Creating the "Heart-Attack Mouse": A Model for Atherosclerosis

Dr. Breslow (right) with his student Andrew Plump who made the apo E knockout mouse as part of his thesis work

About one-third of all deaths in the United States each year are due to heart disease, most of it caused by atherosclerosis. In this disease process, there is build-up of cholesterol and other materials that alter the inner linings of arteries supplying blood to the heart, leading to blood clots and death of heart muscle tissue (heart attack). Research on atherosclerosis was long hampered by the lack of a small animal model in which to study how plaques of cholesterol form; to unravel the genetic basis for susceptibility to atherosclerosis; and to test new therapies. Mice—among the most convenient laboratory animals—are in fact highly resistant to developing atherosclerosis. But in the early 1990s, Jan Breslow (1943 - ) used new genetic techniques to engineer mice lacking a gene called apo E. The mice developed plaques similar to those in humans—and the lesions were exacerbated when the mice ate a high-cholesterol, high-fat Western-type diet. This "heart-attack mouse" transformed scientific research on atherosclerosis.

Breslow had already pioneered the discovery of human genes that play a role in atherosclerosis. These genes code for molecules called apolipoproteins, which carry cholesterol through the blood. He also was the first to demonstrate that a mutation in one of these genes could lead to atherosclerosis at a young age in humans. Breslow investigated what would happen by removing the gene for apolipoprotein E (apo E) in mice because he knew that apoE on lipoproteins was a signal for their removal from plasma and that human variations in this gene could alter blood levels of low density lipoprotein (LDL)—the "bad" cholesterol that contributes to plaques in arteries.

Scientists inject DNA into mouse embryos. Jan Breslow has developed several such mouse models for reseach on heart disease

Today more than 95 percent of experimental pathology research in atherosclerosis is carried out using the apo E knockout mouse. Not only has it provided a system for studying how lesions form in arteries, it also has given scientists a way to test the effects of other genes on how atherosclerosis develops, by breeding so-called candidate genes onto the apo E knockout mouse background. In addition, when Breslow crossed the apo E knockout trait onto different inbred mouse strains, he found a wide range in the size of the lesions that formed. This indicated modifier genes, and through genetic crosses he has found additional genes involved in atherosclerosis susceptibility. The apo E knockout mouse is also widely used in the pharmaceutical industry to test compounds for treating atherosclerosis.

Jan L. Breslow received the AB from Columbia College (1963), the MA from Columbia University (1964), and the MD from Harvard Medical School (1968). After an internship and residency in pediatrics at Boston Children's Hospital and a post as staff associate at the Molecular Disease Branch of the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda. In 1973 he returned to Boston Children's Hospital as chief of the metabolism division and assistant and then associate professor of pediatrics at Harvard Medical School. He joined Rockefeller University as professor in 1984 and was named Frederick Henry Leonhardt Professor in 1986. He is a senior physician at The Rockefeller University Hospital, where he also served as physician-in-chief in the early 1990s. Among many honors, Breslow has received the American Academy of Pediatrics E. Mead Johnson Award (1984), Germany's Heinrich Wieland Prize in Lipid Research (1991), the American Heart Association's Basic Research Prize (1994), the Bristol-Myers Squibb Award for Distinguished Achievement in Cardiovascular Research (2000), the New York City Mayor's Award for Excellence in Science and Technology (2005), and the American Heart Association's Distinguished Scientist Award (2006). He is a past president of the American Heart Association and has been elected to the U.S. National Academy of Sciences (1995), the Institute of Medicine (1997), and the German National Academy of Sciences (1996).

Selected Publications

Karathanasis SK, Zannis VI, Breslow JL. Isolation and characterization of the human apolipoprotein A-I gene. Proc Natl Acad Sci USA, 1983, 80: 6147-6151

Karathanasis SK, McPherson J, Zannis VI, Breslow JL. Linkage of human apolipoprotein A-I and C-III genes. Nature, 1983, 304: 371-373

Plump AS, Smith JD, Hayek T, Aalto-Setälä K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell, 1992, 71: 343-353

Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. Apo E-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arteriosclerosis and Thrombosis, 1994, 14: 133-140

Palinski W, Ord VA, Plump AS, Breslow JL, Steinberg D, Witztum JL. Apoprotein E-deficient mice are a model of lipoprotein oxidation in atherogenesis: Demonstration of oxidation-specific epitopes in lesions and high titers of auto antibodies to malonyldialdehyde-lysine in serum. Arteriosclerosis and Thrombosis, 1994, 14: 605-616

Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene expression raises HDL and suppresses atherosclerosis in the apo E-deficient mouse. Proc Natl Acad Sci USA, 1994, 91: 9607-9611

Dansky HM, Charlton SA, Sikes JL, Heath SC, Simantov R, Levin LF, Shu P, Moore KJ, Breslow JL, Smith JD. Genetic background determines the extent of atherosclerosis in apo E-deficient mice. Arterioscler Thromb Vasc Biol, 1999, 19: 1960-1968

Rong JX, Li J, Reis ED, Choudhury RP, Dansky HM, Elmalem VI, Fallon JT, Breslow JL, Fisher EA. Elevating HDL cholesterol in apo E-deficient mice remodels advanced atherosclerotic lesions by decreasing macrophage and increasing smooth muscle cell content. Circulation, 2001, 104: 2447-2452

Trogan E, Choudhury RP, Dansky HM, Rong JX, Breslow JL, Fisher EA. Laser capture micro dissection analysis of gene expression in macrophages from atherosclerotic lesions of apolipoprotein E-deficient mice. Proc Natl Acad Sci USA, 2002, 99: 2234-2239

Dansky HM, Shu P, Donavan M, Montagno J, Nagle DL, Smutko JS, Roy N, Whiteing S, Barrios J, McBride TJ, Smith JD, Duyk G, Breslow JL, Moore KJ. A phenotype-sensitizing Apoe deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse. Genetics, 2002, 160: 1599-1608

Further Reading

American Heart Association


Jan Breslow, Laboratory of Biochemical Genetics and Metabolism