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

Abstract

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-β 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-β, both of which are thought to be protective against atherosclerosis in humans and animal models.