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Effect of everolimus on pre-existing atherosclerosis in LDL-receptor deficient mice
Frank Beutner1, Désiré Brendel, Daniel Teupser
1Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Leipzig, Germany. frank.beutner@medizin.uni-leipzig.de
Objective:
Proliferation signal inhibitors/mTOR-inhibitors have been shown to reduce de novo development of hypercholesterolemic atherosclerosis in animal models. However, their effect on pre-existing atherosclerosis has not yet been studied.
Methods And Results:
Feeding LDL-R-KO mice a high cholesterol diet for 12 weeks resulted in formation of moderate fibroatheroma (induction phase). Sixty mice received either everolimus (1 or 5 mg/kg) or no everolimus for further 12 weeks (treatment phase). Everolimus significantly enhanced hypercholesterolemia (plasma cholesterol +45%, p<0.001). Atherosclerosis progressed obstructively in treated and non-treated mice. Everolimus (5 mg/kg) tended to reduced progression in aortic root lesions (0.28±0.02 vs. 0.33±0.03 mm(2), p=ns) and brachiocephalic lesions (0.044±0.006 vs. 0.066±0.012 mm(2), p=ns) but without significance. Everolimus (5mg/kg) resulted in an arrest of CD68 positive plaque area (p=0.03) and nearly halved CD68 fraction (p=0.05) in aortic root lesions but not in brachiocephalic lesions. Taken together, despite a trend to reduced progression and inflammatory cell content there was less conclusive net effect of everolimus treatment than expected.
Conclusion:
A higher potential of everolimus in the treatment of atherosclerosis might be obscured by its concomitant hypercholesterolemia. Considering stronger effects in previous studies we suggest that everolimus might exert more potent anti-atherogenic properties in earlier stages of atherogenesis than in advanced atherosclerosis.
Insights
mTOR inhibitors like everolimus did not significantly reduce advanced atherosclerosis in mice, despite a trend towards reduced lesion progression and inflammation. The drug unexpectedly increased cholesterol levels, potentially masking its anti-atherogenic effects.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Immunology
Background:
- Proliferation signal inhibitors/mTOR inhibitors show promise in preventing atherosclerosis development.
- The impact of these inhibitors on pre-existing atherosclerosis remains uninvestigated.
Purpose of the Study:
- To evaluate the efficacy of everolimus in treating established hypercholesterolemic atherosclerosis in LDL-R-KO mice.
Main Methods:
- Mice were fed a high-cholesterol diet to induce atherosclerosis.
- Subsequently, mice received either everolimus (1 or 5 mg/kg) or no treatment for 12 weeks.
- Atherosclerosis progression, plasma cholesterol, and inflammatory cell content were assessed.
Main Results:
- Everolimus significantly increased plasma cholesterol levels by 45%.
- While a trend towards reduced lesion progression and inflammatory cell infiltration was observed with 5 mg/kg everolimus, these effects were not statistically significant.
- A significant arrest in CD68-positive plaque area was noted in aortic root lesions but not in brachiocephalic lesions.
Conclusions:
- Everolimus's potential anti-atherogenic effects may be hindered by its hypercholesterolemic side effect in advanced disease.
- The drug might be more effective in earlier stages of atherogenesis, as suggested by previous studies.
