title: Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant.
abstract: 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.affiliation: Department of Cardiology, Aarhus University Hospital, and Department of Clinical Medicine, Aarhus University, Brendstrupgaardsvej 100, DK-8200 Aarhus N, Denmark.
authors.forename: Rozh H
authors.initials: RH
authors.lastname: Al-Mashhadi
authors.forename: Charlotte B
authors.initials: CB
authors.lastname: Sørensen
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kragh
authors.forename: Christina
authors.initials: C
authors.lastname: Christoffersen
authors.forename: Martin B
authors.initials: MB
authors.lastname: Mortensen
authors.forename: Lars P
authors.initials: LP
authors.lastname: Tolbod
authors.forename: Troels
authors.initials: T
authors.lastname: Thim
authors.forename: Yutao
authors.initials: Y
authors.lastname: Du
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Brian
authors.initials: B
authors.lastname: Moldt
authors.forename: Mette
authors.initials: M
authors.lastname: Schmidt
authors.forename: Gabor
authors.initials: G
authors.lastname: Vajta
authors.forename: Torben
authors.initials: T
authors.lastname: Larsen
authors.forename: Stig
authors.initials: S
authors.lastname: Purup
authors.forename: Lars
authors.initials: L
authors.lastname: Bolund
authors.forename: Lars B
authors.initials: LB
authors.lastname: Nielsen
authors.forename: Henrik
authors.initials: H
authors.lastname: Callesen
authors.forename: Erling
authors.initials: E
authors.lastname: Falk
authors.forename: Jacob Giehm
authors.initials: JG
authors.lastname: Mikkelsen
authors.forename: Jacob F
authors.initials: JF
authors.lastname: Bentzon
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D050197:Atherosclerosis / Q000235:genetics*; D019976:Cloning, Organism; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D009154:Mutation; D010641:Phenotype; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics*; D013552:Swine; D013556:Swine, Miniature; D019076:Transgenes
chemical_list: D012333:RNA, Messenger; D011973:Receptors, LDL; D004247:DNA; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases