Diet-Induced Occlusive Coronary Atherosclerosis, Myocardial Infarction, Cardiac Dysfunction, And Premature Death In Scavenger Receptor Class B Type I-Deficient, Hypomorphic Apolipoprotein Er61 Mice

Background - Normal chow ( low fat) - fed mice deficient in both the HDL receptor SR- BI and apolipoprotein E ( SR- BI/ apoE dKO) provide a distinctive model of coronary heart disease ( CHD). They exhibit early- onset hypercholesterolemia characterized by unesterified cholesterol - rich abnormal lipoproteins ( lamellar/ vesicular and stacked discoidal particles), occlusive coronary atherosclerosis, spontaneous myocardial infarction, cardiac dysfunction, and premature death ( approximate to 6 weeks of age). Mice in which similar features of CHD could be induced with a lipid- rich diet would represent a powerful tool to study CHD.Methods and Results - To generate a diet- inducible model of CHD, we bred SR- BI - deficient ( SR- BI KO) mice with hypomorphic apolipoprotein E mice ( ApoeR61(h/h)) that express reduced levels of an apoE4- like murine apoE isoform and exhibit diet- induced hypercholesterolemia. When fed a normal chow diet, SR- BI KO/ ApoeR61(h/h) h mice did not exhibit early- onset atherosclerosis or CHD; the low expression level of the apoE4- like murine apoE was atheroprotective and cardioprotective. However, when fed an atherogenic diet rich in fat, cholesterol, and cholate, they rapidly developed hypercholesterolemia, atherosclerosis, and CHD, a response strikingly similar to that of SR- BI/ apoE dKO mice fed a chow diet, and they died 32 +/- 6 days ( 50% mortality) after initiation of the high- fat feeding.Conclusions - The SR- BI KO/ ApoeR61(h/h) mouse is a new model of diet- induced occlusive coronary atherosclerosis and CHD ( myocardial infarction, cardiac dysfunction and premature death), allowing control of the age of onset, duration, severity, and possibly regression of disease. Thus, SR- BI KO/ ApoeR61(h/h) mice have the potential to contribute to our understanding of CHD and its prevention and treatment.