RT Journal Article
SR Electronic
T1 Familial Hypercholesterolemia and Atherosclerosis in Cloned Minipigs Created by DNA Transposition of a Human <em>PCSK9</em> Gain-of-Function Mutant
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 166ra1
OP 166ra1
DO 10.1126/scitranslmed.3004853
VO 5
IS 166
A1 Al-Mashhadi, Rozh H.
A1 Sørensen, Charlotte B.
A1 Kragh, Peter M.
A1 Christoffersen, Christina
A1 Mortensen, Martin B.
A1 Tolbod, Lars P.
A1 Thim, Troels
A1 Du, Yutao
A1 Li, Juan
A1 Liu, Ying
A1 Moldt, Brian
A1 Schmidt, Mette
A1 Vajta, Gabor
A1 Larsen, Torben
A1 Purup, Stig
A1 Bolund, Lars
A1 Nielsen, Lars B.
A1 Callesen, Henrik
A1 Falk, Erling
A1 Mikkelsen, Jacob Giehm
A1 Bentzon, Jacob F.
YR 2013
UL http://stm.sciencemag.org/content/5/166/166ra1.abstract
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.