TAMOXIFEN DECREASES CHOLESTEROL SEVENFOLD AND ABOLISHES LIPID LESION DEVELOPMENT IN APOLIPOPROTEIN-E KNOCKOUT MICE

Background Apolipoprotein E (apo E) knockout mice develop severe vascu lar lipid lesions resembling human atherosclerotic plaques, irrespecti ve of the fat content of their diet. Methods and Results Oral tamoxife n (TM) at a dose of 1.9 mg . kg body wt(-1). d(-1) abolished lipid les ion 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 mic e showed a sevenfold decrease in total cholesterol. However, the propo rtion of plasma cholesterol present in VLDL remained unchanged, wherea s 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 a nd acid-activatable latent plus active TGF-beta in the aorta were subs tantially elevated by TMX (87% and 24% increase, respectively). Conclu sions Although the mechanism of cardiovascular protection by TMX in ap o E knockout mice is unknown, the inhibition of lipid lesion formation may be attributable to the changes in lipoprotein profile and the ele vated levels of TGF-beta, both of which are thought to be protective a gainst atherosclerosis in humans and animal models.