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2015 ; 220
(11
): 1246-54
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TLR4 antagonist attenuates atherogenesis in LDL receptor-deficient mice with
diet-induced type 2 diabetes
#MMPMID26162692
Lu Z
; Zhang X
; Li Y
; Lopes-Virella MF
; Huang Y
Immunobiology
2015[Nov]; 220
(11
): 1246-54
PMID26162692
show ga
Although a large number of studies have well documented a key role of toll-like
receptor (TLR)4 in atherosclerosis, it remains undetermined if TLR4 antagonist
attenuates atherogenesis in mouse model for type 2 diabetes. In this study, we
induced type 2 diabetes in low-density lipoprotein receptor-deficient (LDLR(-/-))
mice by high-fat diet (HFD). At 8 weeks old, 20 mice were fed HFD and 20 mice fed
regular chow (RC) for 24 weeks. In the last 10 weeks, half HFD-fed mice and half
RC-fed mice were treated with Rhodobacter sphaeroides lipopolysaccharide
(Rs-LPS), an established TLR4 antagonist. After the treatment, atherosclerotic
lesions in aortas were analyzed. Results showed that the HFD significantly
increased bodyweight, glucose, lipids including total cholesterol, triglycerides
and free fatty acids, and insulin resistance, indicating that the HFD induced
type 2 diabetes in LDLR(-/-) mice. Results also showed that Rs-LPS had no effect
on HFD-increased metabolic parameters in both nondiabetic and diabetic mice.
Lipid staining of aortas and histological analysis of cross-sections of aortic
roots showed that diabetes increased atherosclerotic lesions, but Rs-LPS
attenuated atherogenesis in diabetic mice. Furthermore, immunohistochemical
studies showed that Rs-LPS reduced infiltration of monocytes/macrophages and
expression of interleukin (IL)-6 and matrix metalloproteinase-9 in
atherosclerotic lesions of diabetic mice. Finally, the antagonistic effect of
Rs-LPS on TLR4 was demonstrated by our in vitro studies showing that Rs-LPS
inhibited IL-6 secretion from macrophages and endothelial cells stimulated by LPS
or LPS plus saturated fatty acid palmitate. Taken together, our study
demonstrated that TLR4 antagonist was capable of attenuating vascular
inflammation and atherogenesis in mice with HFD-induced type 2 diabetes.