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(Circulation. 2005;111:3457-3464.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Diet-Induced Occlusive Coronary Atherosclerosis, Myocardial Infarction, Cardiac Dysfunction, and Premature Death in Scavenger Receptor Class B Type I-Deficient, Hypomorphic Apolipoprotein ER61 Mice

Songwen Zhang, PhD; Michael H. Picard, MD; Eliza Vasile, PhD; Yu Zhu, MD; Robert L. Raffai, PhD; Karl H. Weisgraber, PhD; Monty Krieger, PhD

From the Department of Biology, Massachusetts Institute of Technology, Cambridge (S.Z., E.V., Y.Z., M.K.); Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston (M.H.P.); Division of Vascular Surgery, Department of Surgery, University of California, San Francisco and San Francisco Veterans Administration Medical Research Center (R.L.R.); and Department of Pathology and Cardiovascular Research Institute, Gladstone Institutes of Cardiovascular Disease and Neurological Disease, University of California, San Francisco (K.H.W.).

Correspondence to Monty Krieger, Biology Department, Room 68-483, Massachusetts Institute of Technology, Cambridge, MA 02139. E-mail krieger{at}mit.edu

Received November 23, 2004; revision received February 4, 2005; accepted February 16, 2005.

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 (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 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.

Key Words: apolipoproteins • atherosclerosis • diet • myocardial infarction • receptors

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