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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.

SUBMITTER: Yin YW

PROVIDER: S-EPMC4454165 | biostudies-other | 2014 Dec

REPOSITORIES: biostudies-other

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Project description:Background This study aimed at investigating whether NLRP 3 (the Nod like receptor family, pyrin domain-containing 3 protein) inflammasome activation induced HMGB 1 (high mobility group box-1 protein) secretion and foam cell formation in human vascular smooth muscle cells ( VSMC s) and atherosclerosis in ApoE-/- mice. Methods and Results VSMC s or ApoE-/- mice were treated with lipopolysaccharides ( LPS ) and/or ATP or LPS and high-fat diet to induce NLRP 3 inflammasome activation. HMGB 1 distribution and foam cell formation in VSMC s were characterized. Liver X receptor α and ATP -binding cassette transporter expression were determined. The impact of NLRP 3 or receptor for advanced glycation end product silencing, ZYVAD - FMK (caspase-1 inhibitor), glycyrrhizin ( HMGB 1 inhibitor) or receptor for advanced glycation end product antagonist peptide on HMGB 1 secretion, foam cell formation, liver X receptor α and ATP -binding cassette transporter expression was examined. Expression level of HMGB 1 in human atherosclerosis obliterans arterial tissues was characterized. Our results found that NLRP 3 inflammasome activation promoted foam cell formation and HMGB 1 secretion in VSMC s. Extracellular HMGB 1 was a key signal molecule in inflammasome activation-mediated foam cell formation. Furthermore, inflammasome activation-induced HMGB 1 activity and foam cell formation were achieved by receptor for advanced glycation end product/liver X receptor α / ATP -binding cassette transporter glycyrrhizin. Experiments in vivo found glycyrrhizin significantly attenuated the LPS /high-fat diet-induced atherosclerosis and serum HMGB 1 levels in mice. Finally, levels of HMGB 1 and NLRP 3 were increased in tunica media adjacent to intima of atherosclerosis obliteran arteries. Conclusions Our results revealed that HMGB1 is a key downstream signal molecule of NLRP 3 inflammasome activation and plays an important role in VSMC s foam cell formation and atherogenesis by downregulating liver X receptor α and ATP -binding cassette transporter expression through receptor for advanced glycation end product.

Project description:Dickkopf-1 (DKK1) was recently shown to play an important role in cardiovascular disease. The aim of this work was to assess the role of DKK1 in the regulation of smooth muscle cell function by mechanical stretch and the mechanisms underlying this process. Methods: Wild-type C57BL/6J mice were subjected to sham or abdominal aortic constriction (AAC) surgery. The expression level of DKK1 was examined by immunohistochemical staining and Western blotting. Analyses of DKK1 function in vascular smooth muscle cell (VSMC) proliferation and migration were performed. Transcriptome sequencing analysis was performed to identify the differentially expressed genes and pathways regulated by DKK1. Smooth muscle-specific Dkk1 knockout mice were used to confirm the function of DKK1 in vivo. Chromatin immunoprecipitation (ChIP) was used to confirm DNA-protein interactions. Promoter luciferase analysis was used to detect transcription factor activity. Results: We found that AAC significantly increased DKK1 protein levels in the thoracic aorta and coronary artery in vivo. In vitro, high-level stretch (18%) induced the expression of DKK1 in VSMCs. Knocking down DKK1 inhibited VSMC proliferation and migration under high-level stretch (18%). We identified ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) as a target gene of DKK1. Knockdown of UHRF1 with small interfering RNAs partially reversed the regulatory effect of recombinant DKK1 on VSMCs. Specific deletion of DKK1 in VSMCs was sufficient to attenuate the AAC-induced upregulation of UHRF1, thickening of arterial media and increase in VSMC proliferation. Furthermore, we found that DKK1 regulated UHRF1 expression through the YAP-TEAD pathway. TEAD1 and TEAD4 bound directly to the promoter of UHRF1, and blocking the YAP-TEAD interaction inhibited UHRF1 upregulation due to DKK1. Conclusions: This study reveals that DKK1 mediates the mechanical stretch regulation of smooth muscle cell function by modulating UHRF1 expression through the YAP-TEAD pathway.

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

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