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 ( approximately 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.


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.
Zhang
Songwen
S
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Picard
Michael H
MH
Vasile
Eliza
E
Zhu
Yu
Y
Raffai
Robert L
RL
Weisgraber
Karl H
KH
Krieger
Monty
M
D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D006332:Cardiomegaly / Q000473:pathology; D003324:Coronary Artery Disease / Q000209:etiology; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004562:Electrocardiography; D006331:Heart Diseases / Q000209:etiology* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D006333:Heart Failure / Q000209:etiology; D006937:Hypercholesterolemia / Q000209:etiology; D008055:Lipids / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009026:Mortality; D009203:Myocardial Infarction / Q000209:etiology; D051122:Scavenger Receptors, Class B / Q000172:deficiency*
D001057:Apolipoproteins E; D008055:Lipids; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; C502425:apolipoprotein E (Arg61), mouse