Induction of atherosclerosis in mice and hamsters without germline genetic engineering

Martin Mæng Bjørklund; Anne Kruse Hollensen; Mette Kallestrup Hagensen; Frederik Dagnæs-Hansen; Christina Christoffersen; Jacob Giehm Mikkelsen; Jacob Fog Bentzon

doi:10.1161/circresaha.114.302937

Induction of atherosclerosis in mice and hamsters without germline genetic engineering

Martin Mæng Bjørklund, Anne Kruse Hollensen, Mette Kallestrup Hagensen, Frederik Dagnæs-Hansen, Christina Christoffersen, Jacob Giehm Mikkelsen, Jacob Fog Bentzon

Physiology of circulation, kidney and lung

96 Citations (Scopus)

Abstract

RATIONALE: 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.

METHODS AND 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.

Original language	English
Journal	Circulation Research
Volume	114
Issue number	11
Pages (from-to)	1684-9
Number of pages	6
DOIs	https://doi.org/10.1161/circresaha.114.302937
Publication status	Published - 23 May 2014

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10.1161/circresaha.114.302937

https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.114.302937

Cite this

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title = "Induction of atherosclerosis in mice and hamsters without germline genetic engineering",

abstract = "RATIONALE: 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.METHODS AND 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.",

author = "Bj{\o}rklund, {Martin M{\ae}ng} and Hollensen, {Anne Kruse} and Hagensen, {Mette Kallestrup} and Frederik Dagn{\ae}s-Hansen and Christina Christoffersen and Mikkelsen, {Jacob Giehm} and Bentzon, {Jacob Fog}",

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doi = "10.1161/circresaha.114.302937",

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T1 - Induction of atherosclerosis in mice and hamsters without germline genetic engineering

AU - Bjørklund, Martin Mæng

AU - Hollensen, Anne Kruse

AU - Hagensen, Mette Kallestrup

AU - Dagnæs-Hansen, Frederik

AU - Christoffersen, Christina

AU - Mikkelsen, Jacob Giehm

AU - Bentzon, Jacob Fog

PY - 2014/5/23

Y1 - 2014/5/23

N2 - RATIONALE: 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.METHODS AND 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.

AB - RATIONALE: 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.METHODS AND 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.

U2 - 10.1161/circresaha.114.302937

DO - 10.1161/circresaha.114.302937

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C2 - 24677271

SN - 0009-7330

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SP - 1684

EP - 1689

JO - Circulation Research

JF - Circulation Research

IS - 11

ER -

Induction of atherosclerosis in mice and hamsters without germline genetic engineering

Abstract

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