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Familial Hypercholesterolemia and Atherosclerosis in Cloned Minipigs Created by DNA Transposition of a Human PCSK9 Gain-of-Function Mutant.
MedLine Citation:
PMID:  23283366     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
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.
Authors:
Rozh H Al-Mashhadi; Charlotte B Sørensen; Peter M Kragh; Christina Christoffersen; Martin B Mortensen; Lars P Tolbod; Troels Thim; Yutao Du; Juan Li; Ying Liu; Brian Moldt; Mette Schmidt; Gabor Vajta; Torben Larsen; Stig Purup; Lars Bolund; Lars B Nielsen; Henrik Callesen; Erling Falk; Jacob Giehm Mikkelsen; Jacob F Bentzon
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Science translational medicine     Volume:  5     ISSN:  1946-6242     ISO Abbreviation:  Sci Transl Med     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-03     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101505086     Medline TA:  Sci Transl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  166ra1     Citation Subset:  IM    
Affiliation:
Department of Cardiology, Aarhus University Hospital, and Department of Clinical Medicine, Aarhus University, Brendstrupgaardsvej 100, DK-8200 Aarhus N, Denmark.
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