Gene Transfer and Hepatic Overexpression of the HDL Receptor SR-BI Reduces Atherosclerosis in the Cholesterol-Fed LDL Receptor–Deficient Mouse

Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 20 Số 3 - Trang 721-727 - 2000
Karen Kozarsky1, Mary H. Donahee2, Jane M. Glick3, Monty Krieger4, Daniel J. Rader5
1Karen F. Kozarsky From the Department of Molecular and Cellular Engineering (K.F.K., M.H.D., J.M.G.), Department of Medicine (D.J.R.), and Institute for Human Gene Therapy (K.F.K., M.H.D., J.M.G., D.J.R.), University of Pennsylvania Health System, Philadelphia, Pa, and the Department of Biology, Massachusetts Institute of Technology, Cambridge (M.K.). K.F. Kozarsky and M.H. Donahee are now at the Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.
2Mary H. Donahee From the Department of Molecular and Cellular Engineering (K.F.K., M.H.D., J.M.G.), Department of Medicine (D.J.R.), and Institute for Human Gene Therapy (K.F.K., M.H.D., J.M.G., D.J.R.), University of Pennsylvania Health System, Philadelphia, Pa, and the Department of Biology, Massachusetts Institute of Technology, Cambridge (M.K.). K.F. Kozarsky and M.H. Donahee are now at the Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.
3Jane M. Glick From the Department of Molecular and Cellular Engineering (K.F.K., M.H.D., J.M.G.), Department of Medicine (D.J.R.), and Institute for Human Gene Therapy (K.F.K., M.H.D., J.M.G., D.J.R.), University of Pennsylvania Health System, Philadelphia, Pa, and the Department of Biology, Massachusetts Institute of Technology, Cambridge (M.K.). K.F. Kozarsky and M.H. Donahee are now at the Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.
4Monty Krieger From the Department of Molecular and Cellular Engineering (K.F.K., M.H.D., J.M.G.), Department of Medicine (D.J.R.), and Institute for Human Gene Therapy (K.F.K., M.H.D., J.M.G., D.J.R.), University of Pennsylvania Health System, Philadelphia, Pa, and the Department of Biology, Massachusetts Institute of Technology, Cambridge (M.K.). K.F. Kozarsky and M.H. Donahee are now at the Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.
5Daniel J. Rader From the Department of Molecular and Cellular Engineering (K.F.K., M.H.D., J.M.G.), Department of Medicine (D.J.R.), and Institute for Human Gene Therapy (K.F.K., M.H.D., J.M.G., D.J.R.), University of Pennsylvania Health System, Philadelphia, Pa, and the Department of Biology, Massachusetts Institute of Technology, Cambridge (M.K.). K.F. Kozarsky and M.H. Donahee are now at the Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.

Tóm tắt

Abstract —HDL cholesterol levels in humans are inversely correlated with the risk of atherosclerosis. The class B scavenger receptor type I (SR-BI) is the first molecularly well-defined HDL receptor, and hepatic overexpression of SR-BI in normal mice has been shown to result in decreased plasma HDL cholesterol levels. To determine whether SR-BI overexpression is proatherogenic or is protective against atherosclerosis, LDL receptor–deficient mice were placed on a high-fat/high-cholesterol diet for 2 or 12 weeks to induce atherosclerotic lesions of different stages and then were injected with a recombinant adenovirus encoding murine SR-BI. Transient hepatic overexpression of SR-BI in mice with both early and advanced lesions significantly decreased atherosclerosis. SR-BI expression was associated with markedly decreased HDL cholesterol and either unchanged or only modestly reduced non-HDL cholesterol levels; in all experiments, the mean HDL cholesterol levels were significantly correlated with atherosclerotic lesion size. These data suggest that interventions that promote HDL cholesterol transport and lower plasma HDL cholesterol levels can suppress atherosclerosis, even when initiated after significant lesion development. Thus, stimulation of hepatic SR-BI activity may provide a novel target for therapeutic intervention in atherosclerotic cardiovascular disease.

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Tài liệu tham khảo

10.1056/NEJM198911093211907

10.1172/JCI114722

10.1161/01.ATV.9.6.785

10.1073/pnas.80.17.5435

10.1126/science.271.5248.460

10.1172/JCI118883

10.1073/pnas.94.23.12610

10.1073/pnas.95.8.4619

10.1073/pnas.95.8.4077

10.1038/387414a0

10.1146/annurev.biochem.68.1.523

10.1074/jbc.273.49.32920

10.1074/jbc.274.11.7165

10.1016/S0021-9258(17)31921-X

10.1074/jbc.274.4.2366

10.1172/JCI117179

10.1126/science.272.5262.685

10.1016/S0022-2275(20)37161-3

10.1074/jbc.271.7.3639

10.1172/JCI1461

10.1073/pnas.94.19.10335

10.1016/S0022-2275(20)39713-3

10.1161/atvb.17.11.2341

10.1016/S0022-2275(20)42106-6

10.1016/0021-9150(94)90042-6

10.1172/JCI118255

10.1172/JCI118751

10.1038/nm0797-744

10.1073/pnas.91.20.9607

10.1172/JCI117412

10.1016/S0022-2275(20)33893-1

10.1161/atvb.17.9.1725

1999, Proc Natl Acad Sci U S A, 6, 9322

10.1016/S0021-9258(17)46716-0

10.1074/jbc.272.28.17551

10.1074/jbc.272.52.33068

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Arteriosclerosis, Thrombosis, and Vascular Biology

Tập 20 Số 3

721-727

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