Identification of a mutation in the low density lipoprotein receptor gene associated with recessive familial hypercholesterolemia in swine

Hasler‐Rapacz, Judith; Ellegren, Hans; Fridolfsson, Anna‐Karin; Kirkpatrick, Brian; Kirk, Scott M.; Andersson, Leif; Rapacz, J.

doi:10.1002/(sici)1096-8628(19980413)76:5<379::aid-ajmg3>3.3.co;2-g

Cited by 19 publications

(27 citation statements)

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“…Finally, the WT background for RFH swine was only recently developed, and this study used the most aged animals available from this herd. None of the previous publications describing the use of RFH swine as models for atherosclerosis and restenosis have included a background‐matched WT control 24, 25, 26, 27…”

Section: Discussionmentioning

confidence: 99%

“…RFH swine express elevated LDL levels as a result of a mutation in the gene encoding the LDL receptor (LDL‐R),24 as is commonly observed in humans with FH. Due to their ability to develop complex atherosclerotic lesions that closely mimic those found in humans, these animals have been used extensively in the study of atherosclerosis over the past 2 decades,25 as well as in the development and validation of therapeutic and diagnostic cardiovascular technologies 26, 27.…”

Section: Introductionmentioning

confidence: 99%

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Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Porras

Shanmuganayagam

Meudt

et al. 2015

JAHA

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BackgroundFamilial hypercholesterolemia (FH) is a prevalent hereditary disease associated with increased atherosclerosis and calcific aortic valve disease (CAVD). However, in both FH and non‐FH individuals, the role of hypercholesterolemia in the development of CAVD is poorly understood. This study used Rapacz FH (RFH) swine, an established model of human FH, to investigate the role of hypercholesterolemia alone in the initiation and progression of CAVD. The valves of RFH swine have not previously been examined.Methods and ResultsAortic valve leaflets were isolated from wild‐type (0.25‐ and 1‐year‐old) and RFH (0.25‐, 1‐, 2‐, and 3‐year‐old) swine. Adult RFH animals exhibited numerous hallmarks of early CAVD. Significant leaflet thickening was found in adult RFH swine, accompanied by extensive extracellular matrix remodeling, including proteoglycan enrichment, collagen disorganization, and elastin fragmentation. Increased lipid oxidation and infiltration of macrophages were also evident in adult RFH swine. Intracardiac echocardiography revealed mild aortic valve sclerosis in some of the adult RFH animals, but unimpaired valve function. Microarray analysis of valves from adult versus juvenile RFH animals revealed significant upregulation of inflammation‐related genes, as well as several commonalities with atherosclerosis and overlap with human CAVD.ConclusionsAdult RFH swine exhibited several hallmarks of early human CAVD, suggesting potential for these animals to help elucidate CAVD etiology in both FH and non‐FH individuals. The development of advanced atherosclerotic lesions, but only early‐stage CAVD, in RFH swine supports the hypothesis of an initial shared disease process, with additional stimulation necessary for further progression of CAVD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Porras

Shanmuganayagam

Meudt

et al. 2015

JAHA

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“…The Rapacz FH swine model is characterized by a single missense mutation in the LDL receptor that decreases its affinity for LDL, resulting in elevated LDL and total cholesterol levels (7,8). Most studies into human hypercholesterolemia define their patients by a high cholesterol and LDL combined with a family history of hypercholesterolemia.…”

Section: Methodological Considerationsmentioning

confidence: 99%

“…For this purpose, we chronically instrumented Yucatan (Control) and Rapacz FH swine (7) and assessed the effects of hypercholesterolemia on endothelial and smooth muscle function, as well as vascular tone at rest and during exercise in the systemic and pulmonary vascular beds.…”

Section: Familial Hypercholesterolemia Impairs Exercise-induced Systementioning

confidence: 99%

Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability

Beer

Merkus

Bender

et al. 2013

Journal of Applied Physiology

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Hypercholesterolemia impairs endothelial function [e.g., the nitric oxide (NO)-cyclic GMP-phosphodiesterase 5 (PDE5) pathway], limits shear stress-induced vasodilation, and is therefore expected to reduce exercise-induced vasodilation. To assess the actual effects of hypercholesterolemia on endothelial function and exercise-induced vasodilation, we compared the effects of endothelial NO synthase (eNOS) and PDE5 inhibition in chronically instrumented Yucatan (Control) and Rapacz familial hypercholesterolemic (FH) swine, at rest and during treadmill exercise. The increases in systemic vascular conductance produced by ATP (relative to nitroprusside) and exercise were blunted in FH compared with Control swine. The vasoconstrictor response to eNOS inhibition, with nitro-l-arginine (NLA), was attenuated in FH compared with Control swine, both at rest and during exercise. Furthermore, whereas the vasodilator response to nitroprusside was enhanced slightly, the vasodilator response to PDE5 inhibition, with EMD360527, was reduced in FH compared with Control swine. Finally, in the pulmonary circulation, FH resulted in attenuated vasodilator responses to ATP, while maintaining the responses to both NLA and EMD360527. In conclusion, hypercholesterolemia reduces exercise-induced vasodilation in the systemic but not the pulmonary circulation. This reduction appears to be the principal result of a decrease in NO bioavailability, which is mitigated by a lower PDE5 activity.

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“…The pig, by virtue of its similarity to humans with respect to size of the coronary artery, pathoanatomy, and physiology, is an ideal animal for the study of human coronary artery disease 5. Porcine models of atherosclerosis have gained attention, and several pig/minipig models, such as the Rapacz familial hypercholesterolemic (FH) pig and the low‐density lipoprotein receptor (LDLR) knockout Yucatan minipig, were developed recently 6, 7, 8, 9, 10, 11. These models, however, are not ideal.…”

Section: Introductionmentioning

confidence: 99%

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

Fuchimoto

Sudo

et al. 2016

JAHA

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BackgroundAlthough clinical trials have proved that statin can be used prophylactically against cardiovascular events, the direct effects of statin on plaque development are not well understood. We generated low‐density lipoprotein receptor knockout (LDLR −/−) pigs to study the effects of early statin administration on development of atherosclerotic plaques, especially advanced plaques.Methods and Results LDLR −/− pigs were generated by targeted deletion of exon 4 of the LDLR gene. Given a standard chow diet, LDLR −/− pigs showed atherosclerotic lesions starting at 6 months of age. When 3‐month‐old LDLR −/− pigs were fed a high‐cholesterol, high‐fat (HCHF) diet for 4 months (HCHF group), human‐like advanced coronary plaques developed. We also fed 3‐month‐old LDLR −/− pigs an HCHF diet with pitavastatin for 4 months (Statin Prophylaxis Group). Although serum cholesterol concentrations did not differ significantly between the 2 groups, intravascular ultrasound revealed 52% reduced plaque volume in statin‐treated pigs. Pathological examination revealed most lesions (87%) in the statin prophylaxis group were early‐stage lesions, versus 45% in the HCHF diet group (P<0.01). Thin‐cap fibroatheroma characterized 40% of the plaques in the HCHF diet group versus 8% in the statin prophylaxis group (P<0.01), intraplaque hemorrhage characterized 11% versus 1% (P<0.01), and calcification characterized 22% versus 1% (P<0.01).ConclusionsResults of our large animal experiment support statin prophylaxis before the occurrence of atherosclerosis. Early statin treatment appears to retard development of coronary artery atherosclerosis and ensure lesion stability. In addition, the LDLR −/− pigs we developed represent a large animal model of human‐like advanced coronary plaque suitable for translational research.

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Identification of a mutation in the low density lipoprotein receptor gene associated with recessive familial hypercholesterolemia in swine

Cited by 19 publications

References 0 publications

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology

Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

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