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1.
Int J Mol Sci ; 24(24)2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-38138967

RESUMO

In response to injury, vascular smooth muscle cells (VSMCs) of the arterial wall dedifferentiate into a proliferative and migratory phenotype, leading to intimal hyperplasia. The ERK1/2 pathway participates in cellular proliferation and migration, while dual-specificity phosphatase 6 (DUSP6, also named MKP3) can dephosphorylate activated ERK1/2. We showed that DUSP6 was expressed in low baseline levels in normal arteries; however, arterial injury significantly increased DUSP6 levels in the vessel wall. Compared with wild-type mice, Dusp6-deficient mice had smaller neointima. In vitro, IL-1ß induced DUSP6 expression and increased VSMC proliferation and migration. Lack of DUSP6 reduced IL-1ß-induced VSMC proliferation and migration. DUSP6 deficiency did not affect IL-1ß-stimulated ERK1/2 activation. Instead, ERK1/2 inhibitor U0126 prevented DUSP6 induction by IL-1ß, indicating that ERK1/2 functions upstream of DUSP6 to regulate DUSP6 expression in VSMCs rather than downstream as a DUSP6 substrate. IL-1ß decreased the levels of cell cycle inhibitor p27 and cell-cell adhesion molecule N-cadherin in VSMCs, whereas lack of DUSP6 maintained their high levels, revealing novel functions of DUSP6 in regulating these two molecules. Taken together, our results indicate that lack of DUSP6 attenuated neointima formation following arterial injury by reducing VSMC proliferation and migration, which were likely mediated via maintaining p27 and N-cadherin levels.


Assuntos
Fosfatases de Especificidade Dupla , Neointima , Lesões do Sistema Vascular , Animais , Camundongos , Caderinas , Movimento Celular , Proliferação de Células , Células Cultivadas , Fosfatases de Especificidade Dupla/genética , Hiperplasia , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso , Neointima/genética , Neointima/prevenção & controle , Lesões do Sistema Vascular/genética
2.
Br J Pharmacol ; 180(20): 2605-2622, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37263748

RESUMO

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide, yet pharmacotherapies for TBI are currently lacking. Neuroregeneration is important in brain repair and functional recovery. In this study, probucol, a cholesterol-lowering drug with established safety profiles, was examined for its therapeutic effects and neuroregenerative actions in TBI. EXPERIMENTAL APPROACH: Male mice were subjected to the controlled cortical impact model of TBI, followed by daily administration of probucol. Neurological and cognitive functions were evaluated. Histological analyses of the neocortex and hippocampus were performed to detect the lesion, dendritic degeneration (microtubule-associated protein 2), synaptic density (synaptophysin), neurogenesis (doublecortin), brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) activation. Involvement of BDNF/TrkB pathway in probucol-mediated effects was examined in primary cultures of cortical neurons. KEY RESULTS: Probucol reduced brain lesion volume, enhanced the recovery of body symmetry, improved motor function and attenuated memory dysfunction after TBI. Meanwhile, probucol promoted post-injury dendritic growth and synaptogenesis and increased hippocampal proliferating neuronal progenitor cells, along with the formation as well as the survival of newborn neurons. Moreover, probucol enhances BDNF expression and TrkB activation. In vitro, probucol promoted neurite outgrowth, which was inhibited by a selective TrkB antagonist ANA-12. CONCLUSIONS AND IMPLICATIONS: Probucol enhanced functional restoration and ameliorated cognitive impairment after TBI by promoting post-injury neuronal remodelling and neurogenesis. Increased activation of BDNF/TrkB pathway by probucol, at least in part, contributed to the neuroregenerative effects of probucol. Together, it may be promising to repurpose probucol for TBI.


Assuntos
Lesões Encefálicas Traumáticas , Receptor trkB , Camundongos , Animais , Masculino , Receptor trkB/metabolismo , Probucol/farmacologia , Probucol/uso terapêutico , Tropomiosina , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Regeneração Nervosa
3.
Int J Mol Sci ; 21(10)2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32414036

RESUMO

Zinc oxide nanoparticles (ZnONPs) are frequently encountered nanomaterials in our daily lives. Despite the benefits of ZnONPs in a variety of applications, many studies have shown potential health hazards of exposure to ZnONPs. We have shown that oropharyngeal aspiration of ZnONPs in mice increases lung inflammation. However, the detailed mechanisms underlying pulmonary inflammatory cell infiltration remain to be elucidated. Endothelium functions as a barrier between the blood stream and the blood vessel wall. Endothelial barrier dysfunction may increase infiltration of immune cells into the vessel wall and underlying tissues. This current study examined the effects of ZnONPs exposure on endothelial barriers. ZnONPs exposure increased leukocyte infiltration in the mouse lungs. In endothelial cells, ZnONPs reduced the continuity of tight junction proteins claudin-5 and zonula occludens-1 (ZO-1) at the cell junctions. ZnONPs induced adherens junction protein VE-cadherin internalization from membrane to cytosol and dissociation with ß-catenin, leading to reduced and diffused staining of VE-cadherin and ß-catenin at cell junctions. Our results demonstrated that ZnONPs disrupted both tight and adherens junctions, compromising the integrity and stability of the junction network, leading to inflammatory cell infiltration. Thus, ZnONPs exposure in many different settings should be carefully evaluated for vascular effects and subsequent health impacts.


Assuntos
Claudina-5/genética , Endotélio/efeitos dos fármacos , Pneumonia/genética , Óxido de Zinco/efeitos adversos , Proteína da Zônula de Oclusão-1/genética , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/genética , Animais , Vasos Sanguíneos/efeitos dos fármacos , Humanos , Leucócitos/efeitos dos fármacos , Camundongos , Nanopartículas/efeitos adversos , Orofaringe/efeitos dos fármacos , Pneumonia/induzido quimicamente , Pneumonia/patologia
4.
Oncotarget ; 7(42): 67760-67776, 2016 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-27626316

RESUMO

Abdominal aortic aneurysm (AAA) is a chronic but often fatal disease in elderly population. Heme oxygenase-1 (HO-1) is a stress response protein with antioxidative and anti-inflammatory properties. HO-1 has been shown to protect against atherogenesis and arterial intimal thickening. Emerging evidences suggest that AAA and arterial occlusive disease have distinct pathogenic mechanisms. Thus, in this study we investigated the role of HO-1 in angiotensin II-induced AAA formation in HO-1+/+apoE-/- and HO-1-/-apoE-/- mice. We found that complete loss of HO-1 increased AAA incidence and rupture rate, and drastically increased aneurysmal area and severity, accompanied with severe elastin degradation and medial degeneration. Interestingly, we often observed not only AAA but also thoracic aortic aneurysm in HO-1-/-apoE-/- mice. Furthermore, reactive oxygen species levels, vascular smooth muscle cell (VSMC) loss, macrophage infiltration, matrix metalloproteinase (MMP) activity were markedly enhanced in the aneurysmal aortic wall in HO-1-/-apoE-/- mice. In addition, HO-1-/-apoE-/- VSMCs were more susceptible to oxidant-induced cell death and macrophages from HO-1-/-apoE-/- mice had aggravated responses to angiotensin II with substantial increases in inflammatory cytokine productions and MMP9 activity. Taken together, our results demonstrate the essential roles of HO-1 in suppressing the pathogenesis of AAA. Targeting HO-1 might be a promising therapeutic strategy for AAA.


Assuntos
Anemia Hemolítica/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Transtornos do Crescimento/metabolismo , Heme Oxigenase-1/deficiência , Distúrbios do Metabolismo do Ferro/metabolismo , Anemia Hemolítica/genética , Angiotensina II , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Citocinas/metabolismo , Transtornos do Crescimento/genética , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Distúrbios do Metabolismo do Ferro/genética , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo
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