title: Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E-deficient mice.
abstract: Murine models of atherosclerosis, such as the apolipoprotein E (apoE) or the LDL receptor knockout mice, usually do not exhibit many of the cardinal features of human coronary heart disease (CHD), eg, spontaneous myocardial infarction, severe cardiac dysfunction, and premature death. Here we show that mice with homozygous null mutations in the genes for both the high density lipoprotein receptor SR-BI and apoE (SR-BI/apoE double knockout [dKO] mice) exhibit morphological and functional defects with similarities to those seen in human CHD. When fed a standard chow diet, these hypercholesterolemic animals developed significant atherosclerotic lesions in the aortic sinus as early as 4 to 5 weeks after birth. We now show that they also exhibited extensive lipid-rich coronary artery occlusions and spontaneously developed multiple myocardial infarctions and cardiac dysfunction (eg, enlarged hearts, reduced ejection fraction and contractility, and ECG abnormalities). Their coronary arterial lesions, which were strikingly similar to human atherosclerotic plaques, exhibited evidence of cholesterol clefts and extensive fibrin deposition, indicating hemorrhage and clotting. All of the dKO mice died by 8 weeks of age (50% mortality at 6 weeks). Thus, SR-BI/apoE dKO mice provide a new murine model for CHD and may help better define the role of lipoprotein metabolism and atherosclerosis in the pathogenesis of myocardial infarction and cardiac dysfunction. Furthermore, these animals may be useful for preclinical testing of potential genetic and/or pharmacological therapies for CHD.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Mass 02139, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Braun
authors.forename: Bernardo L
authors.initials: BL
authors.lastname: Trigatti
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Post
authors.forename: Kaori
authors.initials: K
authors.lastname: Sato
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.forename: Jay M
authors.initials: JM
authors.lastname: Edelberg
authors.forename: Robert D
authors.initials: RD
authors.lastname: Rosenberg
authors.forename: Mark
authors.initials: M
authors.lastname: Schrenzel
authors.forename: Monty
authors.initials: M
authors.lastname: Krieger
mesh_terms: D017668:Age of Onset; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics*; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004195:Disease Models, Animal; D018450:Disease Progression; D004562:Electrocardiography; D006321:Heart / Q000503:physiopathology*; D006439:Hemodynamics; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D015996:Survival Rate
chemical_list: D001057:Apolipoproteins E; D018955:CD36 Antigens; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B