Mouse model of chronic heart failure and coronary atherosclerosis regression
Inventors
Raffai, Robert L. • Weisgraber, Karl
Assignees
J David Gladstone Institutes • US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-7960606-B2
Publication Date
2011-06-14
Expiration Date
2027-06-19
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Abstract
An animal model has been developed where the animals can survive myocardial infarctions caused by diet-induced coronary atherosclerosis, and live with chronic heart failure. This animal model is a result of reduced activity of scavenger receptor class BI (SR-BI) and ApoE and the inducible activity of the Mx1-Cre gene. In a preferred embodiment, the model is a result of crossbreeding two transgenic mouse lines: a knockout of SR-BI (SRBI−/−) and an impaired ApoE expressor (Apoeh/h) to generate a strain referred to as Apoeh/hSRB1−/− mice, which is then crossbred to mice that carry the inducible Mx1-Cre transgene. The Apoeh/hSRB1−/− mouse model is genetically modified, enabling the offspring to rapidly and permanently lower their high blood cholesterol levels caused by dietary challenge. The ability to rapidly and permanently lower blood cholesterol levels in these mice stops and may cause the regression of occlusive coronary atherosclerosis restoring blood flow to the heart, allowing the mice to survive from myocardial infarction and live with chronic heart failure.
Core Innovation
An animal model has been developed that enables survival after myocardial infarctions caused by diet-induced coronary atherosclerosis, allowing the animals to live with chronic heart failure. This model results from reduced activity of scavenger receptor class BI (SR-BI) and ApoE combined with inducible activity of the Mx1-Cre gene. The preferred embodiment of the model is achieved by crossbreeding two transgenic mouse lines: a knockout of SR-BI (SRB1−/−) and an impaired ApoE expressor (Apoeh/h) to create Apoeh/hSRB1−/− mice, which are further crossbred with mice carrying the inducible Mx1-Cre transgene.
The offspring from this breeding can rapidly and permanently lower their high blood cholesterol levels caused by dietary challenge through induced expression of the Mx1-Cre gene. This cholesterol reduction halts and may reverse occlusive coronary atherosclerosis, restoring blood flow to the heart. This restoration allows the mice to survive myocardial infarction and develop chronic heart failure, mimicking the human condition of surviving heart attacks caused by coronary atherosclerosis.
The problem solved by this invention addresses the lack of reliable animal models that display human-like chronic heart failure (CHF) following myocardial infarction due to coronary atherosclerosis. Previous models did not allow recovery or survival after heart attacks induced by diet, limiting their use in studying CHF progression and treatments. This new model overcomes the limitation of previous animals that had high mortality within 45 days, enabling investigations into CHF and coronary atherosclerosis regression and the development of potential therapies.
Claims Coverage
The patent includes one independent claim directed to the genetically engineered mouse model and two independent claims related to methods for compound screening and making the mouse model.
Transgenic mouse model with inducible regulation of ApoE and SR-BI knockout
A transgenic mouse comprising homozygous disruption of the endogenous SR-BI gene (SR-B1−/−), a homozygous Arg-61 allelic variant of mouse apolipoprotein E gene (ApoEh/h) with each allele carrying a floxed neomycin cassette, and an inducible Mx1-Cre transgene. Feeding the mouse a cholesterol enriched diet induces myocardial infarction. Subsequent induction of Mx1-Cre expression restores normal ApoE levels, rapidly lowers blood cholesterol, and enables survival with chronic heart failure characterized by myocardial infarctions and enlarged ventricles.
Sensitivity to diet-induced coronary atherosclerosis and fatal myocardial infarction within 35 days
The mouse is sensitive to diet-induced coronary atherosclerosis and develops fatal myocardial infarctions within 35 days of initiating a high cholesterol diet before Mx1-Cre induction.
Method for screening compounds affecting atherosclerosis and chronic heart failure
A method comprising administering a compound to the described transgenic mouse exhibiting chronic heart failure with myocardial infarctions and enlarged ventricles, and determining the compound's effect on disorders such as atherosclerosis and chronic heart failure relative to a control.
Method for producing the transgenic mouse model
A method involving crossing: 1) a mouse homozygous for the Arg-61 ApoE variant carrying floxed neomycin cassette with a mouse carrying inducible Mx1-Cre transgene to produce ApoEh/h/Mx1-Cre mice; and 2) crossing these mice with SR-B1 knockout mice to produce ApoEh/h/SR-B1−/−Mx1-Cre mice. Feeding these mice a cholesterol enriched diet induces myocardial infarction, which can be reversed by Mx1-Cre induction to restore ApoE expression and enable survival with chronic heart failure.
The claims cover the transgenic mouse model genetically engineered to induce myocardial infarction by diet and allow recovery via inducible gene expression, and the associated methods for screening therapeutic compounds and producing this animal model.
Stated Advantages
The animal model enables survival following myocardial infarctions caused by diet-induced coronary atherosclerosis, which was not possible in previous models.
The model allows rapid and permanent lowering of high blood cholesterol, potentially causing regression of coronary atherosclerosis and restoration of blood flow.
It provides a unique platform to study mechanisms and progression of chronic heart failure, and to screen drugs and therapeutic compounds for efficacy and side effects.
The animal model simulates human chronic heart failure with myocardial infarctions and ventricular enlargement, enabling research on treatments to reverse coronary atherosclerosis and promote heart tissue regeneration.
Documented Applications
Studying mechanisms and progression of chronic heart failure as a function of diet.
Screening potential drugs and therapeutic compounds for effects on chronic heart failure and coronary atherosclerosis regression.
Testing therapies to promote growth of new blood vessels or heart muscle in damaged heart tissue.
Screening therapeutic agents for accelerating coronary atherosclerosis regression or influencing cardiac fibrosis, myocardial infarction, defects in electrical conductance, unstable plaque, infertility, reduced life span, and abnormal apolipoprotein metabolism.
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