From the Departments of Clinical Medicine (M.M.B., M.K.H., J.F.B.) and Biomedicine (A.K.H., F.D.-H., J.G.M.), Aarhus University, Aarhus, Denmark; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark (M.M.B., M.K.H., J.F.B.); and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark (C.C.).
Circ Res. 2014 May 23;114(11):1684-9. doi: 10.1161/CIRCRESAHA.114.302937. Epub 2014 Mar 27.
Atherosclerosis can be achieved in animals by germline genetic engineering, leading to hypercholesterolemia, but such models are constrained to few species and strains, and they are difficult to combine with other powerful techniques involving genetic manipulation or variation.
To develop a method for induction of atherosclerosis without germline genetic engineering.
Recombinant adeno-associated viral vectors were engineered to encode gain-of-function proprotein convertase subtilisin/kexin type 9 mutants, and mice were given a single intravenous vector injection followed by high-fat diet feeding. Plasma proprotein convertase subtilisin/kexin type 9 and total cholesterol increased rapidly and were maintained at high levels, and after 12 weeks, mice had atherosclerotic lesions in the aorta. Histology of the aortic root showed progression of lesions to the fibroatheromatous stage. To demonstrate the applicability of this method for rapid analysis of the atherosclerosis susceptibility of a mouse strain and for providing temporal control over disease induction, we demonstrated the accelerated atherosclerosis of mature diabetic Akita mice. Furthermore, the versatility of this approach for creating atherosclerosis models also in nonmurine species was demonstrated by inducing hypercholesterolemia and early atherosclerosis in Golden Syrian hamsters.
Single injections of proprotein convertase subtilisin/kexin type 9-encoding recombinant adeno-associated viral vectors are a rapid and versatile method to induce atherosclerosis in animals. This method should prove useful for experiments that are high-throughput or involve genetic techniques, strains, or species that do not combine well with current genetically engineered models.
通过种系基因工程可在动物中实现动脉粥样硬化，导致高胆固醇血症，但此类模型仅限于少数物种和品系，且难以与涉及基因操作或变异的其他强大技术结合。
开发一种无需种系基因工程即可诱导动脉粥样硬化的方法。
设计了编码功能获得性前蛋白转化酶枯草溶菌素/凝血酶 9 突变体的重组腺相关病毒载体，并对小鼠进行单次静脉注射载体注射，然后进行高脂肪饮食喂养。血浆前蛋白转化酶枯草溶菌素/凝血酶 9 和总胆固醇迅速增加并维持在高水平，12 周后，小鼠主动脉出现动脉粥样硬化病变。主动脉根部组织学显示病变进展至纤维粥样硬化阶段。为了证明该方法可快速分析小鼠品系的动脉粥样硬化易感性并提供对疾病诱导的时间控制，我们证明了成熟糖尿病 Akita 小鼠的动脉粥样硬化加速。此外，通过在金黄地鼠中诱导高胆固醇血症和早期动脉粥样硬化，证明了该方法在非啮齿动物物种中创建动脉粥样硬化模型的多功能性。
前蛋白转化酶枯草溶菌素/凝血酶 9 编码重组腺相关病毒载体的单次注射是一种在动物中快速且多功能的诱导动脉粥样硬化的方法。该方法对于需要高通量实验或涉及不易与现有基因工程模型结合的遗传技术、品系或物种的实验应该是有用的。
