title: Targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis in Yucatan miniature pigs.
abstract: 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.
authors.affiliation: Exemplar Genetics, Coralville, Iowa, United States of America.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Davis
authors.affiliation: Exemplar Genetics, Coralville, Iowa, United States of America.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Exemplar Genetics, Coralville, Iowa, United States of America.
authors.forename: Judy A
authors.initials: JA
authors.lastname: Rohret
authors.affiliation: Exemplar Genetics, Coralville, Iowa, United States of America.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Struzynski
authors.affiliation: Departments of Medicine and Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Merricks
authors.affiliation: Departments of Medicine and Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Dwight A
authors.initials: DA
authors.lastname: Bellinger
authors.affiliation: Exemplar Genetics, Coralville, Iowa, United States of America.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Rohret
authors.affiliation: Departments of Medicine and Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Nichols
authors.affiliation: Exemplar Genetics, Coralville, Iowa, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Rogers
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D023061:Gene Order; D018390:Gene Targeting; D056426:Genetic Loci; D005838:Genotype; D006937:Hypercholesterolemia / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors
chemical_list: D008055:Lipids; D011973:Receptors, LDL