Targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis in Yucatan miniature pigs.
Targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis in Yucatan miniature pigs.
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DOI：
10.1371/journal.pone.0093457
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Rogers CS
中科院分区：
文献类型：
--
作者：
Davis BT;Wang XJ;Rohret JA;Struzynski JT;Merricks EP;Bellinger DA;Rohret FA;Nichols TC;Rogers CS
大型动物基因组工程的最新进展激发了人们对开发更好的动物模型来治疗当前选择不足的疾病的兴趣。在这里，我们报告了尤卡坦小型猪的创建，该猪对低密度脂蛋白受体（LDLR）基因进行了有针对性的破坏，以期提供一种改进的家族性高胆固醇血症和动脉粥样硬化的大型动物模型。由于尤卡坦小型猪在生理学、解剖学、遗传学和体型方面与人类相似，因此已成为转化研究模型。使用重组腺相关病毒介导的基因靶向和体细胞核移植，产生了雄性和雌性LDLR+/-猪。随后的杂合子育种产生了 LDLR−/− 猪。当饲喂标准猪饲料（低脂肪、无胆固醇）时，LDLR+/-猪的总胆固醇和LDL胆固醇适度但持续增加，而LDLR+/-猪的水平则显着升高。纯合子动物中的严重高胆固醇血症导致冠状动脉和腹主动脉出现类似于人类动脉粥样硬化的动脉粥样硬化病变。当喂食含有天然脂肪和胆固醇的饮食时，这些表型更加严重，并且在较短的时间内形成。与现有大型动物模型相比，针对 LDLR 的尤卡坦小型猪具有多种优势，包括尺寸、一致性、可用性和多功能性。这种心血管疾病的新模型可能成为开发和测试冠状动脉和主动脉粥样硬化及其并发症的新检测和治疗策略的重要资源。
Recent progress in engineering the genomes of large animals has spurred increased interest in developing better animal models for diseases where current options are inadequate. Here, we report the creation of Yucatan miniature pigs with targeted disruptions of the low-density lipoprotein receptor (LDLR) gene in an effort to provide an improved large animal model of familial hypercholesterolemia and atherosclerosis. Yucatan miniature pigs are well established as translational research models because of similarities to humans in physiology, anatomy, genetics, and size. Using recombinant adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer, male and female LDLR+/− pigs were generated. Subsequent breeding of heterozygotes produced LDLR−/− pigs. When fed a standard swine diet (low fat, no cholesterol), LDLR+/− pigs exhibited a moderate, but consistent increase in total and LDL cholesterol, while LDLR−/− pigs had considerably elevated levels. This severe hypercholesterolemia in homozygote animals resulted in atherosclerotic lesions in the coronary arteries and abdominal aorta that resemble human atherosclerosis. These phenotypes were more severe and developed over a shorter time when fed a diet containing natural sources of fat and cholesterol. LDLR-targeted Yucatan miniature pigs offer several advantages over existing large animal models including size, consistency, availability, and versatility. This new model of cardiovascular disease could be an important resource for developing and testing novel detection and treatment strategies for coronary and aortic atherosclerosis and its complications.
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影响因子：
15.9
作者：
ISHIBASHI, S;BROWN, MS;HERZ, J
通讯作者：
HERZ, J
影响因子：
17.1
作者：
Al-Mashhadi, Rozh H.;Sorensen, Charlotte B.;Bentzon, Jacob F.
通讯作者：
Bentzon, Jacob F.
影响因子：
7.7
作者：
Gerrity, RG;Natarajan, R;Kimsey, T
通讯作者：
Kimsey, T
DOI：
10.1161/01.atv.19.12.2981
发表时间：
1999-12-01
影响因子：
8.7
作者：
Dixon, JL;Stoops, JD;Sturek, M
通讯作者：
Sturek, M
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影响因子：
17.1
作者：
Ostedgaard LS;Meyerholz DK;Chen JH;Pezzulo AA;Karp PH;Rokhlina T;Ernst SE;Hanfland RA;Reznikov LR;Ludwig PS;Rogan MP;Davis GJ;Dohrn CL;Wohlford-Lenane C;Taft PJ;Rector MV;Hornick E;Nassar BS;Samuel M;Zhang Y;Richter SS;Uc A;Shilyansky J;Prather RS;McCray PB Jr;Zabner J;Welsh MJ;Stoltz DA
通讯作者：
Stoltz DA