Low-dose oral sirolimus reduces atherogenesis, vascular inflammation and modulates plaque composition in mice lacking the LDL receptor.
OBJECTIVE
Chronic proliferative responses of different vascular cell types have been involved in the pathogenesis of atherosclerosis. However, their functional role remains to be established. Sirolimus reduces neointimal proliferation after balloon angioplasty and chronic graft vessel disease. These studies were undertaken to investigate the effects of this anti-proliferative drug on atherogenesis.


METHODS
Low-density lipoprotein receptor-deficient (LDL r-KO) mice on a cholesterol-rich diet were randomized to receive placebo or sirolimus (0.1; 0.3; or 1 mg.kg(-1)) in their diet for 8 or 16 weeks.


RESULTS
In both studies, plasma levels of the drug increased in a dose-dependent fashion, animals gained weight normally and, among groups, plasma lipids levels did not differ significantly. Compared with placebo, plasma levels of interleukin-6, monocyte chemoattractant protein-1, interferon gamma, tumour necrosis factor alpha and CD40, and their mRNA levels in aortic tissue were significantly reduced in sirolimus-treated mice. This effect resulted in a significant and dose-dependent reduction in atherosclerotic lesions, in both the root and aortic tree. Also these lesions contained less monocyte/macrophages and smooth muscle cells, but more collagen.


CONCLUSIONS
The present results demonstrated that at low doses, sirolimus was an effective and safe anti-atherogenic agent in the LDL r-KO mice. It attenuated the progression of atherosclerosis and modulated the plaque phenotype by reducing the pro-inflammatory vascular responses typical of the disease.
Zhao
L
L
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Ding
T
T
Cyrus
T
T
Cheng
Y
Y
Tian
H
H
Ma
M
M
Falotico
R
R
Praticò
D
D
D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives / Q000652:urine; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D016207:Cytokines / Q000652:urine; D004036:Diet, Atherogenic; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D028421:Isoprostanes / Q000652:urine; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011897:Random Allocation; D011973:Receptors, LDL / Q000235:genetics*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D016207:Cytokines; D028421:Isoprostanes; D011973:Receptors, LDL; D014280:Triglycerides; C438786:isoprostane F2alpha III; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C028965:2,3-dinor-thromboxane B2; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; D003094:Collagen; D002784:Cholesterol; D003404:Creatinine; D020123:Sirolimus