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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:858.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Cholesteryl Ester Transfer Protein (CETP) Expression Protects Against Diet Induced Atherosclerosis in SR-BI Deficient Mice

Christopher Harder; Paulina Lau; Andrew Meng; Stewart C. Whitman; Ruth McPherson

From the Lipoprotein and Atherosclerosis Research Group & Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Canada

Correspondence to Ruth McPherson, University of Ottawa Heart Institute, Rm H453, 40 Ruskin Street, Ottawa, Canada, K1Y 4W7. E-mail rmcpherson{at}ottawaheart.ca

Objective— To determine whether expression of the human CETP transgene protects against diet-induced atherosclerosis in SR-BI deficient mice.

Methods and Results— SR-BI deficient (–/–) mice were crossed with CETP transgenic (CETPtg) mice to produce a colony of SR-BI^–/– x CETPtg mice in a C57Bl/6 background. Age and sex matched groups of genetically modified and wild-type C57Bl/6 mice were fed a high fat, high cholesterol diet for 22 weeks. In both wild-type and SR-BI^–/– mice, expression of the CETP transgene reduced the cholesterol content and increased the density of lipoprotein particles in the HDL density range. In SR-BI^–/– x CETPtg mice, CETP activity inversely correlated with total plasma cholesterol levels and shifted the buoyant HDL typical of SR-BI deficiency toward a more normal density HDL particle. Atherosclerosis at the level of the aortic arch was evident in both male and female SR-BI deficient mice but occurred to a greater extent in the females. Expression of CETP markedly attenuated the development of atherosclerosis in SR-BI deficient mice fed an atherogenic diet (P<0.003).

Conclusions— Expression of the human CETP transgene protects SR-BI deficient mice from atherosclerosis, consistent with a role for CETP in remodeling HDL and providing an alternative pathway for the selective uptake of HDL-CE by the liver.

To determine whether expression of the human CETP transgene protects against diet-induced atherosclerosis in SR-BI deficient (–/–) mice, we crossed these with CETP transgenic mice to create SR-BI^–/– x CETPtg mice in a C57Bl/6 background. CETP expression reduced HDL cholesterol, increased HDL density, and markedly attenuated the development of atherosclerosis.

Key Words: CETP • SR-BI • atherosclerosis • HDL

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