title: Induction of atherosclerosis in mice and hamsters without germline genetic engineering.
abstract: BACKGROUND
  Atherosclerosis can be achieved in animals by germline genetic engineering, leading to hypercholesterolemia, but such models are constrained to few species and strains, and they are difficult to combine with other powerful techniques involving genetic manipulation or variation.
  
  
  OBJECTIVE
  To develop a method for induction of atherosclerosis without germline genetic engineering.
  
  
  RESULTS
  Recombinant adeno-associated viral vectors were engineered to encode gain-of-function proprotein convertase subtilisin/kexin type 9 mutants, and mice were given a single intravenous vector injection followed by high-fat diet feeding. Plasma proprotein convertase subtilisin/kexin type 9 and total cholesterol increased rapidly and were maintained at high levels, and after 12 weeks, mice had atherosclerotic lesions in the aorta. Histology of the aortic root showed progression of lesions to the fibroatheromatous stage. To demonstrate the applicability of this method for rapid analysis of the atherosclerosis susceptibility of a mouse strain and for providing temporal control over disease induction, we demonstrated the accelerated atherosclerosis of mature diabetic Akita mice. Furthermore, the versatility of this approach for creating atherosclerosis models also in nonmurine species was demonstrated by inducing hypercholesterolemia and early atherosclerosis in Golden Syrian hamsters.
  
  
  CONCLUSIONS
  Single injections of proprotein convertase subtilisin/kexin type 9-encoding recombinant adeno-associated viral vectors are a rapid and versatile method to induce atherosclerosis in animals. This method should prove useful for experiments that are high-throughput or involve genetic techniques, strains, or species that do not combine well with current genetically engineered models.
authors.affiliation: From the Departments of Clinical Medicine (M.M.B., M.K.H., J.F.B.) and Biomedicine (A.K.H., F.D.-H., J.G.M.), Aarhus University, Aarhus, Denmark; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark (M.M.B., M.K.H., J.F.B.); and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark (C.C.).
authors.forename: Martin Maeng
authors.initials: MM
authors.lastname: Bjørklund
authors.affiliation: From the Departments of Clinical Medicine (M.M.B., M.K.H., J.F.B.) and Biomedicine (A.K.H., F.D.-H., J.G.M.), Aarhus University, Aarhus, Denmark; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark (M.M.B., M.K.H., J.F.B.); and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark (C.C.).
authors.forename: Anne Kruse
authors.initials: AK
authors.lastname: Hollensen
authors.affiliation: From the Departments of Clinical Medicine (M.M.B., M.K.H., J.F.B.) and Biomedicine (A.K.H., F.D.-H., J.G.M.), Aarhus University, Aarhus, Denmark; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark (M.M.B., M.K.H., J.F.B.); and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark (C.C.).
authors.forename: Mette Kallestrup
authors.initials: MK
authors.lastname: Hagensen
authors.affiliation: From the Departments of Clinical Medicine (M.M.B., M.K.H., J.F.B.) and Biomedicine (A.K.H., F.D.-H., J.G.M.), Aarhus University, Aarhus, Denmark; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark (M.M.B., M.K.H., J.F.B.); and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark (C.C.).
authors.forename: Frederik
authors.initials: F
authors.lastname: Dagnaes-Hansen
authors.affiliation: From the Departments of Clinical Medicine (M.M.B., M.K.H., J.F.B.) and Biomedicine (A.K.H., F.D.-H., J.G.M.), Aarhus University, Aarhus, Denmark; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark (M.M.B., M.K.H., J.F.B.); and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark (C.C.).
authors.forename: Christina
authors.initials: C
authors.lastname: Christoffersen
authors.affiliation: From the Departments of Clinical Medicine (M.M.B., M.K.H., J.F.B.) and Biomedicine (A.K.H., F.D.-H., J.G.M.), Aarhus University, Aarhus, Denmark; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark (M.M.B., M.K.H., J.F.B.); and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark (C.C.).
authors.forename: Jacob Giehm
authors.initials: JG
authors.lastname: Mikkelsen
authors.affiliation: From the Departments of Clinical Medicine (M.M.B., M.K.H., J.F.B.) and Biomedicine (A.K.H., F.D.-H., J.G.M.), Aarhus University, Aarhus, Denmark; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark (M.M.B., M.K.H., J.F.B.); and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark (C.C.). jben@ki.au.dk.
authors.forename: Jacob Fog
authors.initials: JF
authors.lastname: Bentzon
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology*; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000235:genetics; D018095:Germ-Line Mutation; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D011973:Receptors, LDL; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: atherosclerosis; models, animal