TLR4-mediated inflammation promotes foam cell formation of vascular smooth muscle cell by upregulating ACAT1 expression

• Published in: Cell death & disease 2014-12, Vol.5 (12), p.e1574-e1574
• Main Authors: Yin, Y-W, Liao, S-Q, Zhang, M-J, Liu, Y, Li, B-H, Zhou, Y, Chen, L, Gao, C-Y, Li, J-C, Zhang, L-L
• Format: Article
• Language: English
• Subjects: 13/95; 631/250/2504/342/1494; 631/443/592/75/593/2100; 631/80/86; 692/420/256; Acetyl-CoA C-Acetyltransferase - genetics; Acetyl-CoA C-Acetyltransferase - immunology; Animals; Antibodies; Atherosclerosis - genetics; Atherosclerosis - immunology; Atherosclerosis - physiopathology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cells, Cultured; Female; Foam Cells - cytology; Foam Cells - immunology; Humans; Immunology; Inflammation; Life Sciences; Lipoproteins, LDL - immunology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular - cytology; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; Myocytes, Smooth Muscle - immunology; NF-kappa B - genetics; NF-kappa B - immunology; Original; original-article; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Up-Regulation
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.535

Vascular smooth muscle cell (VSMC) foam cell formation is an important hallmark, especially in advanced atherosclerosis lesions. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) promotes foam cell formation by promoting intracellular cholesteryl ester synthesis. The present study tests the hypothesis that oxidized low-density lipoprotein (oxLDL) increases the ACAT1 expression by activating the Toll-like receptor 4 (TLR4)-mediated inflammation, and ultimately promotes VSMC foam cell formation. Wild-type, ApoE −/− , TLR4 −/− and ACAT1 −/− mice on a C57BL/6J background were used. Increased TLR4, proinflammatory cytokines and ACAT1 were observed in high-fat (HF) diet-induced atherosclerotic plaque formation and in oxLDL-stimulated VSMCs. ACAT1 deficiency impeded the HF diet-induced atherosclerotic plaque formation and impaired the TLR4-manipulated VSMC foam cell formation in response to oxLDL. TLR4 deficiency inhibited the upregulation of myeloid-differentiating factor 88 (MyD88), nuclear factor- κ B (NF- κ B), proinflammatory cytokines and ACAT1, and eventually attenuated the HF diet-induced atherosclerotic plaque formation and suppressed the oxLDL-induced VSMC foam cell formation. Knockdown of MyD88 and NF- κ B, respectively, impaired the TLR4-manipulated VSMC foam cell formation in response to oxLDL. Rosiglitazone (RSG) attenuated HF diet-induced atherosclerotic plaque formation in ApoE −/− mice, accompanied by reduced expression of TLR4, proinflammatory cytokines and ACAT1 accordingly. Activation of peroxisome proliferator-activated receptor γ (PPAR γ ) suppressed oxLDL-induced VSMC foam cell formation and inhibited the expression of TLR4, MyD88, NF- κ B, proinflammatory cytokines and ACAT1, whereas inhibition of PPAR γ exerted the opposite effect. TLR4 −/− mice and VSMCs showed impaired atherosclerotic plaque formation and foam cell formation, and displayed no response to PPAR γ manipulation. In conclusion, our data showed that oxLDL stimulation can activate the TLR4/MyD88/NF- κ B inflammatory signaling pathway in VSMCs, which in turn upregulates the ACAT1 expression and finally promotes VSMC foam cell formation.