PT  - JOURNAL ARTICLE
AU  - Al-Mashhadi, Rozh H.
AU  - Sørensen, Charlotte B.
AU  - Kragh, Peter M.
AU  - Christoffersen, Christina
AU  - Mortensen, Martin B.
AU  - Tolbod, Lars P.
AU  - Thim, Troels
AU  - Du, Yutao
AU  - Li, Juan
AU  - Liu, Ying
AU  - Moldt, Brian
AU  - Schmidt, Mette
AU  - Vajta, Gabor
AU  - Larsen, Torben
AU  - Purup, Stig
AU  - Bolund, Lars
AU  - Nielsen, Lars B.
AU  - Callesen, Henrik
AU  - Falk, Erling
AU  - Mikkelsen, Jacob Giehm
AU  - Bentzon, Jacob F.
TI  - Familial Hypercholesterolemia and Atherosclerosis in Cloned Minipigs Created by DNA Transposition of a Human <em>PCSK9</em> Gain-of-Function Mutant
AID  - 10.1126/scitranslmed.3004853
DP  - 2013 Jan 02
TA  - Science Translational Medicine
PG  - 166ra1--166ra1
VI  - 5
IP  - 166
4099  - http://stm.sciencemag.org/content/5/166/166ra1.short
4100  - http://stm.sciencemag.org/content/5/166/166ra1.full
AB  - Lack of animal models with human-like size and pathology hampers translational research in atherosclerosis. Mouse models are missing central features of human atherosclerosis and are too small for intravascular procedures and imaging. Modeling the disease in minipigs may overcome these limitations, but it has proven difficult to induce rapid atherosclerosis in normal pigs by high-fat feeding alone, and genetically modified models similar to those created in mice are not available. D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans. Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9. D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging. This model should prove useful for several types of translational research in atherosclerosis.