Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Tennessee Institute of Regenerative Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Exp Biol Med (Maywood). 2021 Dec;246(24):2671-2678. doi: 10.1177/15353702211046541. Epub 2021 Sep 16.
Dietary cholesterol supplements cause hypercholesterolemia and atherosclerosis along with a reduction of copper concentrations in the atherosclerotic wall in animal models. This study was to determine if target-specific copper delivery to the copper-deficient atherosclerotic wall can block the pathogenesis of atherosclerosis. Male New Zealand white rabbits, 10-weeks-old and averaged 2.0 kg, were fed a diet containing 1% (w/w) cholesterol or the same diet without cholesterol as control. Twelve weeks after the feeding, the animals were injected with copper-albumin microbubbles and subjected to ultrasound sonication specifically directed at the atherosclerotic lesions (Cu-MB-US) for target-specific copper delivery, twice a week for four weeks. This regiment was repeated 3 times with a gap of two weeks in between. Two weeks after the last treatment, the animals were harvested for analyses of serum and aortic pathological changes. Compared to controls, rabbits fed cholesterol-rich diet developed atherosclerotic lesion with a reduction in copper concentrations in the lesion tissue. Cu-MB-US treatment significantly increased copper concentrations in the lesion, and reduced the size of the lesion. Furthermore, copper repletion reduced the number of apoptotic cells as well as the content of cholesterol and phospholipids in the atherosclerotic lesion without a disturbance of the stability of the lesion. The results thus demonstrate that target-specific copper supplementation suppresses the progression of atherosclerosis at least in part through preventing endothelial cell death, thus reducing lipid infiltration in the atherosclerotic lesion.
膳食胆固醇补充剂会导致动物模型中的高胆固醇血症和动脉粥样硬化，以及动脉粥样硬化壁中铜浓度降低。本研究旨在确定是否可以通过向铜缺乏的动脉粥样硬化壁中特异性地输送靶向铜来阻止动脉粥样硬化的发病机制。10 周龄、平均体重 2.0kg 的雄性新西兰白兔喂食含有 1%（w/w）胆固醇的饮食或不含胆固醇的相同饮食作为对照。喂食 12 周后，将动物注射铜白蛋白微泡，并对动脉粥样硬化病变进行超声靶向铜输送（Cu-MB-US），每周两次，共 4 周。该方案重复 3 次，每次间隔 2 周。最后一次治疗后 2 周，收获动物进行血清和主动脉病理变化分析。与对照组相比，喂食富含胆固醇饮食的兔子会发展出动脉粥样硬化病变，病变组织中的铜浓度降低。Cu-MB-US 治疗显著增加了病变中的铜浓度，并减少了病变的大小。此外，铜补充剂还减少了凋亡细胞的数量以及动脉粥样硬化病变中的胆固醇和磷脂含量，而不会干扰病变的稳定性。因此，这些结果表明，靶向铜补充至少部分通过防止内皮细胞死亡来抑制动脉粥样硬化的进展，从而减少动脉粥样硬化病变中的脂质浸润。
