| First Author | Higashimori M | Year | 2011 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 31 |
| Issue | 1 | Pages | 50-7 |
| PubMed ID | 20966403 | Mgi Jnum | J:184191 |
| Mgi Id | MGI:5320403 | Doi | 10.1161/ATVBAHA.110.210971 |
| Citation | Higashimori M, et al. (2011) Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 31(1):50-7 |
| abstractText | OBJECTIVE: Atherosclerosis encompasses a conspicuously maladaptive inflammatory response that might involve innate immunity. Here, we compared the role of Toll-like receptor 4 (TLR4) with that of TLR2 in intimal foam cell accumulation and inflammation in apolipoprotein E (ApoE) knockout (KO) mice in vivo and determined potential mechanisms of upstream activation and downstream action. METHODS AND RESULTS: We measured lipid accumulation and gene expression in the lesion-prone lesser curvature of the aortic arch. TLR4 deficiency reduced intimal lipid by approximately 75% in ApoE KO mice, despite unaltered total serum cholesterol and triglyceride levels, whereas TLR2 deficiency reduced it by approximately 45%. TLR4 deficiency prevented the increased interleukin-1alpha (IL-1alpha) and monocyte chemoattractant protein-1 mRNA levels seen within lesional tissue, and it also lowered serum IL-1alpha levels. Smooth muscle cells (SMC) were present within the intima of the lesser curvature of the aortic arch at this early lesion stage, and they enveloped and permeated nascent lesions, which consisted of focal clusters of foam cells. Cholesterol enrichment of SMC in vitro stimulated acyl-coenzyme A:cholesterol acyltransferase-1 mRNA expression, cytoplasmic cholesterol ester accumulation, and monocyte chemoattractant protein-1 mRNA and protein expression in a TLR4-dependent manner. CONCLUSIONS: TLR4 contributes to early-stage intimal foam cell accumulation at lesion-prone aortic sites in ApoE KO mice, as does TLR2 to a lesser extent. Intimal SMC surround and penetrate early lesions, where TLR4 signaling within them may influence lesion progression. |
