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SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis.

ABSTRACT: AIMS: Endothelial activation, macrophage infiltration, and foam cell formation are pivotal steps in atherogenesis. Our aim in this study was to analyse the role of SIRT1, a class III deacetylase with important metabolic functions, in plaque macrophages and atherogenesis. METHODS AND RESULTS: Using partial SIRT1 deletion in atherosclerotic mice, we demonstrate that SIRT1 protects against atherosclerosis by reducing macrophage foam cell formation. Peritoneal macrophages from heterozygous SIRT1 mice accumulate more oxidized low-density lipoprotein (oxLDL), thereby promoting foam cell formation. Bone marrow-restricted SIRT1 deletion confirmed that SIRT1 function in macrophages is sufficient to decrease atherogenesis. Moreover, we show that SIRT1 reduces the uptake of oxLDL by diminishing the expression of lectin-like oxLDL receptor-1 (Lox-1) via suppression of the NF-?B signalling pathway. CONCLUSION: Our findings demonstrate protective effects of SIRT1 in atherogenesis and suggest pharmacological SIRT1 activation as a novel anti-atherosclerotic strategy by reducing macrophage foam cell formation.

SUBMITTER: Stein S

PROVIDER: S-EPMC2938465 | biostudies-other | 2010 Sep

REPOSITORIES: biostudies-other

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SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis.

Stein Sokrates S Lohmann Christine C Schäfer Nicola N Hofmann Janin J Rohrer Lucia L Besler Christian C Rothgiesser Karin M KM Becher Burkhard B Hottiger Michael O MO Borén Jan J McBurney Michael W MW Landmesser Ulf U Lüscher Thomas F TF Matter Christian M CM

European heart journal 20100423 18

<h4>Aims</h4>Endothelial activation, macrophage infiltration, and foam cell formation are pivotal steps in atherogenesis. Our aim in this study was to analyse the role of SIRT1, a class III deacetylase with important metabolic functions, in plaque macrophages and atherogenesis.<h4>Methods and results</h4>Using partial SIRT1 deletion in atherosclerotic mice, we demonstrate that SIRT1 protects against atherosclerosis by reducing macrophage foam cell formation. Peritoneal macrophages from heterozyg ...[more]

PMID: 20418343

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Project description:ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1) play a vital role in promoting cholesterol efflux. Although, the dysregulation of these transporters was attributed as one of the mechanisms of atherogenesis, what renders their dysfunction is not well explored. Previously, we have reported that thrombin without having any effect on ABCG1 levels depletes ABCA1 levels affecting cholesterol efflux. In this study, we explored the mechanisms underlying thrombin-induced depletion of ABCA1 levels both in macrophages and smooth muscle cells. Under normal physiological conditions, COP9 signalosome subunit 3 (CSN3) was found to exist in complex with ABCA1 and in the presence of proatherogenic stimulants such as thrombin, ABCA1 was phosphorylated and dissociated from CSN3, leading to its degradation. Forced expression of CSN3 inhibited thrombin-induced ABCA1 ubiquitination and degradation, restored cholesterol efflux and suppressed foam cell formation. In Western diet (WD)-fed ApoE-/- mice, CSN3 was also disassociated from ABCA1 otherwise remained as a complex in Chow diet (CD)-fed ApoE-/- mice. Interestingly, depletion of CSN3 levels in WD-fed ApoE-/- mice significantly lowered ABCA1 levels, inhibited cholesterol efflux and intensified foam cell formation exacerbating the lipid laden atherosclerotic plaque formation. Mechanistic studies have revealed the involvement of Par1-Gα12-Pyk2-Gab1-PKCθ signaling in triggering phosphorylation of ABCA1 and its disassociation from CSN3 curtailing cholesterol efflux and amplifying foam cell formation. In addition, although both CSN3 and ABCA1 were found to be colocalized in human non-lesion coronary arteries, their levels were decreased as well as dissociated from each other in advanced atherosclerotic lesions. Together, these observations reveal for the first time an anti-atherogenic role of CSN3 and hence, designing therapeutic drugs protecting its interactions with ABCA1 could be beneficial against atherosclerosis.

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:BackgroundThe accumulation of lipid-laden macrophages, foam cells, within sub-endothelial intima is a key feature of early atherosclerosis. Siglec-E, a mouse orthologue of human Siglec-9, is a sialic acid binding lectin predominantly expressed on the surface of myeloid cells to transduce inhibitory signal via recruitment of SH2-domain containing protein tyrosine phosphatase SHP-1/2 upon binding to its sialoglycan ligands. Whether Siglec-E expression on macrophages impacts foam cell formation and atherosclerosis remains to be established.MethodsApoE-deficient (apoE-/-) and apoE/Siglec-E-double deficient (apoE-/-/Siglec-E-/-) mice were placed on high fat diet for 3 months and their lipid profiles and severities of atherosclerosis were assessed. Modified low-density lipoprotein (LDL) uptake and foam cell formation in wild type (WT) and Siglec-E-/-- peritoneal macrophages were examined in vitro. Potential Siglec-E-interacting proteins were identified by proximity labeling in conjunction with proteomic analysis and confirmed by coimmunoprecipitation experiment. Impacts of Siglec-E expression and cell surface sialic acid status on oxidized LDL uptake and signaling involved were examined by biochemical assays.ResultsHere we show that genetic deletion of Siglec-E accelerated atherosclerosis without affecting lipid profile in apoE-/- mice. Siglec-E deficiency promotes foam cell formation by enhancing acetylated and oxidized LDL uptake without affecting cholesterol efflux in macrophages in vitro. By performing proximity labeling and proteomic analysis, we identified scavenger receptor CD36 as a cell surface protein interacting with Siglec-E. Further experiments performed in HEK293T cells transiently overexpressing Siglec-E and CD36 and peritoneal macrophages demonstrated that depletion of cell surface sialic acids by treatment with sialyltransferase inhibitor or sialidase did not affect interaction between Siglec-E and CD36 but retarded Siglec-E-mediated inhibition on oxidized LDL uptake. Subsequent experiments revealed that oxidized LDL induced transient Siglec-E tyrosine phosphorylation and recruitment of SHP-1 phosphatase in macrophages. VAV, a downstream effector implicated in CD36-mediated oxidized LDL uptake, was shown to interact with SHP-1 following oxidized LDL treatment. Moreover, oxidized LDL-induced VAV phosphorylation was substantially lower in WT macrophages comparing to Siglec-E-/- counterparts.ConclusionsThese data support the protective role of Siglec-E in atherosclerosis. Mechanistically, Siglec-E interacts with CD36 to suppress downstream VAV signaling involved in modified LDL uptake.

Project description:Objective: Atherosclerosis is an arterial occlusive disease with hypercholesterolemia and hypertension as common risk factors. Advanced-stage stenotic plaque, which features inflammation and necrotic core formation, is the major reason for clinical intervention. Receptor interacting serine/threonine-protein kinase 1 (RIPK1) mediates inflammation and cell death and is expressed in atherosclerotic lesions. The role of RIPK1 in advanced-stage atherosclerosis is unknown. Approach and Results: To investigate the effect of RIPK1 inhibition in advanced atherosclerotic plaque formation, we used ApoE SA/SA mice, which exhibit hypercholesterolemia, and develop angiotensin-II mediated hypertension upon administration of doxycycline in drinking water. These mice readily develop severe atherosclerosis, including that in coronary arteries. Eight-week-old ApoE SA/SA mice were randomized to orally receive a highly selective RIPK1 inhibitor (RIPK1i, GSK547) mixed with a western diet, or control diet. RIPK1i administration reduced atherosclerotic plaque lesion area at 2 weeks of treatment, consistent with suppressed inflammation (MCP-1, IL-1β, TNF-α) and reduced monocyte infiltration. However, administration of RIPK1i unexpectedly exacerbated atherosclerosis at 4 weeks of treatment, concomitant with increased macrophages and lipid deposition in the plaques. Incubation of isolated macrophages with oxidized LDL resulted in foam cell formation in vitro. RIPK1i treatment promoted such foam cell formation while suppressing the death of these cells. Accordingly, RIPK1i upregulated the expression of lipid metabolism-related genes (Cd36, Ppara, Lxrα, Lxrb, Srebp1c) in macrophage foam cells with ABCA1/ABCG1 unaltered. Furthermore, RIPK1i treatment inhibited ApoA1 synthesis in the liver and reduced plasma HDL levels. Conclusion: RIPK1 modulates the development of atherosclerosis in a stage-dependent manner, implicating both pro-atherosclerotic (monocyte infiltration and inflammation) and anti-atherosclerotic effects (suppressing foam cell accumulation and promoting ApoA1 synthesis). It is critical to identify an optimal therapeutic duration for potential clinical use of RIPK1 inhibitor in atherosclerosis or other related disease indications.

Project description: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.

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SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis.

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SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis.

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