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1.
Arterioscler Thromb Vasc Biol ; 40(3): 583-596, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31996026

RESUMO

OBJECTIVE: Inflammatory activation changes the mitochondrial function of macrophages from oxidative phosphorylation to reactive oxygen species production, which may promote necrotic core formation in atherosclerotic lesions. In hypoxic and cancer cells, HIF-1α (hypoxia-inducible factor) promotes oxygen-independent energy production by microRNAs. Therefore, we studied the role of HIF-1α in the regulation of macrophage energy metabolism in the context of atherosclerosis. Approach and Results: Myeloid cell-specific deletion of Hif1a reduced atherosclerosis and necrotic core formation by limiting macrophage necroptosis in apolipoprotein E-deficient mice. In inflammatory bone marrow-derived macrophages, deletion of Hif1a increased oxidative phosphorylation, ATP levels, and the expression of genes encoding mitochondrial proteins and reduced reactive oxygen species production and necroptosis. microRNA expression profiling showed that HIF-1α upregulates miR-210 and downregulates miR-383 levels in lesional macrophages and inflammatory bone marrow-derived macrophages. In contrast to miR-210, which inhibited oxidative phosphorylation and enhanced mitochondrial reactive oxygen species production, miR-383 increased ATP levels and inhibited necroptosis. The effect of miR-210 was due to targeting 2,4-dienoyl-CoA reductase, which is essential in the ß oxidation of unsaturated fatty acids. miR-383 affected the DNA damage repair pathway in bone marrow-derived macrophages by targeting poly(ADP-ribose)-glycohydrolase (Parg), which reduced energy consumption and increased cell survival. Blocking the targeting of Parg by miR-383 prevented the protective effect of Hif1a deletion in macrophages on atherosclerosis and necrotic core formation in mice. CONCLUSIONS: Our findings unveil a new mechanism by which activation of HIF-1α in inflammatory macrophages increases necroptosis through microRNA-mediated ATP depletion, thus increasing atherosclerosis by necrotic core formation.


Assuntos
Aorta/metabolismo , Aterosclerose/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , MicroRNAs/metabolismo , Necroptose , Trifosfato de Adenosina/metabolismo , Animais , Aorta/patologia , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Modelos Animais de Doenças , Metabolismo Energético , Regulação da Expressão Gênica , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/deficiência , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Inflamação/genética , Inflamação/patologia , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , MicroRNAs/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
2.
Circulation ; 138(18): 2007-2020, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-29748186

RESUMO

BACKGROUND: Alternative macrophage activation, which relies on mitochondrial oxidative metabolism, plays a central role in the resolution of inflammation and prevents atherosclerosis. Moreover, macrophages handle large amounts of cholesterol and triglycerides derived from the engulfed modified lipoproteins during atherosclerosis. Although several microRNAs regulate macrophage polarization, the role of the microRNA-generating enzyme Dicer in macrophage activation during atherosclerosis is unknown. METHODS: To evaluate the role of Dicer in atherosclerosis, Apoe-/- mice with or without macrophage-specific Dicer deletion were fed a high-fat diet for 12 weeks. Anti-argonaute 2 RNA immunoprecipitation chip and RNA deep sequencing combined with microRNA functional screening were performed in the Dicer wild-type and knockout bone marrow-derived macrophages to identify the individual microRNAs and the mRNA targets mediating the phenotypic effects of Dicer. The role of the identified individual microRNA and its target in atherosclerosis was determined by tail vein injection of the target site blockers in atherosclerotic Apoe-/- mice. RESULTS: We show that Dicer deletion in macrophages accelerated atherosclerosis in mice, along with enhanced inflammatory response and increased lipid accumulation in lesional macrophages. In vitro, alternative activation was limited whereas lipid-filled foam cell formation was exacerbated in Dicer-deficient macrophages as a result of impaired mitochondrial fatty acid oxidative metabolism. Rescue of microRNA (miR)-10a, let-7b, and miR-195a expression restored the oxidative metabolism in alternatively activated Dicer-deficient macrophages. Suppression of ligand-dependent nuclear receptor corepressor by miR-10a promoted fatty acid oxidation, which mediated the lipolytic and anti-inflammatory effect of Dicer. miR-10a expression was negatively correlated to the progression of atherosclerosis in humans. Blocking the interaction between ligand-dependent nuclear receptor corepressor and miR-10a by target site blockers aggravated atherosclerosis development in mice. CONCLUSIONS: Dicer plays an atheroprotective role by coordinately regulating the inflammatory response and lipid metabolism in macrophages through enhancing fatty acid-fueled mitochondrial respiration, suggesting that promoting Dicer/miR-10a-dependent metabolic reprogramming in macrophages has potential therapeutic implications to prevent atherosclerosis.


Assuntos
Aterosclerose/patologia , Macrófagos/metabolismo , Ribonuclease III/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Antagomirs/metabolismo , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Células da Medula Óssea/citologia , Dieta Hiperlipídica , Ácidos Graxos/química , Feminino , Humanos , Macrófagos/citologia , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/metabolismo , Mitocôndrias/metabolismo , Correpressor 2 de Receptor Nuclear/química , Correpressor 2 de Receptor Nuclear/metabolismo , Estresse Oxidativo , Ribonuclease III/genética
3.
Arterioscler Thromb Vasc Biol ; 35(4): 796-803, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25810298

RESUMO

OBJECTIVE: The function of microRNAs is highly context and cell type dependent because of their highly dynamic expression pattern and the regulation of multiple mRNA targets. MicroRNA-155 (miR-155) plays an important role in the innate immune response by regulating macrophage function; however, the effects of miR-155 in macrophages on atherosclerosis are controversial. We hypothesized that the stage-dependent target selection of miR-155 in macrophages determines its effects on atherosclerosis. APPROACH AND RESULTS: The expression of miR-155 increased in lesional macrophages of apolipoprotein E-deficient mice between 12 and 24 weeks of a high-cholesterol diet. Mir155 knockout in apolipoprotein E-deficient mice enhanced lesion formation, increased the lesional macrophage content, and promoted macrophage proliferation after 12 weeks of the high-cholesterol diet. In vitro, miR-155 inhibited macrophage proliferation by suppressing colony-stimulating factor-1 receptor, which was upregulated in lesional macrophages of Mir155(-/-) apolipoprotein E-deficient mice. By contrast, Mir155 deficiency reduced necrotic core formation and the deposition of apoptotic cell debris, thereby preventing the progression of atherosclerosis between 12 and 24 weeks of the high-cholesterol diet. miR-155 inhibited efferocytosis in vitro by targeting B-cell leukemia/lymphoma 6 and thus activating RhoA (ras homolog gene family, member A). Accordingly, B-cell leukemia/lymphoma 6 was upregulated in lesional macrophages of Mir155(-/-) apolipoprotein E-deficient mice after 24 weeks, but not after 12 weeks of the high-cholesterol diet. CONCLUSIONS: Our findings demonstrate a stage-specific role of miR-155 in lesion formation. miR-155 suppressed macrophage proliferation by targeting colony-stimulating factor-1 receptor in early and impaired efferocytosis by downregulating B-cell leukemia/lymphoma 6 in advanced atherosclerosis. Therefore, targeting the interaction between miR-155 and B-cell leukemia/lymphoma 6 may be a promising approach to inhibit the progression of atherosclerosis.


Assuntos
Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Proteínas de Ligação a DNA/metabolismo , Macrófagos/metabolismo , MicroRNAs/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Animais , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apoptose , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Transplante de Medula Óssea , Proliferação de Células , Células Cultivadas , Colesterol/sangue , Proteínas de Ligação a DNA/genética , Dieta Hiperlipídica , Modelos Animais de Doenças , Regulação da Expressão Gênica , Ativação de Macrófagos , Macrófagos/imunologia , Camundongos Knockout , MicroRNAs/genética , Necrose , Proteínas Proto-Oncogênicas c-bcl-6 , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Transdução de Sinais , Fatores de Tempo , Proteínas rho de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP
4.
Circulation ; 127(15): 1609-19, 2013 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-23513069

RESUMO

BACKGROUND: Atherosclerosis is a chronic inflammatory vascular disease driven by the subendothelial accumulation of macrophages. The mechanism regulating the inflammatory response in macrophages during atherogenesis remains unclear. Because microRNAs (miRNAs) play a crucial role in cellular signaling by posttranscriptional regulation of gene expression, we studied the miRNA expression profiles during the progression of atherosclerosis. METHODS AND RESULTS: Using an miRNA real-time polymerase chain reaction array, we found that macrophage-derived miR-342-5p and miR-155 are selectively upregulated in early atherosclerotic lesions in Apoe(-/-) mice. miR-342-5p directly targets Akt1 through its 3'-untranslated region. Akt1 suppression by miR-342-5p induces proinflammatory mediators such as Nos2 and II6 in macrophages via the upregulation of miR-155. The local application of an miR-342-5p antagomir inhibits the development of atherosclerosis in partially ligated carotid arteries. In atherosclerotic lesions, the miR-342-5p antagomir upregulated Akt1 expression and suppressed the expression of miR-155 and Nos2. This reduced Nos2 expression was associated with a diminished generation of nitrotyrosine in the plaques. Furthermore, systemic treatment with an inhibitor of miR-342-5p reduced the progression of atherosclerosis in the aorta of Apoe(-/-) mice. CONCLUSIONS: Macrophage-derived miR-342-5p promotes atherosclerosis and enhances the inflammatory stimulation of macrophages by suppressing the Akt1-mediated inhibition of miR-155 expression. Therefore, targeting miR-342-5p may offer a promising strategy to treat atherosclerotic vascular disease.


Assuntos
Aterosclerose/patologia , Regulação da Expressão Gênica , Ativação de Macrófagos , MicroRNAs/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Vasculite/patologia , Animais , Doenças da Aorta/genética , Doenças da Aorta/patologia , Doenças da Aorta/fisiopatologia , Apolipoproteínas E/deficiência , Aterosclerose/genética , Aterosclerose/fisiopatologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/biossíntese , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Estenose das Carótidas/genética , Estenose das Carótidas/patologia , Estenose das Carótidas/fisiopatologia , Estenose das Carótidas/prevenção & controle , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , RNA Helicases DEAD-box/deficiência , RNA Helicases DEAD-box/genética , Progressão da Doença , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/biossíntese , Interleucina-6/genética , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/antagonistas & inibidores , MicroRNAs/biossíntese , MicroRNAs/genética , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Oligonucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , RNA Antissenso/farmacologia , RNA Antissenso/uso terapêutico , Ribonuclease III/deficiência , Ribonuclease III/genética , Transdução de Sinais/fisiologia , Tirosina/análogos & derivados , Tirosina/metabolismo , Regulação para Cima , Vasculite/genética , Vasculite/fisiopatologia
5.
Diabetes ; 66(12): 3072-3084, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28970282

RESUMO

A high-fat diet increases bacterial lipopolysaccharide (LPS) in the circulation and thereby stimulates glucagon-like peptide 1 (GLP-1)-mediated insulin secretion by upregulating interleukin-6 (IL-6). Although microRNA-155-5p (miR-155-5p), which increases IL-6 expression, is upregulated by LPS and hyperlipidemia and patients with familial hypercholesterolemia less frequently develop diabetes, the role of miR-155-5p in the islet stress response to hyperlipidemia is unclear. In this study, we demonstrate that hyperlipidemia-associated endotoxemia upregulates miR-155-5p in murine pancreatic ß-cells, which improved glucose metabolism and the adaptation of ß-cells to obesity-induced insulin resistance. This effect of miR-155-5p is because of suppression of v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B, which promotes ß-cell function through IL-6-induced GLP-1 production in α-cells. Moreover, reduced GLP-1 levels are associated with increased obesity progression, dyslipidemia, and atherosclerosis in hyperlipidemic Mir155 knockout mice. Hence, induction of miR-155-5p expression in ß-cells by hyperlipidemia-associated endotoxemia improves the adaptation of ß-cells to insulin resistance and represents a protective mechanism in the islet stress response.


Assuntos
Hiperlipidemias/genética , Células Secretoras de Insulina/fisiologia , Fator de Transcrição MafB/genética , MicroRNAs/fisiologia , Animais , Células Cultivadas , Endotoxemia/genética , Peptídeo 1 Semelhante ao Glucagon/sangue , Glucose/metabolismo , Insulina/biossíntese , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos C57BL , Receptores de LDL/fisiologia
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