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Published on: September 26, 2018
Tamoxifen decreases cholesterol sevenfold and abolishes lipid lesion development in apolipoprotein E knockout mice
J Reckless1, J C Metcalfe, D J Grainger
1Department of Biochemistry, University of Cambridge, UK. jr3@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-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.
Insights
Tamoxifen (TMX) treatment significantly reduced lipid lesions in apolipoprotein E (apo E) knockout mice, lowering cholesterol and triglycerides. This suggests TMX may offer cardiovascular protection by altering lipoprotein profiles and increasing TGF-beta.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Atherosclerosis Research
Background:
- Apolipoprotein E (apo E) knockout mice are a model for atherosclerosis, developing severe vascular lipid lesions.
- Lesion development in these mice is independent of dietary fat content.
Purpose of the Study:
- To investigate the effect of tamoxifen (TMX) on lipid lesion development in apo E knockout mice.
- To explore potential mechanisms underlying TMX's cardiovascular effects.
Main Methods:
- Oral administration of tamoxifen (TMX) to apo E knockout mice.
- Assay of lipid lesion development using oil red O staining.
- Analysis of plasma lipoprotein profiles (VLDL, LDL, HDL) and triglyceride levels.
- Measurement of active and latent TGF-beta concentrations in the aorta.
Main Results:
- TMX abolished lipid lesion development in mice on both normal and high-fat diets.
- TMX treatment led to a sevenfold decrease in total cholesterol and a 62% decrease in total triglycerides.
- Plasma LDL cholesterol decreased by 37%, while HDL cholesterol increased by 64%.
- TMX significantly elevated aortic concentrations of active (87%) and latent plus active (24%) TGF-beta.
Conclusions:
- TMX inhibits lipid lesion formation in apo E knockout mice.
- Cardiovascular protection by TMX may be linked to favorable changes in lipoprotein profiles (increased HDL, decreased LDL).
- Elevated TGF-beta levels induced by TMX are also proposed as a protective mechanism against atherosclerosis.
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