Ossabaw Pigs With a PCSK9 Gain-of-Function Mutation Develop Accelerated Coronary Atherosclerotic Lesions

A Novel Model for Preclinical Studies

Fang Yuan, Liang Guo, Kyoung Ha Park, John R. Woollard, Kwon Taek-Geun, Kai Jiang, Tamene Melkamu, Bin Zang, Samantha L. Smith, Scott C. Fahrenkrug, Frank D. Kolodgie, Amir Lerman, Renu Virmani, Lilach O Lerman, Daniel F. Carlson

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

BACKGROUND: Ossabaw pigs are unique miniature swine with genetic predisposition to develop metabolic syndrome and coronary atherosclerosis after extended periods receiving atherogenic diets. We have hypothesized that transgenic Ossabaw swine expressing chimp PCSK9 (proprotein convertase subtilisin-like/kexin type 9) containing the D374Y gain of function would develop familial hypercholesterolemia and coronary artery plaques more rapidly than Landrace swine with the same transgene. METHODS AND RESULTS: Ossabaw and Landrace PCSK9 gain-of-function founders were generated by Sleeping Beauty transposition and cloning. Histopathologic findings in the Ossabaw founder animal showed more advanced plaques and higher stenosis than in the Landrace founder, underscoring the Ossabaw genetic predisposition to atherosclerosis. We chose to further characterize the Ossabaw PCSK9 gain-of-function animals receiving standard or atherogenic diets in a 6-month longitudinal study using computed tomography, magnetic resonance (MR) imaging, intravascular ultrasound, and optical coherence tomography, followed by pathological analysis of atherosclerosis focused on the coronary arteries. The Ossabaw model was consistently hypercholesterolemic, with or without dietary challenge, and by 6 months had consistent and diffuse fibrofatty or fibroatheromatous plaques with necrosis, overlying fibrous caps, and calcification in up to 10% of coronary plaques. CONCLUSIONS: The Ossabaw PCSK9 gain-of-function model provides consistent and robust disease development in a time frame that is practical for use in preclinical therapeutic evaluation to drive innovation. Although no animal model perfectly mimics the human condition, this genetic large-animal model is a novel tool for testing therapeutic interventions in the context of developing and advanced coronary artery disease.

Original languageEnglish (US)
JournalJournal of the American Heart Association
Volume7
Issue number6
DOIs
StatePublished - Mar 23 2018

Fingerprint

Swine
Atherogenic Diet
Mutation
Genetic Predisposition to Disease
Coronary Artery Disease
Atherosclerosis
Coronary Vessels
Animal Models
Miniature Swine
Beauty
Hyperlipoproteinemia Type II
Optical Coherence Tomography
Medical Genetics
Atherosclerotic Plaques
Transgenes
Longitudinal Studies
Organism Cloning
Pathologic Constriction
Necrosis
Tomography

Keywords

  • atherosclerosis
  • coronary artery disease
  • PCSK9
  • pig

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Ossabaw Pigs With a PCSK9 Gain-of-Function Mutation Develop Accelerated Coronary Atherosclerotic Lesions : A Novel Model for Preclinical Studies. / Yuan, Fang; Guo, Liang; Park, Kyoung Ha; Woollard, John R.; Taek-Geun, Kwon; Jiang, Kai; Melkamu, Tamene; Zang, Bin; Smith, Samantha L.; Fahrenkrug, Scott C.; Kolodgie, Frank D.; Lerman, Amir; Virmani, Renu; Lerman, Lilach O; Carlson, Daniel F.

In: Journal of the American Heart Association, Vol. 7, No. 6, 23.03.2018.

Research output: Contribution to journalArticle

Yuan, F, Guo, L, Park, KH, Woollard, JR, Taek-Geun, K, Jiang, K, Melkamu, T, Zang, B, Smith, SL, Fahrenkrug, SC, Kolodgie, FD, Lerman, A, Virmani, R, Lerman, LO & Carlson, DF 2018, 'Ossabaw Pigs With a PCSK9 Gain-of-Function Mutation Develop Accelerated Coronary Atherosclerotic Lesions: A Novel Model for Preclinical Studies', Journal of the American Heart Association, vol. 7, no. 6. https://doi.org/10.1161/JAHA.117.006207
Yuan, Fang ; Guo, Liang ; Park, Kyoung Ha ; Woollard, John R. ; Taek-Geun, Kwon ; Jiang, Kai ; Melkamu, Tamene ; Zang, Bin ; Smith, Samantha L. ; Fahrenkrug, Scott C. ; Kolodgie, Frank D. ; Lerman, Amir ; Virmani, Renu ; Lerman, Lilach O ; Carlson, Daniel F. / Ossabaw Pigs With a PCSK9 Gain-of-Function Mutation Develop Accelerated Coronary Atherosclerotic Lesions : A Novel Model for Preclinical Studies. In: Journal of the American Heart Association. 2018 ; Vol. 7, No. 6.
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abstract = "BACKGROUND: Ossabaw pigs are unique miniature swine with genetic predisposition to develop metabolic syndrome and coronary atherosclerosis after extended periods receiving atherogenic diets. We have hypothesized that transgenic Ossabaw swine expressing chimp PCSK9 (proprotein convertase subtilisin-like/kexin type 9) containing the D374Y gain of function would develop familial hypercholesterolemia and coronary artery plaques more rapidly than Landrace swine with the same transgene. METHODS AND RESULTS: Ossabaw and Landrace PCSK9 gain-of-function founders were generated by Sleeping Beauty transposition and cloning. Histopathologic findings in the Ossabaw founder animal showed more advanced plaques and higher stenosis than in the Landrace founder, underscoring the Ossabaw genetic predisposition to atherosclerosis. We chose to further characterize the Ossabaw PCSK9 gain-of-function animals receiving standard or atherogenic diets in a 6-month longitudinal study using computed tomography, magnetic resonance (MR) imaging, intravascular ultrasound, and optical coherence tomography, followed by pathological analysis of atherosclerosis focused on the coronary arteries. The Ossabaw model was consistently hypercholesterolemic, with or without dietary challenge, and by 6 months had consistent and diffuse fibrofatty or fibroatheromatous plaques with necrosis, overlying fibrous caps, and calcification in up to 10{\%} of coronary plaques. CONCLUSIONS: The Ossabaw PCSK9 gain-of-function model provides consistent and robust disease development in a time frame that is practical for use in preclinical therapeutic evaluation to drive innovation. Although no animal model perfectly mimics the human condition, this genetic large-animal model is a novel tool for testing therapeutic interventions in the context of developing and advanced coronary artery disease.",
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T1 - Ossabaw Pigs With a PCSK9 Gain-of-Function Mutation Develop Accelerated Coronary Atherosclerotic Lesions

T2 - A Novel Model for Preclinical Studies

AU - Yuan, Fang

AU - Guo, Liang

AU - Park, Kyoung Ha

AU - Woollard, John R.

AU - Taek-Geun, Kwon

AU - Jiang, Kai

AU - Melkamu, Tamene

AU - Zang, Bin

AU - Smith, Samantha L.

AU - Fahrenkrug, Scott C.

AU - Kolodgie, Frank D.

AU - Lerman, Amir

AU - Virmani, Renu

AU - Lerman, Lilach O

AU - Carlson, Daniel F.

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N2 - BACKGROUND: Ossabaw pigs are unique miniature swine with genetic predisposition to develop metabolic syndrome and coronary atherosclerosis after extended periods receiving atherogenic diets. We have hypothesized that transgenic Ossabaw swine expressing chimp PCSK9 (proprotein convertase subtilisin-like/kexin type 9) containing the D374Y gain of function would develop familial hypercholesterolemia and coronary artery plaques more rapidly than Landrace swine with the same transgene. METHODS AND RESULTS: Ossabaw and Landrace PCSK9 gain-of-function founders were generated by Sleeping Beauty transposition and cloning. Histopathologic findings in the Ossabaw founder animal showed more advanced plaques and higher stenosis than in the Landrace founder, underscoring the Ossabaw genetic predisposition to atherosclerosis. We chose to further characterize the Ossabaw PCSK9 gain-of-function animals receiving standard or atherogenic diets in a 6-month longitudinal study using computed tomography, magnetic resonance (MR) imaging, intravascular ultrasound, and optical coherence tomography, followed by pathological analysis of atherosclerosis focused on the coronary arteries. The Ossabaw model was consistently hypercholesterolemic, with or without dietary challenge, and by 6 months had consistent and diffuse fibrofatty or fibroatheromatous plaques with necrosis, overlying fibrous caps, and calcification in up to 10% of coronary plaques. CONCLUSIONS: The Ossabaw PCSK9 gain-of-function model provides consistent and robust disease development in a time frame that is practical for use in preclinical therapeutic evaluation to drive innovation. Although no animal model perfectly mimics the human condition, this genetic large-animal model is a novel tool for testing therapeutic interventions in the context of developing and advanced coronary artery disease.

AB - BACKGROUND: Ossabaw pigs are unique miniature swine with genetic predisposition to develop metabolic syndrome and coronary atherosclerosis after extended periods receiving atherogenic diets. We have hypothesized that transgenic Ossabaw swine expressing chimp PCSK9 (proprotein convertase subtilisin-like/kexin type 9) containing the D374Y gain of function would develop familial hypercholesterolemia and coronary artery plaques more rapidly than Landrace swine with the same transgene. METHODS AND RESULTS: Ossabaw and Landrace PCSK9 gain-of-function founders were generated by Sleeping Beauty transposition and cloning. Histopathologic findings in the Ossabaw founder animal showed more advanced plaques and higher stenosis than in the Landrace founder, underscoring the Ossabaw genetic predisposition to atherosclerosis. We chose to further characterize the Ossabaw PCSK9 gain-of-function animals receiving standard or atherogenic diets in a 6-month longitudinal study using computed tomography, magnetic resonance (MR) imaging, intravascular ultrasound, and optical coherence tomography, followed by pathological analysis of atherosclerosis focused on the coronary arteries. The Ossabaw model was consistently hypercholesterolemic, with or without dietary challenge, and by 6 months had consistent and diffuse fibrofatty or fibroatheromatous plaques with necrosis, overlying fibrous caps, and calcification in up to 10% of coronary plaques. CONCLUSIONS: The Ossabaw PCSK9 gain-of-function model provides consistent and robust disease development in a time frame that is practical for use in preclinical therapeutic evaluation to drive innovation. Although no animal model perfectly mimics the human condition, this genetic large-animal model is a novel tool for testing therapeutic interventions in the context of developing and advanced coronary artery disease.

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