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Mediators Inflamm ; 2015: 439759, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26101463


Erythropoietin (EPO), the key factor for erythropoiesis, also protects macrophage foam cells from lipid accumulation, yet the definitive mechanisms are not fully understood. ß common receptor (ßCR) plays a crucial role in the nonhematopoietic effects of EPO. In the current study, we investigated the role of ßCR in EPO-mediated protection in macrophages against oxidized low-density lipoprotein- (oxLDL-) induced deregulation of lipid metabolism and inflammation. Here, we show that ßCR expression was mainly in foamy macrophages of atherosclerotic aortas from apolipoprotein E-deficient mice. Results of confocal microscopy and immunoprecipitation analyses revealed that ßCR was colocalized and interacted with EPO receptor (EPOR) in macrophages. Inhibition of ßCR activation by neutralizing antibody or small interfering RNA (siRNA) abolished the EPO-conferred protection in oxLDL-induced lipid accumulation. Furthermore, EPO-promoted cholesterol efflux and upregulation of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 were prevented by pretreatment with ßCR neutralizing antibody or ßCR siRNA. Additionally, blockage of ßCR abrogated the EPO-conferred anti-inflammatory action on oxLDL-induced production of macrophage inflammatory protein-2. Collectively, our findings suggest that ßCR may play an important role in the beneficial effects of EPO against oxLDL-elicited dysfunction of macrophage foam cells.

Subunidade beta Comum dos Receptores de Citocinas/fisiologia , Eritropoetina/farmacologia , Metabolismo dos Lipídeos , Lipoproteínas LDL/farmacologia , Macrófagos/metabolismo , Animais , Células Cultivadas , Colesterol/metabolismo , Subunidade beta Comum dos Receptores de Citocinas/química , Inflamação/etiologia , Camundongos , Multimerização Proteica
Circulation ; 121(16): 1828-37, 2010 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-20385932


BACKGROUND: In addition to the hematopoietic effect of erythropoietin, increasing evidence suggests that erythropoietin also exerts protective effects for cardiovascular diseases. However, the role of erythropoietin and its underlying mechanism in macrophage foam cell formation are poorly understood. METHODS AND RESULTS: Compared with wild-type specimens, erythropoietin was increased in atherosclerotic aortas of apolipoprotein E-deficient (apoE(-/-)) mice, mainly in the macrophage foam cells of the lesions. Erythropoietin levels in culture medium and macrophages were significantly elevated in response to oxidized low-density lipoprotein in a dose-dependent manner. Furthermore, erythropoietin markedly attenuated lipid accumulation in oxidized low-density lipoprotein-treated macrophages, a result that was due to an increase in cholesterol efflux. Erythropoietin treatment significantly increased ATP-binding cassette transporters (ABC) A1 and ABCG1 mRNA and protein levels without affecting protein expression of scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI. The upregulation of ABCA1 and ABCG1 by erythropoietin resulted from liver X receptor alpha activation, which was confirmed by its prevention on expression of ABCA1 and ABCG1 after pharmacological or small interfering RNA inhibition of liver X receptor alpha. Moreover, the erythropoietin-mediated attenuation on lipid accumulation was abolished by such inhibition. Finally, reduced lipid accumulation and marked increase in ABCA1 and ABCG1 were demonstrated in erythropoietin-overexpressed macrophages. CONCLUSIONS: Our data suggest that erythropoietin suppresses foam cell formation via the liver X receptor alpha-dependent upregulation of ABCA1 and ABCG1.

Aterosclerose/tratamento farmacológico , Cardiotônicos/farmacologia , Eritropoetina/farmacologia , Células Espumosas/efeitos dos fármacos , Receptores Nucleares Órfãos/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Doenças da Aorta/tratamento farmacológico , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Apolipoproteínas E/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Antígenos CD36/genética , Células Cultivadas , Células Espumosas/metabolismo , Células Espumosas/patologia , Lipídeos/biossíntese , Lipoproteínas/genética , Lipoproteínas/metabolismo , Lipoproteínas LDL/farmacologia , Receptores X do Fígado , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe B/genética
Life Sci ; 84(3-4): 97-104, 2009 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-19041881


AIMS: Resistin promotes macrophage-foam cell formation, but the mechanisms are unclear. In macrophages, lipid uptake is regulated by scavenger receptors (SR-A and CD36), while the cholesterol efflux is regulated by SR-BI, ATP-binding cassette transporter-A1 (ABCA1) and ABCG1. We investigated the mechanisms underlying the dysregulation by resistin of these regulators leading to promotion of lipid accumulation in bone marrow-derived macrophages. MAIN METHODS: Western blotting, real-time PCR and oil red O staining were performed. KEY FINDINGS: Resistin exacerbated lipid accumulation in oxLDL-treated macrophages. Resistin treatment of oxLDL-untreated macrophages showed increased SR-A and CD36 mRNA and protein levels, and decreased ABCA1 protein level, while having no effect on SR-BI or ABCG1 expression. Up-regulation of SR-A and CD36 by resistin resulted from activation of AP-1 and PPARgamma, respectively, and this was confirmed by the lack of activation of either after AP-1 inhibition using curcumin or SP600125, or PPARgamma inhibition using GW9662, respectively. The down-regulation of ABCA1 by resistin was not accompanied by a reduced mRNA level or an activation of LXRalpha/RXR, but resulted from enhanced protein degradation as revealed by the abolition of the down-regulation after inhibition of the proteasome pathway using ALLN or MG-132. A combined inhibition by SP600125, GW9662 and ALLN prevented resistin-induced exacerbation of lipid accumulation in oxLDL-treated macrophages. SIGNIFICANCE: Resistin promotes foam cell formation via dysregulation of SR-A, CD36 and ABCA1. SR-A and CD36 are transcriptionally up-regulated by resistin through AP-1 and PPARgamma, respectively, whereas ABCA1 is down-regulated by resistin through proteasome-mediated enhancement of protein degradation.

Transportadores de Cassetes de Ligação de ATP/fisiologia , Antígenos CD36/fisiologia , Metabolismo dos Lipídeos , Macrófagos/metabolismo , Resistina/fisiologia , Receptores Depuradores Classe A/fisiologia , Transportador 1 de Cassete de Ligação de ATP , Animais , Colesterol/metabolismo , Lipoproteínas LDL/fisiologia , PPAR gama/fisiologia , Complexo de Endopeptidases do Proteassoma/fisiologia , Ratos , Ratos Sprague-Dawley , Fator de Transcrição AP-1/fisiologia