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Published on: September 26, 2018
Low-dose oral sirolimus reduces atherogenesis, vascular inflammation and modulates plaque composition in mice lacking
1Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Background And Purpose:
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.
Experimental Approach:
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 And Implications:
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.
Insights
Sirolimus effectively reduces atherosclerosis progression in mice by lowering inflammation and modulating plaque composition. This anti-proliferative drug shows promise as a safe anti-atherogenic agent.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Immunology
Background:
- Atherosclerosis pathogenesis involves chronic vascular cell proliferation.
- Sirolimus is known to reduce neointimal proliferation post-angioplasty and in graft disease.
- The specific anti-atherogenic effects of sirolimus required investigation.
Purpose of the Study:
- To investigate the effects of sirolimus on atherogenesis.
- To determine if sirolimus can inhibit the development of atherosclerotic plaques.
Main Methods:
- Low-density lipoprotein receptor-deficient (LDL r-KO) mice were fed a cholesterol-rich diet.
- Mice were randomized to receive placebo or varying doses of sirolimus (0.1, 0.3, 1 mg/kg) for 8 or 16 weeks.
Main Results:
- Sirolimus treatment led to dose-dependent reductions in plasma and aortic inflammatory markers (IL-6, MCP-1, IFN-γ, TNF-α, CD40).
- A significant, dose-dependent reduction in atherosclerotic lesion size was observed in the aorta.
- Lesions in sirolimus-treated mice showed decreased monocyte/macrophage and smooth muscle cell content, with increased collagen.
Conclusions:
- Low-dose sirolimus demonstrated efficacy and safety as an anti-atherogenic agent in LDL r-KO mice.
- Sirolimus attenuated atherosclerosis progression and altered plaque phenotype by suppressing pro-inflammatory responses.
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