。
用胆固醇喂养的 LDL 受体缺陷型小鼠每周接受一次抗 Apob 反义寡核苷酸或错配对照反义寡核苷酸治疗，共 1 或 4 周，然后注射碘化 LDL 颗粒制剂。抗 Apob 反义寡核苷酸使血浆胆固醇降低约 90%。尽管主动脉碘化 LDL 颗粒的池大小不变，但在治疗 1 周后，新进入的 LDL 颗粒的主动脉 LDL 通透性和降解率降低了约 50%和 85%。相比之下，直到用抗 Apob 反义寡核苷酸治疗 4 周后，动脉粥样硬化斑块中的主动脉碘代 LDL 颗粒的大小、泡沫细胞含量和主动脉池大小才减少。
内皮屏障功能对血浆 LDL 颗粒进入的改善以及新进入的 LDL 颗粒在主动脉中的降解减少先于斑块消退。
