Induction of Atherosclerosis in Mice and Hamsters Without Germline Genetic Engineering

Björklund, Martin; Hollensen, Anne Kruse; Hagensen, Mette K.; Dagnæs‐Hansen, Frederik; Christoffersen, Christina; Mikkelsen, Jacob Giehm; Bentzon, Jacob F.

doi:10.1161/circresaha.114.302937

Cited by 241 publications

(288 citation statements)

References 13 publications

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“…The total cholesterol levels achieved were lower and the variation higher than previously reported by us for the rAAV8-D377Y-PCSK9 technique (16). This may have been due to the close temporal proximity of the liver-directed rAAV8-D377Y-PCSK9 gene transfer and the series of hepatotoxic tamoxifen injections, since other work conducted by us concurrently (unpublished observations, 2015), in which rAAV8-D377Y-PCSK9 treatment was deferred 1 month after the last tamoxifen injection, led to levels and variation of cholesterol similar to our previous report (16).…”

Section: Apoecontrasting

confidence: 68%

“…The combination of the 2 transgenes, thus, allowed us to track the progeny of single medial SMCs during the development of atherosclerosis, irrespective of phenotypic changes they might undergo. To meet the third limitation, we induced atherosclerosis without deleting Apoe with adeno-associated virus encoding a murine gain-of-function mutant (D377Y) of PCSK9 in hepatocytes, which renders the mice functionally LDL receptor deficient and severely hypercholesterolemic when fed a high-fat diet (16). We induced CRE recombinase activity between 6 and 8 weeks of age in Myh11-CreER T2 Confetti mice and in Myh11-CreER T2 littermate controls.…”

Section: Apoementioning

confidence: 99%

“…Three to 5 days after the last injection, hypercholesterolemia and atherosclerosis was induced by i.v. injection of rAAV8-mD377Y-mPCSK9 virus particles (1 × 10 11 vector genomes, produced at Vector Core at the University of North Carolina, Chapel Hill, North Carolina, USA) combined with feeding a high-fat diet (D12079B, Research Diets Inc.) containing 21% fat and 0.2% cholesterol as previously described (16). Plasma total cholesterol was measured in duplicate with an enzymatic cholesterol reagent (CHOD-PAP, Roche Diagnostics).…”

Section: Embryo Aggregation Apoementioning

confidence: 99%

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Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs

et al. 2017

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Section: Apoecontrasting

confidence: 68%

Section: Apoementioning

confidence: 99%

Section: Embryo Aggregation Apoementioning

confidence: 99%

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Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs

et al. 2017

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“…[145][146][147] Gainof-function mutations of PCSK9 lead to hypercholesterolemia. 148,149 Therefore, an adenovirus-associated vector technique has been applied to introduce a gain-of-function mutation of human PCSK9D374Y or its mouse equivalent, D377Y, in mice, [150][151][152][153] which results in profound increases of plasma cholesterol concentration with lipoprotein distribution comparable to that of Ldlr −/− mice fed a Western diet. This approach is rapid and efficient and mimics the Ldlr-deficient condition, augmenting atherosclerosis within a short period in C57BL/6 mice.…”

Section: Viral-based Expression Systemsmentioning

confidence: 99%

“…This approach is rapid and efficient and mimics the Ldlr-deficient condition, augmenting atherosclerosis within a short period in C57BL/6 mice. [150][151][152]154 However, the C57BL/6 mouse strain, but not other normolipidemic mouse strains such as FVB, 129, and BALB/C, responds to enhanced expression of PCSK9 activity. 151,152 There is also evidence that PCSK9 has effects independent of LDL receptor regulation.…”

Section: Viral-based Expression Systemsmentioning

confidence: 99%

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association

Daugherty¹,

Tall²,

Daemen³

et al. 2017

Circulation Research

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Abstract-Animal studies are a foundation for defining mechanisms of atherosclerosis and potential targets of drugs to prevent lesion development or reverse the disease. In the current literature, it is common to see contradictions of outcomes in animal studies from different research groups, leading to the paucity of extrapolations of experimental findings into understanding the human disease. The purpose of this statement is to provide guidelines for development and execution of experimental design and interpretation in animal studies. Recommendations include the following: (1) animal model selection, with commentary on the fidelity of mimicking facets of the human disease; (2) experimental design and its impact on the interpretation of data; and (3) standard methods to enhance accuracy of measurements and characterization of atherosclerotic lesions. (Circ Res. 2017;121:e53-e79.

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Atherosclerosis: Pathogenesis, Genetics and Experimental Models

Mota

Homeister

Willis

et al. 2017

Encyclopedia of Life Sciences

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Atherosclerosis is a progressive disease of the arteries that results in the development of heart disease and stroke – the most common causes of death in developed countries and a growing socioeconomic burden in developing countries. Atherosclerosis results from an initial injury to the artery endothelium caused by mechanical and environmental factors, resulting in an inflammatory response in the vessel wall. The location and morphology of the atherosclerotic lesions predict the nature of the resulting vascular disease. Many risk factors for the disease are well known, and current therapies are largely directed at modifying them; however, the large array of poorly understood polygenetic factors affects the development of atherosclerosis. Recent developments in genetic studies have been applied to atherosclerosis and are beginning to rapidly reveal the genetic factors that modulate the pathogenesis of this disease. Key Concepts Atherosclerosis is a common, costly and deadly vascular disease that affects peoples of developed countries and increasingly burdens developing countries. Atherosclerosis is an inflammatory disease of the arterial vascular wall. The pathogenesis of atherosclerosis is complex but is generally explained by the ‘response to injury’ hypothesis for which recent studies in the field extend such hypothesis towards the degree of the inflammatory response to such injury. Atherosclerotic lesions in humans have distinctive morphological characteristics and complications that differ in current animal models, the clinical manifestations correlate mostly with lesion type and location. Both environmental and heritable risk factors modulate atherosclerosis development. Candidate gene and linkage analysis studies have failed to identify previously unknown pathways in the pathogenesis of atherosclerosis. Recent genome‐wide association studies have reproducibly identified several loci involved in the pathogenesis of atherosclerosis, and most of the identified genes are newly implicated in the disease process. Rodent models such as APOE‐ and LDLR‐deficient mice are widely used to study the pathogenesis of atherosclerosis because of its reproducibility and genetic manipulation; however, recent studies with novel and bigger animal models more accurately resemble human disease.

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Induction of Atherosclerosis in Mice and Hamsters Without Germline Genetic Engineering

Cited by 241 publications

References 13 publications

Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs

Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association

Atherosclerosis: Pathogenesis, Genetics and Experimental Models

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