RESUMO
OBJECTIVE: To determine whether increased 12/15-lipoxygenase (12/15LO) expression in vivo enhances neointimal formation in response to injury. METHODS AND RESULTS: 12/15LO expression in the vessel wall is increased in animal models of metabolic syndrome and diabetes mellitus. Increased expression of 12/15LO enhances cultured vascular smooth muscle cell (VSMC) proliferation, an effect mediated by the helix-loop-helix factor inhibitor of differentiation 3 (Id3). Carotid endothelial denudation was performed on apolipoprotein (Apo) E(-/-), ApoE(-/-)/12/15LO(-/-), C57BL/6, and 12/15LO-overexpressing transgenic mice. ApoE(-/-)/12/15LO(-/-) mice had attenuated and 12/15LO-overexpressing transgenic mice had enhanced neointimal formation compared with control mice. 12/15LO-overexpressing transgenic mice had greater postinjury carotid Id3 and Ki-67 expression, cell number, and fibronectin deposition compared with C57BL/6 mice. Loss of 12/15LO attenuated proliferation of cultured ApoE(-/-) VSMCs, whereas 12/15LO overexpression induced VSMC proliferation. Loss of Id3 enhanced immunoglobulin trascription factor (ITF)-2b binding to and activation of the p21(cip1) promoter and abrogated 12/15LO-induced VSMC proliferation. CONCLUSIONS: To our knowledge, these data are the first demonstration that increased expression of 12/15LO in the vessel wall enhances Id3-dependent cell proliferation, fibronectin deposition, and neointimal formation in response to injury. Results identify p21(cip1) as a potential target of the 12/15LO-Id3 pathway and suggest that modulation of this pathway may have therapeutic implications for targeting the increased risk of restenosis in patients with diabetes.
Assuntos
Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Lesões das Artérias Carótidas/enzimologia , Proliferação de Células , Fibronectinas/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Túnica Íntima/enzimologia , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Araquidonato 12-Lipoxigenase/deficiência , Araquidonato 12-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/deficiência , Araquidonato 15-Lipoxigenase/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Sítios de Ligação , Lesões das Artérias Carótidas/patologia , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Modelos Animais de Doenças , Hiperplasia , Proteínas Inibidoras de Diferenciação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Regiões Promotoras Genéticas , Fatores de Tempo , Fator de Transcrição 4 , Túnica Íntima/patologiaRESUMO
Adiponectin is an adipocyte-derived cytokine with beneficial effects on insulin sensitivity and the development of atherosclerosis. Id3 is a helix-loop-helix factor that binds to E-proteins such as E47 and inhibits their binding to DNA. Although the helix-loop-helix factor sterol regulatory element binding protein (SREBP)-1c is a known activator of adiponectin transcription, this study provides the first evidence of a role for Id3 and E47 in adiponectin expression. Decreased Id3 in differentiating adipocytes correlates with increased adiponectin expression and forced expression of Id3 inhibits adiponectin expression. Moreover, Id3-null mice have increased adiponectin expression in visceral fat tissue and in serum. We demonstrate that E47 potentiates SREBP-1c-mediated adiponectin promoter activation and that Id3 can dose-dependently inhibit this action via interaction with E47. Mutation of a consensus E47 binding site results in nearly complete loss of promoter activation. Furthermore, we demonstrate E47 binding to the endogenous adiponectin promoter both in vitro and in vivo by chromatin immunoprecipitation analysis. Binding is not detected in undifferentiated cells which express Id3 but peaks during differentiation in parallel with Id3 decline. This promoter binding can be completely abolished by the overexpression of Id3 and is enhanced in adipose tissue null for Id3. These data establish Id3 and E47 as novel regulators of SREBP-1c-mediated adiponectin expression in differentiating adipocytes and provide evidence that Id3 regulates adiponectin expression in vivo.
Assuntos
Adiponectina/fisiologia , Proteínas Inibidoras de Diferenciação/fisiologia , Fatores de Transcrição TCF/fisiologia , Células 3T3-L1 , Adiponectina/antagonistas & inibidores , Adiponectina/genética , Adiponectina/metabolismo , Animais , Regulação da Expressão Gênica/fisiologia , Sequências Hélice-Alça-Hélice/genética , Proteínas Inibidoras de Diferenciação/biossíntese , Proteínas Inibidoras de Diferenciação/deficiência , Proteínas Inibidoras de Diferenciação/metabolismo , Camundongos , Camundongos Knockout , Células NIH 3T3 , Regiões Promotoras Genéticas , Ligação Proteica/genética , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/fisiologia , Fatores de Transcrição TCF/metabolismo , Proteína 1 Semelhante ao Fator 7 de TranscriçãoRESUMO
Most cervical spine fractures are caused by high-level trauma or by malignancy. Compression-type fractures usually affect the lumbar and thoracic spine below the T8 level and rarely the cervical spine. In the elderly, however, cervical spine compression fractures can occur with relatively minor trauma and are associated with high morbidity and mortality.
Assuntos
Vértebras Cervicais/lesões , Osteoporose/complicações , Fraturas da Coluna Vertebral/etiologia , Acidentes por Quedas , Idoso , Idoso de 80 Anos ou mais , Vértebras Cervicais/diagnóstico por imagem , Evolução Fatal , Feminino , Humanos , Radiografia , Fraturas da Coluna Vertebral/diagnóstico por imagemRESUMO
Several recent reports have described porphyria cutanea tarda (PCT) occurring in patients with HIV infection. Current evidence suggests that HIV infection may impair the hepatic cytochrome oxidase system, which could lead to an aberration in porphyrin metabolism and subsequently cause porphyria. We report a case of PCT in an HIV-infected patient who had multiple risk factors for this disorder.