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Updated: May 17, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice
Zhongyang Lu1, Xiaoming Zhang, Yanchun Li
1Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, USA.
Abstract:
Although it has been reported that deficiency of toll-like receptor 4 (TLR4) is associated with reduced atherosclerosis in atherosclerosis-prone mice and attenuated pro-inflammatory state in diabetic mice, it remains undetermined whether treatment with a TLR4 antagonist reduces atherosclerosis in nondiabetic or diabetic mice that have TLR4 expression. In this study, we determined the effect of Rhodobacter sphaeroides lipopolysaccharide (Rs-LPS), an established TLR4 antagonist, on early-stage atherosclerosis in nondiabetic and streptozotocin-induced diabetic apolipoprotein E-deficient (Apoe(-/-)) mice. Analysis of atherosclerotic lesions of both en face aortas and cross sections of aortic roots showed that administration of Rs-LPS in 14-week-old diabetic Apoe(-/-) mice for 10 weeks significantly reduced atherosclerotic lesions. Although atherosclerotic lesions in nondiabetic Apoe(-/-) mice appeared to be decreased by Rs-LPS treatment, the difference was not statistically significant. Metabolic study showed that Rs-LPS significantly lowered serum levels of cholesterol and triglycerides in nondiabetic mice but not in diabetic mice. Furthermore, immunohistochemistry studies showed that Rs-LPS inhibited the expression of interleukin 6 and matrix metalloproteinase-9 and reduced the content of monocytes and macrophages in atherosclerotic plaques. Taken together, this study demonstrated for the first time that TLR4 antagonist inhibited vascular inflammation and atherogenesis in diabetic Apoe(-/-) mice and lowered serum cholesterol and triglyceride levels in nondiabetic Apoe(-/-) mice.
Insights
Toll-like receptor 4 (TLR4) antagonist, Rhodobacter sphaeroides lipopolysaccharide (Rs-LPS), significantly reduced atherosclerosis in diabetic mice. Rs-LPS also lowered cholesterol and triglycerides in nondiabetic mice, indicating potential therapeutic benefits.
Area of Science:
- Cardiovascular Research
- Immunology
- Metabolic Diseases
Background:
- Toll-like receptor 4 (TLR4) deficiency is linked to reduced atherosclerosis and inflammation.
- The effect of TLR4 antagonists on atherosclerosis in mice with existing TLR4 expression is not fully understood.
Purpose of the Study:
- To investigate the efficacy of a TLR4 antagonist, Rhodobacter sphaeroides lipopolysaccharide (Rs-LPS), in mitigating early-stage atherosclerosis in nondiabetic and diabetic apolipoprotein E-deficient (Apoe(-/-)) mice.
Main Methods:
- Administration of Rs-LPS to 14-week-old nondiabetic and streptozotocin-induced diabetic Apoe(-/-) mice for 10 weeks.
- Analysis of atherosclerotic lesions in en face aortas and aortic root cross-sections.
- Metabolic studies to assess serum lipid levels.
- Immunohistochemistry to evaluate inflammatory markers and immune cell infiltration.
Main Results:
- Rs-LPS significantly reduced atherosclerotic lesions in diabetic Apoe(-/-) mice.
- A trend towards reduced lesions was observed in nondiabetic Apoe(-/-) mice, but it was not statistically significant.
- Rs-LPS lowered serum cholesterol and triglycerides in nondiabetic mice but not in diabetic mice.
- Inhibition of interleukin 6 and matrix metalloproteinase-9 expression, and reduced monocyte/macrophage content in plaques were observed.
Conclusions:
- TLR4 antagonism with Rs-LPS effectively inhibits vascular inflammation and atherogenesis in diabetic Apoe(-/-) mice.
- Rs-LPS demonstrates potential in lowering serum lipid levels in nondiabetic mice.
- These findings highlight TLR4 as a therapeutic target for atherosclerosis, particularly in diabetic contexts.
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