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

Circulation Research - Tập 90 Số 3 - Trang 270-276 - 2002
Anne Braun1,2,3,4,5,6, Bernardo L. Trigatti7,2,3,4,5,6, Mark J. Post2,8,3,4,5,6, Kaori Sato2,9,3,4,5,6, Michael Simons2,10,3,4,5,6, Jay M. Edelberg2,11,3,4,5,6, Robert Rosenberg2,12,3,4,5,6, Mark D. Schrenzel2,13,3,4,5,6, Monty Krieger2,14,3,4,5,6
1Anne Braun 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
2From 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...
3for J.M.E., the Department of Medicine, Weill Medical College of Cornell University, New York, NY
4for K.S., the Division of Cardiovascular Research, St Elizabeth's Medical Center, Boston, Mass
5for M. Schrenzel, Zoological Society of San Diego, San Diego, Calif.
6for M.J.P. and M. Simons, the Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH
7Bernardo L. Trigatti 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
8Mark J. Post 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
9Kaori Sato 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
10Michael Simons 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
11Jay M. Edelberg 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
12Robert D. Rosenberg 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
13Mark Schrenzel 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
14Monty Krieger 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

Tóm tắt

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.

Từ khóa


Tài liệu tham khảo

10.1172/JCI117179

10.1016/0092-8674(92)90362-G

10.1126/science.1411543

10.1172/JCI117460

10.1161/atv91.14.1.8274468

10.1073/pnas.96.12.6920

10.1038/70956

10.1023/A:1006828724405

10.1073/pnas.96.16.9322

10.1073/pnas.94.23.12610

10.1172/JCI2006

Vargas SO, Sampson BA, Schoen FJ. Pathologic detection of early myocardial infarction: a critical review of the evolution and usefulness of modern techniques. Mod Pathol. 1999; 12: 635–645.

10.1172/JCI1330

10.1186/1472-6793-1-6

Stary HC. The Evolution of Human Atherosclerotic Lesions. West Point Pa: Merck & Co Inc; 1993.

10.1016/S0022-0736(00)80072-2

10.1161/atvb.20.12.2587

10.1161/atvb.20.5.1262

10.1097/00041433-200004000-00004

Swertfeger DK, Hui DY. Apolipoprotein E: a cholesterol transport protein with lipid transport-independent cell signaling properties. Front Biosci. 2001; 6: D526–D535.

10.1097/00041433-200006000-00004

10.1146/annurev.biochem.68.1.523

10.1038/387414a0

10.1016/S0022-2275(20)31676-X

10.1074/jbc.272.34.20982

10.1038/89986

10.1046/j.1471-4159.2001.00100.x

Mardones P Strobel P Miranda S Leighton F Quiñones V Amigo L Rozowski J Krieger M Rigotti A. Role of the scavenger receptor class B type I (SR-BI) in α-tocopherol metabolism in mice. J Nutr. In press.

10.1016/S0022-2275(20)32362-2

10.1038/2685

10.1073/pnas.240462697

10.1161/atvb.21.4.585

10.1016/S0008-6363(98)00110-2

10.1016/S0002-9440(10)64055-2

10.1172/JCI8040

10.1038/35025196

10.1016/S0092-8674(01)00242-2

10.1161/circ.92.7.1927

10.1086/315251

Yoshida H, Fujiwara H, Fujiwara T, Ikehara S, Hamashima Y. Quantitative analysis of myocardial infarction in (NZWxBXSB)F1 hybrid mice with systemic lupus erythematosus and small coronary artery disease. Am J Pathol. 1987; 129: 477–485.

Holm TM Braun A Trigatti BL Brugnara C Sakamoto M Krieger M Andrews NC. Failure of red blood cell maturation in mice with defects in the HDL receptor SR-BI. Blood. In press.

10.1161/atvb.20.3.846

10.1182/blood.V96.13.4212

10.1172/JCI1461

10.1161/atvb.17.12.3593

10.1002/path.915

10.1161/01.CIR.90.2.775

10.1016/0046-8177(95)90148-5

10.1073/pnas.94.26.14730

10.1097/00000542-199401000-00013

Atlee JLd. Anaesthesia and cardiac electrophysiology. Eur J Anaesthesiol. 1985; 2: 215–256.

Thông tin
Thông tin xuất bản

Circulation Research

Tập 90 Số 3

270-276

Thông tin tác giả