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(Circulation. 1997;95:1542-1548.)
© 1997 American Heart Association, Inc.

Articles

Tamoxifen Decreases Cholesterol Sevenfold and Abolishes Lipid Lesion Development in Apolipoprotein E Knockout Mice

Jill Reckless, BSc, PhD; James C. Metcalfe, MA, PhD; David J. Grainger, MA, PhD

From the Department of Biochemistry, University of Cambridge, UK.

Correspondence to Jill Reckless, Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 2QQ, UK. E-mail jr3{at}mole.bio.cam.ac.uk.

Background Apolipoprotein E (apo E) knockout mice develop severe vascular lipid lesions resembling human atherosclerotic plaques, irrespective of the fat content of their diet.

Methods and Results Oral tamoxifen (TMX) at a dose of 1.9 mg·kg body wt^-1·d^-1 abolished lipid lesion development, assayed by oil red O staining, whether the mice were fed a normal diet or a diet with high fat content. The TMX-treated mice showed a sevenfold decrease in total cholesterol. However, the proportion of plasma cholesterol present in VLDL remained unchanged, whereas the proportion in LDL decreased by 37%, and that in HDL increased by 64%. Consistent with the shift from LDL to HDL cholesterol, there was a 62% decrease in total triglycerides. The concentrations of active and acid-activatable latent plus active TGF-ß in the aorta were substantially elevated by TMX (87% and 24% increase, respectively).

Conclusions Although the mechanism of cardiovascular protection by TMX in apo E knockout mice is unknown, the inhibition of lipid lesion formation may be attributable to the changes in lipoprotein profile and the elevated levels of TGF-ß, both of which are thought to be protective against atherosclerosis in humans and animal models.

Key Words: atherosclerosis • apolipoproteins • lipids • lesion

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