title: TLR4-mediated inflammation promotes foam cell formation of vascular smooth muscle cell by upregulating ACAT1 expression.
abstract: 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-κB (NF-κB), 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-κB, 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 (PPARγ) suppressed oxLDL-induced VSMC foam cell formation and inhibited the expression of TLR4, MyD88, NF-κB, proinflammatory cytokines and ACAT1, whereas inhibition of PPARγ exerted the opposite effect. TLR4(-/-) mice and VSMCs showed impaired atherosclerotic plaque formation and foam cell formation, and displayed no response to PPARγ manipulation. In conclusion, our data showed that oxLDL stimulation can activate the TLR4/MyD88/NF-κB inflammatory signaling pathway in VSMCs, which in turn upregulates the ACAT1 expression and finally promotes VSMC foam cell formation.
authors.affiliation: Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.
authors.forename: Y W
authors.initials: YW
authors.lastname: Yin
authors.affiliation: Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.
authors.forename: S Q
authors.initials: SQ
authors.lastname: Liao
authors.affiliation: Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.
authors.forename: M J
authors.initials: MJ
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.
authors.forename: B H
authors.initials: BH
authors.lastname: Li
authors.affiliation: Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.
authors.forename: C Y
authors.initials: CY
authors.lastname: Gao
authors.affiliation: Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.
authors.forename: J C
authors.initials: JC
authors.lastname: Li
authors.affiliation: Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China.
authors.forename: L L
authors.initials: LL
authors.lastname: Zhang
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics* / Q000276:immunology; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D002478:Cells, Cultured; D005260:Female; D005487:Foam Cells / Q000166:cytology* / Q000276:immunology; D006801:Humans; D007249:Inflammation; D008077:Lipoproteins, LDL / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D032389:Myocytes, Smooth Muscle / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D008077:Lipoproteins, LDL; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C099252:oxidized low density lipoprotein; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase