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Novel Reversible Model of Atherosclerosis and Regression Using Oligonucleotide Regulation of the LDL Receptor.
Circulation Research ( IF 20.1 ) Pub Date : 2018-01-10 , DOI: 10.1161/circresaha.117.311361
Debapriya Basu 1 , Yunying Hu 1 , Lesley-Ann Huggins 1 , Adam E Mullick 1 , Mark J Graham 1 , Tomasz Wietecha 1 , Shelley Barnhart 1 , Allison Mogul 1 , Katharina Pfeiffer 1 , Andreas Zirlik 1 , Edward A Fisher 1 , Karin E Bornfeldt 1 , Florian Willecke 1 , Ira J Goldberg 1
Affiliation  

RATIONALE Animal models have been used to explore factors that regulate atherosclerosis. More recently, they have been used to study the factors that promote loss of macrophages and reduction in lesion size after lowering of plasma cholesterol levels. However, current animal models of atherosclerosis regression require challenging surgeries, time-consuming breeding strategies, and methods that block liver lipoprotein secretion. OBJECTIVE We sought to develop a more direct or time-effective method to create and then reverse hypercholesterolemia and atherosclerosis via transient knockdown of the hepatic LDLR (low-density lipoprotein receptor) followed by its rapid restoration. METHODS AND RESULTS We used antisense oligonucleotides directed to LDLR mRNA to create hypercholesterolemia in wild-type C57BL/6 mice fed an atherogenic diet. This led to the development of lesions in the aortic root, aortic arch, and brachiocephalic artery. Use of a sense oligonucleotide replicating the targeted sequence region of the LDLR mRNA rapidly reduced circulating cholesterol levels because of recovery of hepatic LDLR expression. This led to a decrease in macrophages within the aortic root plaques and brachiocephalic artery, that is, regression of inflammatory cell content, after a period of 2 to 3 weeks. CONCLUSIONS We have developed an inducible and reversible hepatic LDLR knockdown mouse model of atherosclerosis regression. Although cholesterol reduction decreased early en face lesions in the aortic arches, macrophage area was reduced in both early and late lesions within the aortic sinus after reversal of hypercholesterolemia. Our model circumvents many of the challenges associated with current mouse models of regression. The use of this technology will potentially expedite studies of atherosclerosis and regression without use of mice with genetic defects in lipid metabolism.

中文翻译:

使用LDL受体的寡核苷酸调节的新型动脉粥样硬化和回归可逆模型。

原理动物模型已用于探索调节动脉粥样硬化的因素。最近,他们已被用于研究降低血浆胆固醇水平后促进巨噬细胞丧失和病变大小减少的因素。但是,当前的动脉粥样硬化消退动物模型需要具有挑战性的手术,费时的育种策略和阻断肝脂蛋白分泌的方法。目的我们试图开发一种更直接或更省时的方法,通过暂时性击倒肝LDLR(低密度脂蛋白受体),然后快速恢复来创建并逆转高胆固醇血症和动脉粥样硬化。方法和结果我们使用针对LDLR mRNA的反义寡核苷酸在饲喂致动脉粥样化饮食的野生型C57BL / 6小鼠中产生高胆固醇血症。这导致了在主动脉根,主动脉弓和头臂动脉的病变的发展。由于肝LDLR表达的恢复,使用复制LDLR mRNA靶向序列区域的有义寡核苷酸可快速降低循环胆固醇水平。在2至3周的时间后,这会导致主动脉根斑块和头臂动脉内巨噬细胞的减少,即炎症细胞含量的降低。结论我们已经建立了可诱导和可逆的肝脏LDLR敲低小鼠动脉粥样硬化消退模型。尽管胆固醇降低减少了主动脉弓早期的面部病变,但高胆固醇血症逆转后,主动脉窦内早期和晚期病变的巨噬细胞面积均减少了。我们的模型规避了与当前鼠标回归模型相关的许多挑战。如果不使用脂质代谢具有遗传缺陷的小鼠,使用该技术将有可能加快动脉粥样硬化和消退的研究。
更新日期:2018-02-16
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