Tamoxifen decreases cholesterol sevenfold and abolishes lipid lesion development in apolipoprotein E knockout mice.
BACKGROUND
Apolipoprotein E (apo E) knockout mice develop severe vascular lipid lesions resembling human atherosclerotic plaques, irrespective of the fat content of their diet.


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-beta 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-beta, both of which are thought to be protective against atherosclerosis in humans and animal models.
Reckless
J
J
Department of Biochemistry, University of Cambridge, UK. jr3@mole.bio.cam.ac.uk
Metcalfe
J C
JC
Grainger
D J
DJ
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics*; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002784:Cholesterol / Q000097:blood*; D004041:Dietary Fats / Q000494:pharmacology*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D004041:Dietary Fats; D008074:Lipoproteins; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D002784:Cholesterol