Circulation Research. 2002;90:270-276
Published online before print January 3, 2002, doi: 10.1161/hh0302.104462
Published online before print January 3, 2002, doi: 10.1161/hh0302.104462
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© 2002 American Heart Association, Inc.
Integrative Physiology |
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
From the Department of Biology (A.B., B.L.T., J.M.E., R.D.R., M.K.) and Division of Comparative Medicine (M. Schrenzel), Massachusetts Institute of Technology, Cambridge, Mass; and Angiogenesis Research Center (M.J.P., K.S., M. Simons), Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Mass. Present address for B.L.T. is the Department of Biochemistry, McMaster University, Hamilton, Canada; for J.M.E., the Department of Medicine, Weill Medical College of Cornell University, New York, NY; for M.J.P. and M. Simons, the Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH; for K.S., the Division of Cardiovascular Research, St Elizabeth’s Medical Center, Boston, Mass; and for M. Schrenzel, Zoological Society of San Diego, San Diego, Calif.
Correspondence to Monty Krieger, Biology Department, Room 68-483, Massachusetts Institute of Technology, Cambridge, MA 02139. E-mail krieger{at}mit.edu
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.
Key Words: SR-BI/apolipoprotein E knockout mice • atherosclerosis • myocardial infarction • coronary artery disease • lipoprotein metabolism
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 A. Braun, S. Zhang, H. E. Miettinen, S. Ebrahim, T. M. Holm, E. Vasile, M. J. Post, D. M. Yoerger, M. H. Picard, J. L. Krieger, et al. Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse PNAS, June 10, 2003; 100(12): 7283 - 7288. [Abstract] [Full Text] [PDF]
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 A. Rigotti, H. E. Miettinen, and M. Krieger The Role of the High-Density Lipoprotein Receptor SR-BI in the Lipid Metabolism of Endocrine and Other Tissues Endocr. Rev., June 1, 2003; 24(3): 357 - 387. [Abstract] [Full Text] [PDF]
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D. Osgood, D. Corella, S. Demissie, L. A. Cupples, P. W. F. Wilson, J. B. Meigs, E. J. Schaefer, O. Coltell, and J. M. Ordovas Genetic Variation at the Scavenger Receptor Class B Type I Gene Locus Determines Plasma Lipoprotein Concentrations and Particle Size and Interacts with Type 2 Diabetes: The Framingham Study J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2869 - 2879. [Abstract] [Full Text] [PDF]
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P. Cullen, R. Baetta, S. Bellosta, F. Bernini, G. Chinetti, A. Cignarella, A. von Eckardstein, A. Exley, M. Goddard, M. Hofker, et al. Rupture of the Atherosclerotic Plaque: Does a Good Animal Model Exist? Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 535 - 542. [Abstract] [Full Text] [PDF]
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O. Rozenberg, D. M. Shih, and M. Aviram Human Serum Paraoxonase 1 Decreases Macrophage Cholesterol Biosynthesis: Possible Role for Its Phospholipase-A2-Like Activity and Lysophosphatidylcholine Formation Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 461 - 467. [Abstract] [Full Text] [PDF]
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P. Mardones, A. Pilon, M. Bouly, D. Duran, T. Nishimoto, H. Arai, K. F. Kozarsky, M. Altayo, J. F. Miquel, G. Luc, et al. Fibrates Down-regulate Hepatic Scavenger Receptor Class B Type I Protein Expression in Mice J. Biol. Chem., February 28, 2003; 278(10): 7884 - 7890. [Abstract] [Full Text] [PDF]
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M. Vinals, S. Xu, E. Vasile, and M. Krieger Identification of the N-Linked Glycosylation Sites on the High Density Lipoprotein (HDL) Receptor SR-BI and Assessment of Their Effects on HDL Binding and Selective Lipid Uptake J. Biol. Chem., February 7, 2003; 278(7): 5325 - 5332. [Abstract] [Full Text] [PDF]
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T. J. F. Nieland, M. Penman, L. Dori, M. Krieger, and T. Kirchhausen Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI PNAS, November 26, 2002; 99(24): 15422 - 15427. [Abstract] [Full Text] [PDF]
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W. Palinski and C. Napoli Unraveling Pleiotropic Effects of Statins on Plaque Rupture Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1745 - 1750. [Full Text] [PDF]
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B. Liu and M. Krieger Highly Purified Scavenger Receptor Class B, Type I Reconstituted into Phosphatidylcholine/Cholesterol Liposomes Mediates High Affinity High Density Lipoprotein Binding and Selective Lipid Uptake J. Biol. Chem., September 6, 2002; 277(37): 34125 - 34135. [Abstract] [Full Text] [PDF]
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A. R. Tall MIghty Mouse Circ. Res., February 22, 2002; 90(3): 244 - 245. [Full Text] [PDF]
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 C. MINEO and P.W. SHAUL Modulation of Endothelial NO Production by High-density Lipoprotein Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 459 - 470. [Abstract] [PDF]
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